Clinical trial NCT03029234
Conditions: Relapsed and Refractory Multiple Myeloma
Sponsor: Amgen
Start date: 2017-03-31; Completion date: 2021-06-04
Enrollment: 126 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and overall response rate of carfilzomib in combination with dexamethasone for the treatment of multiple myeloma in China.

Detailed description:

Arms: arm 1: Participants will receive carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter).

Participants will also receive 20 mg dexamethasone IV or orally on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle.

Participants will receive treatment until disease progression, unacceptable toxicity, initiation of new antimyeloma therapy, withdrawal of consent, non-compliance, or intercurrent illness or worsening of a chronic condition, whichever occurs first.
Interventions: intervention 1: Dexamethasone intervention 2: Carfilzomib
Intervention descriptions: intervention 1: 20 mg intravenous (IV) or oral dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 in 28-day cycles. intervention 2: Infusion of IV carfilzomib on days 1, 2, 8, 9, 15 and 16 in each 28-day cycle.

Protocol documents:
Prot_000.pdf: 
Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 1 of 151 
 
Confidential 
12 April  2018 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
An Open-label, Single-arm, Phase 3 Study of 
Carfilzomib in Combination With Dexamethasone 
in Subjects With Relapsed and Refractory Multiple 
Myeloma in China  
 
 
Protocol Number: 
20140242 (CFZ005) 
NCT Number 
NCT03029234 
 
Name of Investigational Product: 
 
Carfilzomib for Injection 
 
 
Sponsor: 
Onyx Therapeutics, Inc., an Amgen subsidiary 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
 
Study Medical Monitors: 
, MD PhD 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
 
 
Date of Original Protocol: 
22 March 2013 
 
 
Date of Protocol Amendment 1.0 
10 May 2016 
 
 
Date of Protocol Amendment 2.0 
09 November 2016 
 
 
Date of Protocol Amendment 3.0 
23 March 2018 
 
 
Date of Superseding Amendment 1.0 12 April 2018 
 
 
Confidentiality Statement: 
This material is the property of Onyx Therapeutics, Inc., a 
wholly owned subsidiary of Onyx Pharmaceuticals, Inc., an 
Amgen Inc. subsidiary.  The material is highly confidential 
and is to be used only in connection with matters authorized 
by a senior representative of Onyx Therapeutics, Inc., and no 
part of it is to be disclosed to a third party without the 
express prior written permission of Amgen, Inc. 
 
 
Compliance Statement: 
This study will be conducted in accordance with 
Protocol 20140242 (CFZ005), the relevant Onyx 
Therapeutics, Inc., an Amgen Inc. subsidiary, policies and 
procedures, the International Conference on Harmonisation 
(ICH), Good Clinical Practice (GCP) guidelines, and the 
applicable country and regional (local) regulatory 
requirements.
PPD
 
PPD
NCT Number: NCT03029234  
This NCT number has been applied to the document  
for purposes of posting on clinicaltrials.gov


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 2 of 151 
 
Confidential 
12 April  2018 
PROTOCOL ACCEPTANCE PAGE  
 
Issue/Date: 20140242 (CFZ005)/Protocol Amendment 3.0/23 March 2018 
Superseding Amendment 1.0 12/April 2018 
I have read this protocol for Study 20140242 (CFZ005) entitled: 
Title:  An Open-label, Single-arm, Phase 3 Study of Carfilzomib in Combination with 
Dexamethasone in Subjects with Relapsed and Refractory Multiple Myeloma in China 
 
As investigator, I understand and agree to conduct this study as outlined herein. 
 
 
 
Investigator Name (print) 
 
 
 
 
 
Investigator Signature 
 
Date 
 
Signature on this page assures the sponsor that, to the best of the investigator’s knowledge, the affiliated 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all governing regulatory 
obligations and the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) while conducting this clinical investigation.  Once signed, the original of this form should be detached 
from the protocol and returned to Onyx Therapeutics, Inc. or its designee (please retain a copy for your files). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 3 of 151 
 
Confidential 
12 April  2018 
SYNOPSIS 
Name of sponsor/company: 
Onyx Therapeutics, Inc. (Subsidiary of Amgen, Inc.) 
Name of product: 
Carfilzomib for Injection 
Title of study and protocol 
number and phase: 
An Open-label, Single-arm, Phase 3 Study of Carfilzomib in Combination 
with Dexamethasone in Subjects with Relapsed and Refractory Multiple 
Myeloma in China 
Protocol Number 20140242 (CFZ005) 
Study objective(s): 
Primary Objective: 
To evaluate the overall response rate (ORR) after at least 6 cycles of 
carfilzomib in combination with dexamethasone (Kd) in subjects with 
multiple myeloma who have previously received an alkylating agent or 
anthracycline, bortezomib and an immunomodulatory drug (IMiD), have 
relapsed after 2 or more lines of therapy, and are refractory to the most 
recently received therapy.  Overall response rate (ORR) is defined as the 
proportion of subjects with the best response of stringent complete 
response (sCR), complete response (CR), very good partial response 
(VGPR), or partial response (PR).  The ORR will be determined using best 
overall response as assessed by the Independent Review Committee (IRC) 
per IMWG-URC (Durie, 2006; Rajkumar, 2011; Kumar, 2016). 
Secondary Objectives: 
• To evaluate ORR after at least 6 cycles of Kd using investigator 
assessment of response 
• To evaluate ORR after at least 12 cycles of Kd  
• To estimate clinical benefit rate (CBR) (the proportion of subjects with 
best response of minimal response, MR, or better) after at least 6 cycles 
and after at least 12 cycles 
• To estimate duration of response (DOR) 
• To estimate duration of clinical benefit (DCB)  
• To estimate progression-free survival (PFS)  
• To estimate overall survival (OS) 
• To estimate time to response (TTR)  
• To characterize pharmacokinetics (PK) in a subset of subjects 
Exploratory Endpoints: 
Efficacy endpoints related to response and disease progression will 
be determined based on a validated computer algorithm (Onyx 
Response Computational Assessment; [ORCA]) are: 
• ORR after at least 6 cycles of Kd and after at least 12 cycles 
• CBR after at least 6 cycles and after at least 12 cycles 
• Duration of response 
• Duration of clinical benefit 
• Progression-free survival  
• Time to response 
 
Study design: 
This Phase 3 study will be conducted as a multicenter, open-label, single-
arm study in China.  The study is designed to evaluate the efficacy and 
safety of carfilzomib at a dose of 20 mg/m2, with step up to 27 mg/m2 on 
Day 8 of Cycle 1, given in combination with low dose dexamethasone in 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 4 of 151 
 
Confidential 
12 April  2018 
subjects with relapsed and refractory multiple myeloma.  Subjects 
must 
have received at least two prior regimens and are required to have previous 
treatment with an alkylating agent or anthracycline, bortezomib, and an 
IMiD.   
Subjects will receive a 30 minute infusion of intravenous (IV) carfilzomib 
on Days 1, 2, 8, 9, 15 and 16, and 20 mg oral dexamethasone on Days 1, 2, 
8, 9, 15, 16, 22, and 23 in 28-day Cycles.  On Cycle 1, Days 1 and 2, 
subjects will receive carfilzomib 20 mg/m2.  If tolerated (defined as 
absence of any treatment-related adverse event [AE] requiring dose 
reduction, delay, or the dose to be held), the dose will be escalated to 
27 mg/m2 on Cycle 1 Day 8 and all subsequent doses.   
Study treatments will be administered until disease progression, 
unacceptable toxicity, or discontinuation of study treatment for any other 
reason, whichever occurs first.  Dose reductions of carfilzomib and 
dexamethasone will be permitted per protocol guidelines.   
The enrollment period is anticipated to be approximately 16 months.   
Upon discontinuation of study treatment for reasons other than disease 
progression, subjects will be followed every 4 weeks until disease 
progression, or withdrawal of consent.  After disease progression, each 
subject will be followed every 3 months (± 2 weeks) for OS for up to 3 
years from the start of their study treatment, or until the subject has 
withdrawn from further participation, is lost to follow-up, has died, or the 
sponsor makes a decision to close the study. 
Pharmacokinetic analyses will be characterized in a subset of 15 subjects at 
selected sites.  Subjects who do not complete all PK assessments will be 
replaced. 
Number of investigational 
sites: 
Approximately 15 sites in China will participate in this study 
Planned number of 
subjects: 
Approximately 120 subjects with relapsed and refractory multiple myeloma 
are planned for enrollment in this study   
Sample size justification: 
This study will enroll approximately 120 subjects with relapsed and 
refractory multiple myeloma to evaluate both efficacy and safety of 
carfilzomib (K) in combination with dexamethasone (d). 
Study population: 
Subjects with relapsed and refractory multiple myeloma with disease that is 
measurable by serum and/or urine protein electrophoresis, and/or serum 
free-light chain (SFLC) assay may participate in this study. 
Test product, dose, and 
mode of administration: 
Subjects will receive IV carfilzomib on Days 1, 2, 8, 9, 15 and 16, and 
dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 in 28-day cycles.  On 
Cycle 1, Days 1 and 2, subjects will receive carfilzomib 20 mg/m2.  If 
Cycle 1, Day 1 and 2 doses are administered and well tolerated  (defined as 
absence of any treatment-related AE requiring dose reduction, delay, or the 
dose to be held), the dose will be escalated to 27 mg/m2 for all subsequent 
doses, beginning with Cycle 1 Day 8.  Dexamethasone will be given at 
20 mg on all dosing days in each cycle. 
CCI
CCI


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 5 of 151 
 
Confidential 
12 April  2018 
Reference therapy, dose, 
and mode of administration: 
Not applicable 
Treatment regimen(s): 
Carfilzomib and dexamethasone treatments will be administered in 28-day 
cycles until disease progression, unacceptable toxicity, or discontinuation 
from study treatment for any other reason, whichever occurs first. 
Inclusion criteria: 
Inclusion Criteria: 
1. Multiple myeloma  
2. Subjects must have measurable disease, defined as one or more of the 
following: 
a. 
Serum M-protein ≥ 1 g/dL 
b. Urine M-protein ≥ 200 mg/24 hours 
c. 
In subjects without measurable serum or urine M-protein, 
SFLC > 100 mg/L (involved light chain) and an abnormal κ/λ 
ratio 
3. Subjects must have been responsive (i.e., achieved a minimal response 
[MR] or better) to at least one of their prior treatment regimens 
4. Refractory to the most recently received therapy.  Refractory disease 
defined as ≤ 25% response to, or progressing during therapy or within 
60 days after last therapy 
5. Subjects must have received ≥ 2 prior regimens.  Induction therapy 
and stem cell transplant (± maintenance) will be considered as 1 
regimen as described in Section 9.1.2 
6. Subjects must have received prior treatment with bortezomib and 
an IMiD 
7. Subjects must have received an alkylating agent or anthracycline alone 
or in combination with other myeloma treatments (this may include 
high-dose melphalan as part of the conditioning regimen prior to a 
stem cell transplant) 
8. Males and females ≥ 18 years of age 
9. Life expectancy of more than 3 months 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status  
of 0–2 
11. Adequate hepatic function, with bilirubin < 2.0 times the upper limit of 
normal (ULN), and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) < 3.0 times the ULN 
12. Absolute neutrophil count (ANC) ≥ 1,000/mm3, 
hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm3 
• 
Subjects should not have received platelet transfusions for at least 
1 week prior to obtaining the screening platelet count 
• 
Screening ANC should be independent of granulocyte colony 
stimulating factor (G-CSF) or granulocyte macrophage colony 
stimulating factor (GM-CSF) support for ≥ 1 week and pegylated 
G-CSF for ≥ 2 weeks 
• 
Use of erythropoietic stimulating factors and red blood cell (RBC) 
transfusions per institutional guidelines is allowed; however, most 
recent RBC transfusion may not have been done within 7 days 
prior to obtaining screening hemoglobin 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 6 of 151 
 
Confidential 
12 April  2018 
13. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min.  
Calculated CrCl should be performed by using a widely accepted 
equation (e.g., the Cockcroft and Gault equation):   
([140 – Age] × Mass [kg] / [72 × Creatinine mg/dL]).   
Multiply the result by 0.85 if the subject is female. 
14. Left ventricular ejection fraction (LVEF) ≥ 40%; 2-dimensional 
transthoracic echocardiogram (ECHO) is the preferred method of 
evaluation; multiple gated acquisition scan (MUGA) is acceptable if 
ECHO is not available 
15. Written informed consent in accordance with national, local, and 
institutional guidelines 
16. Female subjects of child-bearing potential (FCBP) must have a 
negative serum pregnancy test within 7 days prior to first dose of 
carfilzomib and agree to use an effective method of contraception 
during and for 30 days following last dose of carfilzomib.  This 
protocol defines a FCBP as a sexually mature woman who:  1) has not 
undergone a hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy, or 2) has not been naturally postmenopausal for at least 
24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months) 
17. Male subjects must use an effective barrier method of contraception 
during the study and for 90 days following the last dose of carfilzomib 
if sexually active with a FCBP.  Male subjects must not donate sperm 
during treatment and for an additional 90 days after last dose of 
carfilzomib.  Male subjects with pregnant partners must practice 
sexual abstinence or use a condom during vaginal sex  
Exclusion criteria: 
Exclusion Criteria: 
1. Waldenström’s macroglobulinemia or immunoglobulin M (IgM) 
multiple myeloma 
2. Subjects who failed to achieve at least a confirmed MR on any of their 
prior regimens 
 
3. Subjects with non-secretory multiple myeloma, defined as < 1 g/dL 
M-protein in serum and < 200 mg/24 hour M-protein in urine, and 
SFLC ≤ 100 mg/L (involved light chain) 
4. Glucocorticoid therapy (prednisone > 10 mg/day or equivalent) within 
3 weeks prior to Cycle 1 Day 1 
5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein, and skin changes) 
6. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by 
standard differential) 
7. Chemotherapy with approved or investigative anticancer therapeutics 
including steroid therapy within the 3 weeks prior to Cycle 1 Day 1 
8. Radiation therapy or immunotherapy in the 4 weeks prior to Cycle 1 
Day 1; localized radiation therapy within 1 week prior to Cycle 1 
Day 1 
9. Participation in an investigational therapeutic study within 3 weeks or 
within 5 drug half-lives (T½) prior to Cycle 1 Day 1, whichever time is 
greater 
10. Prior treatment with carfilzomib 
11. Major surgery within 3 weeks before Cycle 1 Day 1 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 7 of 151 
 
Confidential 
12 April  2018 
12. Congestive heart failure (New York Heart Association Class III to IV), 
symptomatic ischemia, conduction abnormalities, uncontrolled by 
conventional intervention.Subjects cannot have experienced a 
myocardial infarction within 6 months prior to Cycle 1 Day 1 
13. Uncontrolled hypertension (a sustained systolic blood 
pressure > 140 mmHg and/or diastolic BP > 90 mmHg) 
14. Acute active infection requiring systemic (either intravenous or oral) 
antibiotics, antivirals, or antifungals; the treatment must be 
completed at least 2 weeks prior to Cycle 1 Day 1 
15. Known HIV seropositive, hepatitis C infection, and/or hepatitis B 
(except for patients with hepatitis B surface antigen or core antibody 
receiving and responding to antiviral therapy directed at hepatitis B: 
these patients are allowed; Note: patients who are HepB surface 
antigen negative at screening, or who are receiving interferon alfa-
2a (IFN) or Peginterferon alfa-2a  (PEG-IFN) and have Hepatitis 
B Virus (HBV) DNA < 2000 International Units (IU) at screening, 
or, are receiving a nucleos(t)ide analog and have HBV DNA below 
Lower Limit of Normal (LLN) at screening are eligible  
16. Non-hematologic malignancy within the past 3 years except: 
a. 
Adequately treated basal cell or squamous cell skin cancer, 
b. Carcinoma in situ of the cervix, or 
c. 
Prostate cancer < Gleason Score 6 with stable prostate-specific 
antigen 
17. Subjects with treatment-related myelodysplastic syndrome 
18. Significant neuropathy (Grade 3, 4, or Grade 2 with pain) at the time 
of baseline evaluation 
19. Subjects in whom the required program of fluid hydration is 
contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal 
impairment 
20. Subjects with known or suspected amyloidosis 
21. Subjects with pleural effusions requiring thoracentesis 
22. Subjects with ascites requiring paracentesis 
23. Any clinically significant medical disease or condition that, in the 
investigator’s opinion, may interfere with protocol adherence or a 
subject’s ability to give informed consent 
24. Female subjects who are pregnant or lactating, or are planning to 
become pregnant during treatment and for an additional 30 days after 
discontinuing carfilzomib 
25. Serious psychiatric or medical conditions that could interfere with 
treatment 
Overview of treatment and 
assessments: 
Treatments will be administered in 28 day cycles.  Details are provided in 
Appendix A (Schedule of Assessments). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 8 of 151 
 
Confidential 
12 April  2018 
Criteria for evaluation: 
 
 
Efficacy variables: 
Disease response will be assessed per investigator every 4 weeks according 
to the International Myeloma Working Group – Uniform Response Criteria 
(IMWG-URC) (Durie, 2006; Rajkumar, 2011; Kumar, 2016; MR will be 
assessed as per ;Kumar, 2016).  An IRC will assess best response after at 
least 6 and after at least 12 cycles of Kd, from which ORR, CBR, DOR, 
DCB, TTR, and PFS will also be determined.  Subjects will be followed 
every 4 weeks for disease progression.  After disease progression, subjects 
will be followed every 3 months (± 2 weeks) for OS for up to 3 years from 
the start of their study treatment. 
 
Safety variables: 
The safety and tolerability of carfilzomib will be assessed using the 
following measures:  Incidence of AEs graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE; version 4.03), blood counts, serum chemistries, and vital 
signs.   
 
Pharmacokinetics: 
Pharmacokinetics of carfilzomib will be assessed on Cycle 1 Day 1 and 
Cycle 2 Day 1 using noncompartmental methods.  Following PK 
parameters will be determined: maximum observed plasma concentration 
(Cmax), area under the plasma concentration curve up to the last measurable 
concentration (AUClast), area under the plasma concentration curve 
extrapolated to infinity (AUC0-inf), time to maximum concentration (Tmax), 
terminal elimination half half-life (T½), total plasma clearance (CL), 
volume of distribution ([Varea] and volume of distribution at steady state 
[Vss]), and mean residence time (MRT).   
Statistical methods and 
analyses: 
 
 
All subjects who receive at least 1 dose of study treatment will be 
considered evaluable for both the efficacy and safety analyses (Safety 
Population). 
For the primary efficacy objective, an estimate of the ORR after at least 
6 cycles of Kd, as assessed by the IRC, and its associated 2-sided 95% 
exact binomial confidence interval (CI) will be determined.  Each subject’s 
best overall response after at least 6 cycles will be determined by IRC 
assessment per IMWG-URC (Durie, 2006; Rajkumar, 2011; 
Kumar, 2016). 
Additionally, ORR based on investigator assessment of response after at 
least 6 cycles will be determined.  Overall response rate after at least 
12 cycles of Kd and the CBR will be determined based on both IRC and 
investigators response assessment, along with the associated 2-sided 95% 
exact binomial CI.  
For the exploratory objectives, a validated computer algorithm (Onyx 
Response Computational Assessment [ORCA]) will be used to assess 
response and disease progression.  
Time to event endpoints will include:  
• Duration of response, defined as the time from first evidence of PR or 
better to disease progression or death due to any cause. 
• Duration of clinical benefit, defined as the time from first evidence of 
MR or better to disease progression or death due to any cause. 
• Progression-free survival, defined as the time from first dose to the 
earlier of disease progression or death due to any cause. 
• Overall survival, defined as the time from the first dose to the date of 
death (due to any cause). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 9 of 151 
 
Confidential 
12 April  2018 
The right-censored rule for time to event endpoints is described in 
Section 12.5.1.2.  Analyses for time-to-events endpoints (DOR, DCB, PFS, 
and OS) will be performed using the Kaplan-Meier method.  Medians and 
other quartiles for each time-to-event endpoint will be estimated in addition 
to the corresponding 2-sided 95% CIs. 
Time to response, defined as the time of start of study treatment to first 
confirmed response (PR or greater), will be assessed using descriptive 
statistics. 
Extent of exposure to the study treatment will be summarized using 
descriptive statistics.  The number and percentage of subjects experiencing 
1 or more AEs will be summarized, relationship of AE to study treatment 
and severity.  Results of laboratory parameters and vital signs will be 
summarized.  Laboratory parameters will be summarized using descriptive 
statistics, by post dose shifts relative to baseline, and a summary of the 
incidence of clinically significant abnormal values for key laboratory 
analytes.  Laboratory values will be classified for severity using 
NCI-CTCAE, version 4.03.  Vital signs will be summarized by changes 
from baseline values using descriptive statistics.  The incidence and 
severity of adverse events including congestive heart failure (CHF), 
myocardial infarction, acute kidney injury, adult respiratory distress 
syndrome, pulmonary hypertension, dyspnea, hypertension, 
thromboembolic events, thrombocytopenia, hepatic toxicity, and 
thrombotic thrombocytopenia purpura/hemolytic uremic syndrome will be 
determined. 
Pharmacokinetic data analysis set will include all subjects who received at 
least 1 dose of carfilzomib and have adequate carfilzomib plasma 
concentration versus time data for the estimation of PK parameters by a 
noncompartmental analysis.  Individual and mean plasma concentration 
versus time data will be tabulated and plotted for the subjects participating 
in the PK portion of the study.  All PK parameters will be computed using 
actual elapsed time calculated relative to the start of dose administration.   
 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
TABLE OF CONTENTS 
3DJH
&/,1,&$/678'<35272&2/ 
35272&2/$&&(37$1&(3$*( 
6<1236,6 
7$%/(2)&217(176 
/,672)$%%5(9,$7,216$1''(),1,7,2162)7(506 
 
%$&.*5281',1)250$7,21 
 
0XOWLSOH0\HORPD 
 
3URWHDVRPH%DFNJURXQG 
 
&DUILO]RPLE 
 
3UHFOLQLFDO%DFNJURXQG 
 
&OLQLFDO%DFNJURXQG 
 
'RVH5DWLRQDOH 
 
6WXG\5DWLRQDOH 
 
678'<2%-(&7,9(6 
 
3ULPDU\2EMHFWLYHV 
 
6HFRQGDU\2EMHFWLYHV 
 
(;3/25$725<2%-(&7,9(6 
 
678'<'(6,*1 
 
7\SH'HVLJQRI6WXG\ 
 
0LQLPL]LQJ%LDV 
 
5DQGRPL]DWLRQ 
 
%OLQGLQJ 
 
(QGRI6WXG\ 
 
68%-(&76(/(&7,21 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
68%-(&76&5((1,1* 
 
68%-(&7(152//0(17 
 
678'<'58* 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
 
&DUILO]RPLE 
 
3K\VLFDO'HVFULSWLRQ 
 
)RUPXODWLRQ 
 
+RZ6XSSOLHG 
 
'H[DPHWKDVRQH 
 
6WXG\'UXJ$FFRXQWDELOLW\ 
 
'26$*($1'75($70(17$'0,1,675$7,21 
 
*HQHUDO,QVWUXFWLRQVIRU$GPLQLVWUDWLRQ 
 
2UDODQG,QWUDYHQRXVK\GUDWLRQ 
 
&DUILO]RPLE$GPLQLVWUDWLRQ 
 
'H[DPHWKDVRQH$GPLQLVWUDWLRQ 
 
'RVH0RGLILFDWLRQ*XLGHOLQHV 
 
&DUILO]RPLE'RVH0RGLILFDWLRQ*XLGHOLQHV 
8.2.1.1 
0LVVHG'RVHV 
8.2.1.2 
&KDQJHVLQ%RG\6XUIDFH$UHD 
 
&DUILO]RPLE*XLGHOLQHVIRU7UHDWPHQW(PHUJHQW7R[LFLWLHV 
 
'H[DPHWKDVRQH7R[LFLWLHVDQG7UHDWPHQW 
 
&RQGLWLRQV1RW5HTXLULQJ'RVH5HGXFWLRQ 
 
&RQFRPLWDQW0HGLFDWLRQV 
 
5HTXLUHGDQG2SWLRQDO&RQFRPLWDQW0HGLFDWLRQV 
 
([FOXGHG&RQFRPLWDQW0HGLFDWLRQV 
 
$GGLWLRQDO&RQVLGHUDWLRQV5HJDUGLQJ&RQFRPLWDQW0HGLFDWLRQV 
 
6DIHW\*XLGDQFHIRU,QYHVWLJDWRUV 
 
,QIXVLRQ5HDFWLRQVDQG$GYHUVH(YHQWV([SHULHQFHG:LWKLQD
'D\RI'RVLQJRI&DUILO]RPLE 
 
5HQDO)XQFWLRQ 
 
7XPRU/\VLV6\QGURPH 
 
7KURPERF\WRSHQLDDQG1HXWURSHQLD 
 
&DUGLDF'LVRUGHUV 
 
*DVWURLQWHVWLQDO(YHQWV 
 
+HSDWLF,PSDLUPHQW 
 
3XOPRQDU\(YHQWV 
 
3RVWHULRUUHYHUVLEOHHQFHSKDORSDWK\V\QGURPH 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
 
7KURPERWLFPLFURDQJLRSDWK\ 
 
9HQRXVWKURPERVLV 
 
678'<352&('85(6 
 
'HVFULSWLRQRI6WXG\VSHFLILF3URFHGXUHV 
 
0HGLFDO+LVWRU\ 
 
0XOWLSOH0\HORPD+LVWRU\DQG3ULRU/LQHVRI7KHUDS\
$VVHVVPHQW 
 
9LWDO6LJQV 
 
(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS3HUIRUPDQFH6WDWXV 
 
&RPSOHWHDQG5RXWLQH3K\VLFDO([DPLQDWLRQV 
 
(OHFWURFDUGLRJUDP 
 
(FKRFDUGLRJUDP 
 
/DERUDWRU\(YDOXDWLRQ 
9.1.8.1 
&KHPLVWU\ 
9.1.8.2 
+HPDWRORJ\ 
9.1.8.3 
&RDJXODWLRQ3DQHO 
 
3UHJQDQF\(YDOXDWLRQDQG&RQWUDFHSWLRQ&RQVLGHUDWLRQV 
 
0XOWLSOH0\HORPD'LVHDVH$VVHVVPHQWV 
9.1.10.1 
3ODVPDF\WRPD(YDOXDWLRQV 
9.1.10.2 
6NHOHWDO6XUYH\ 
9.1.10.3 
%RQH0DUURZ$VSLUDWHDQGRU%LRSV\ 
9.1.10.4 
'LVHDVH5HVSRQVHDQG3URJUHVVLRQ$VVHVVPHQWV 
 
$GYHUVH(YHQWV 
 
&RQFRPLWDQW0HGLFDWLRQV 
 
3KDUPDFRNLQHWLF0HDVXUHPHQWV 
 
6FKHGXOHRI6WXG\$VVHVVPHQWV 
 
6FUHHQLQJ$VVHVVPHQWV 
 
&\FOH'D\VDQG 
 
&\FOH'D\ 
 
&\FOH'D\ 
 
&\FOH'D\ 
 
&\FOH'D\ 
 
&\FOH'D\ 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
 
&\FOH'D\VDQG 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\ 
 
&\FOHDQG+LJKHU'D\VDQG 
 
(QGRI7UHDWPHQW$VVHVVPHQWZLWKLQGD\VRI
7UHDWPHQWGLVFRQWLQXDWLRQ 
 
3KDUPDFRNLQHWLF6DPSOLQJ6FKHGXOH 
 
)ROORZ±XSYLVLWV 
 
$FWLYH)ROORZXS 
 
/RQJ7HUP6XUYLYDO)ROORZXS 
 
678'<',6&217,18$7,21 
 
$'9(56((9(176$1'6(5,286$'9(56((9(176 
 
$GYHUVH(YHQW5HSRUWLQJ 
 
'HILQLWLRQV 
 
&DXVDOLW\ 
 
$GYHUVH(YHQWV5HSRUWLQJ3URFHGXUHV 
 
*HQHUDO 
 
'LVHDVH3URJUHVVLRQ 
 
6HULRXV$GYHUVH(YHQWV'HILQLWLRQV 
 
6HULRXV$GYHUVH(YHQW5HSRUWLQJDQG'RFXPHQWDWLRQ5HTXLUHPHQWV 
 
3UHJQDQF\DQG%UHDVWIHHGLQJ5HSRUWLQJ 
 
67$7,67,&$/&216,'(5$7,216 
 
6WXG\(QGSRLQWV 
 
3ULPDU\(QGSRLQW 
 
6HFRQGDU\(QGSRLQWV 
 
([SORUDWRU\(QGSRLQWV 
 
'HWHUPLQDWLRQRI6DPSOH6L]H 
 
$QDO\VLV3RSXODWLRQ 
 
3ODQQHG$QDO\VHV 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
 
3ULPDU\$QDO\VLV 
 
)LQDO$QDO\VLV 
 
(VWLPDWHG6WXG\'XUDWLRQ 
 
,QGHSHQGHQW5HYLHZ&RPPLWWHH 
 
6WDWLVWLFDO0HWKRGV 
 
(IILFDF\$QDO\VHV 
12.5.1.1 
3ULPDU\(IILFDF\$QDO\VLV 
12.5.1.2 
6HFRQGDU\(IILFDF\$QDO\VHV 
12.5.1.3 
([SORUDWRU\(IILFDF\$QDO\VHV 
 
6DIHW\$QDO\VLV 
 
3KDUPDFRNLQHWLF$QDO\VHV 
 
(7+,&$/$1'$'0,1,675$7,9(&216,'(5$7,216 
 
&RPSOLDQFH6WDWHPHQW 
 
,QVWLWXWLRQDO5HYLHZ%RDUGRU,QGHSHQGHQW(WKLFV&RPPLWWHH 
 
,QIRUPHG&RQVHQWDQG+XPDQ6XEMHFW3URWHFWLRQ 
 
'LUHFW$FFHVVWR6RXUFH'DWD6RXUFH'RFXPHQWVDQG6WXG\5HFRUGV 
 
'DWD&ROOHFWLRQDQG+DQGOLQJ 
 
&RQILGHQWLDOLW\ 
 
5()(5(1&(6 
$33(1',;$ 
6&+('8/(2)$66(660(176 
$33(1',;% 
3+$50$&2.,1(7,&6$03/,1*6&+('8/( 
$33(1',;& 
($67(51&223(5$7,9(21&2/2*<*5283
(&2*3(5)250$1&(67$786 
$33(1',;' 
1$7,21$/&$1&(5,167,787(
&200217(50,12/2*<&5,7(5,$)25$'9(56((9(1761&,
&7&$(*5$',1*6&$/( 
$33(1',;( 
,17(51$7,21$/81,)2505(63216(&5,7(5,$
)2508/7,3/(0<(/20$ 
$33(1',;) 
'(),1,7,212)0,1,0$/5(63216(3(5,0:*
&5,7(5,$
 
$33(1',;* 
1(:<25.+($57$662&,$7,211<+$
&/$66,),&$7,21 
$33(1',;+ 
6$03/('(;$0(7+$621(
35(6&5,%,1*,1)250$7,21 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI

&RQILGHQWLDO
$SULO
$33(1',;,35(*1$1&<$1'/$&7$7,21127,),&$7,21
:25.6+((76 
$33(1',;-6$(&217,1*(1&<)250 
$33(1',;.6800$5<2)&+$1*(6 
7$%/(6
7DEOH 
'RVH'HFUHPHQWVIRU&DUILO]RPLE 
7DEOH 
*XLGHOLQHVIRU+HPDWRORJLF7UHDWPHQW(PHUJHQW7R[LFLWLHVLQ&DUILO]RPLE
3DWLHQWV 
7DEOH 
*XLGHOLQHVIRU1RQKHPDWRORJLF7UHDWPHQW(PHUJHQW7R[LFLWLHVLQ
&DUILO]RPLE3DWLHQWV 
7DEOH 
'RVH'HFUHPHQWVIRU'H[DPHWKDVRQH 
7DEOH 
7UHDWPHQW*XLGHOLQHVIRU'H[DPHWKDVRQHUHODWHG7R[LFLW\ 
7DEOH 
/DERUDWRU\7HVWV&KHPLVWU\3DQHO 
7DEOH 
/DERUDWRU\7HVWV+HPDWRORJ\ 
7DEOH 
/DERUDWRU\7HVWV&RDJXODWLRQ3DQHO 
7DEOH 
%ORRG6DPSOH&ROOHFWLRQIRU3KDUPDFRNLQHWLFV 
7DEOH 
7R[LFLW\*UDGLQJIRU$GYHUVH(YHQWV1RW&RYHUHGLQWKH1&,&7&$(
9HUVLRQ 
7DEOH 
&,VIRU9DULRXV2EVHUYHG255V:LWK6WXG\6L]HRI6XEMHFWV 
7DEOH 
'DWHRI3URJUHVVLRQRU&HQVRULQJIRU3URJUHVVLRQIUHH6XUYLYDO 
7DEOH 
6FKHGXOHRI$VVHVVPHQWVIRU6XEMHFWVLQ6FUHHQLQJDQG&\FOH 
7DEOH 
6FKHGXOHRI$VVHVVPHQWVIRU6XEMHFWVLQ&\FOHVDQG+LJKHU 
),*85(6
)LJXUH6WXG\'HVLJQ$QG7UHDWPHQW6FKHPD 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 16 of 151 
 
Confidential 
12 April  2018 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
2-D 
2-dimensional  
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC0-inf 
area under the curve extrapolated to infinity 
AUC0-last 
area under the curve, from time 0 to the last concentration measured 
AUClast 
area under the plasma concentration curve up to the last measurable concentration 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CCSI 
Company Core Safety Information 
CFZ 
carfilzomib [brand name:  Kyprolis® (carfilzomib) for Injection 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
total plasma clearance 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CRF 
case report form 
CrCl 
creatinine clearance 
CT 
computed tomography 
CYP3A4/5 
cytochrome P450 3A4/5 
DOR 
duration of response 
DCB 
duration of clinical benefit 
EBMT 
European Group for Blood and Marrow Transplantation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
EW 
early withdrawal 
FCBP 
female of child-bearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 17 of 151 
 
Confidential 
12 April  2018 
Abbreviation 
Definition 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HA 
alternative hypothesis 
HBV 
Hepatitis B virus 
H0 
null hypothesis 
HIV 
human immunodeficiency virus 
Hr 
hour(s) 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
Interferon alfa-2a 
IgM 
immunoglobulin M 
IMiD 
immunomodulatory drug (thalidomide or lenalidomide) 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IPIM 
Investigational Product Instruction Manual 
IU 
International Units 
IV 
intravenous(ly) 
Kd 
carfilzomib in combination with dexamethasone 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LLN 
Lower limit of normal 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
MRI 
Magnetic resonance imaging 
MRT 
mean residence time 
MUGA 
multiple gated acquisition scan 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORCA 
Onyx Response Computational Assessment 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 18 of 151 
 
Confidential 
12 April  2018 
Abbreviation 
Definition 
ORR 
overall response rate 
ORR6-IRC 
Overall response rate after at least 6 cycles as determined by the IRC 
OS 
overall survival 
PEG-IFN 
Peginterferon alfa-2a   
PD 
progressive disease 
PDn 
pharmacodynamic(s) 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
orally, by mouth, per os 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PT 
prothrombin time 
aPTT 
activated partial thromboplastin time 
PTT 
partial thromboplastin time 
QT interval 
QT interval is measured from the beginning of the QRS complex to the end of the T 
wave, representing the duration of ventricular electrical activity 
QTc 
corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SFLC 
serum-free light chain 
SIFE 
serum immunofixation electrophoresis 
SPEP 
serum protein electrophoresis 
T½ 
terminal elimination half-life or half-life 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum plasma concentration 
TTP/HUS 
thrombotic thrombocytopenic purpura / haemolytic uraemic syndrome 
TTR 
time to response 
UIFE 
urine immunofixation electrophoresis 
ULN 
upper limit of the normal 
UPEP 
urine protein electrophoresis 
US 
United States 
USP 
United States Pharmacopeia 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 19 of 151 
 
Confidential 
12 April  2018 
Abbreviation 
Definition 
Varea 
volume of distribution 
Vss 
volume of distribution at steady state 
VGPR 
very good partial response 
WBC 
white blood cell 
 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO

%$&.*5281',1)250$7,21
08/7,3/(0<(/20$
0XOWLSOHP\HORPDDFORQDOQHRSODVWLFSUROLIHUDWLRQRISODVPDFHOOVLVWKHVHFRQGPRVW
FRPPRQKHPDWRORJLFPDOLJQDQF\DQGLVUHVSRQVLEOHIRUDSSUR[LPDWHO\DQQXDOGHDWKV
ZRUOGZLGH)HUOD\7KHUHDUHDQHVWLPDWHGPXOWLSOHP\HORPDGHDWKVSHU\HDULQ
&KLQD)HUOD\GHDWKVSHU\HDULQWKH8QLWHG6WDWHV86DQGPRUHWKDQ
GHDWKVSHU\HDULQ(XURSH$PHULFDQ&DQFHU6RFLHW\%R\OH0XOWLSOH
P\HORPDLVFKDUDFWHUL]HGE\DQHPLDERQHGHVWUXFWLRQPRQRFORQDOJDPPRSDWK\UHQDO
IDLOXUHK\SHUFDOFHPLDDQGLQFUHDVHGVXVFHSWLELOLW\WRLQIHFWLRQV&XUUHQWWUHDWPHQWRSWLRQV
LQ&KLQDFRPPRQO\LQFOXGHFRPELQDWLRQFKHPRWKHUDS\ZLWKUHJLPHQVXVLQJPHOSKDODQ
ERUWH]RPLEDQGWKDOLGRPLGHDQLPPXQRPRGXODWRU\GUXJ>,0L'@ZLWKDQGZLWKRXW
FRUWLFRVWHURLGVVXFKDVGH[DPHWKDVRQHRUSUHGQLVRQH(OLJLEOHVXEMHFWVWR\HDUVROGRU
\RXQJHUIUHTXHQWO\XQGHUJRLQGXFWLRQWKHUDS\ZLWKP\HORDEODWLYHFKHPRWKHUDS\RUUDGLDWLRQ
IROORZHGE\DXWRORJRXVVWHPFHOOWUDQVSODQWDWLRQ$OWKRXJKLPSURYHPHQWVLQSURJUHVVLRQ
IUHHVXUYLYDO3)6DQGRYHUDOOVXUYLYDO26KDYHRFFXUUHGLQWKHSDVW\HDUVHYHQZLWKWKH
EHVWDYDLODEOHDSSURYHGDJHQWVHVVHQWLDOO\DOOSDWLHQWVHYHQWXDOO\UHODSVH0HGLDQVXUYLYDO
IURPWKHWLPHRIGLDJQRVLVLVDSSUR[LPDWHO\\HDUV.XPDUHWDO
3527($620(%$&.*5281'
7KHSURWHDVRPHLVDPXOWLFDWDO\WLFSURWHLQDVHFRPSOH[WKDWLVUHVSRQVLEOHIRUGHJUDGDWLRQRID
ZLGHYDULHW\RISURWHLQVXEVWUDWHVZLWKLQERWKQRUPDODQGPDOLJQDQWWUDQVIRUPHGFHOOV
,QWUDFHOOXODUSURWHLQVWDUJHWHGIRUGHJUDGDWLRQE\WKHSURWHDVRPHDUHILUVWXELTXLWLQDWHGYLD
WKHXELTXLWLQFRQMXJDWLRQV\VWHP8ELTXLWLQDWHGSURWHLQVDUHFOHDYHGZLWKLQWKHSURWHDVRPH
E\RUPRUHRIVHSDUDWH1WHUPLQDOWKUHRQLQHSURWHDVHDFWLYLWLHVDFK\PRWU\SVLQOLNHD
WU\SVLQOLNHDQGDFDVSDVHOLNHDFWLYLW\
&$5),/=20,%

3UHFOLQLFDO%DFNJURXQG
&DUILO]RPLEIRUPHUO\NQRZQDV3;LVDWHWUDSHSWLGHHSR[\NHWRQHEDVHGLQKLELWRURIWKH
FK\PRWU\SVLQOLNHDFWLYLW\RIWKH6SURWHDVRPH&DUILO]RPLELVVWUXFWXUDOO\DQG
PHFKDQLVWLFDOO\GLIIHUHQWIURPWKHGLSHSWLGHERURQLFDFLGSURWHDVRPHLQKLELWRUERUWH]RPLE


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 21 of 151 
 
Confidential 
12 April  2018 
Compared to bortezomib, carfilzomib showed less off-target activity when measured against 
a broad panel of proteases including metallo-, aspartyl-, and serine proteases.  Bortezomib 
showed off-target inhibitory activity in the nanomolar range against several serine proteases 
(Arastu-Kapur 2009).  This selectivity may be responsible for the reductions in 
myelosuppression and neuropathy observed in preclinical studies comparing carfilzomib with 
bortezomib. 
Based upon in vitro and in vivo studies, it is anticipated that a more intense and sustained 
proteasome inhibition can be achieved with carfilzomib relative to bortezomib, resulting in 
enhanced antitumor activity.  Continuous 72-hour exposure to carfilzomib was associated 
with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived cell 
lines in culture (Demo 2007).  Incubation of hematologic tumor cell lines with carfilzomib 
for as little as 1 hour led to rapid inhibition of proteasome activity followed by accumulation 
of polyubiquitinated proteins and induction of apoptotic cell death.  Carfilzomib was also 
cytotoxic in bortezomib-resistant tumor cell lines (Suzuki 2011; Kuhn 2007). 
Preclinical studies in rats and monkeys have been performed administering carfilzomib 
intravenously (IV) for 5 consecutive days followed by 9 days of rest for 2 cycles.  
Proteasome inhibition of more than 80% was achieved, suggesting that high-level inhibition 
of the proteasome with the epoxyketone class is possible, affording new opportunities to 
escalate dose to optimize antitumor effects (Onyx data on file, and Yang 2011).  This finding 
was in contrast to preclinical testing with the boronate class of proteasome inhibitors that 
prohibited daily dosing due to substantial morbidity and mortality.  Carfilzomib has also been 
administered to rats and monkeys for 6 and 9 months, respectively (once daily dosing for 2 
consecutive days for 3 weeks on a 28-day cycle).  In this setting, carfilzomib was well 
tolerated at doses resulting in more than 80% proteasome inhibition, with no behavioral or 
histological evidence of peripheral neuropathy and no neutropenia (Onyx data on file and 
Carfilzomib Investigator’s Brochure [Carfilzomib IB]).  In contrast, rats treated with 
bortezomib at doses causing 80% proteasome inhibition develop peripheral neuropathy 
(Meregalli et al, 2010). 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO

&OLQLFDO%DFNJURXQG
&DUILO]RPLEHQWHUHGFOLQLFDOVWXGLHVLQ6HSWHPEHU
2Q-XO\.\SUROLVFDUILO]RPLEIRU,QMHFWLRQKHUHDIWHUUHIHUUHGWRDVFDUILO]RPLE
ZDVDSSURYHGXQGHUWKH8QLWHG6WDWHV)RRGDQG'UXJ$GPLQLVWUDWLRQ¶V86)'$
DFFHOHUDWHGDSSURYDOSURJUDPIRUWKHWUHDWPHQWRISDWLHQWVZLWKPXOWLSOHP\HORPDZKRKDYH
UHFHLYHGDWOHDVWSULRUWKHUDSLHVLQFOXGLQJERUWH]RPLEDQGDQ,0L'DQGKDYHGHPRQVWUDWHG
GLVHDVHSURJUHVVLRQRQRUZLWKLQGD\VRIFRPSOHWLRQRIWKHODVWWKHUDS\7KHDSSURYDOZDV
EDVHGRQWKHUHVXOWVRIWKH3KDVH6WXG\3;$VWXG\6LHJHO
$VRI-XO\&DUILO]RPLEIRU,QMHFWLRQKDVEHHQDSSURYHGLQFRXQWULHVUHJLRQV
ZRUOGZLGH,WLVHVWLPDWHGWKDWWKHQXPEHURISDWLHQWVH[SRVHGWRFDUILO]RPLEIURP
ODXQFKLQ-XO\WKURXJK-XO\ZDVLQWKHSRVWPDUNHWLQJVHWWLQJ)RU
DVXPPDU\RIDOO2Q\[VSRQVRUHGVWXGLHVDORQJZLWKWKH2QRVSRQVRUHGFOLQLFDOSURJUDPLQ
-DSDQSOHDVHUHIHUWRWKH&DUILO]RPLE,%IRUGHWDLOHGLQIRUPDWLRQ

'26(5$7,21$/(
7KHGRVHVFKHGXOHVHOHFWHGIRUWKLVVWXG\PJPLVEDVHGRQWKHUHJLPHQWKDWKDV
EHHQZLGHO\VWXGLHGLQSDWLHQWVZLWKUHODSVHGDQGUHIUDFWRU\PXOWLSOHP\HORPD(YDOXDWLRQ
RIWKLVGRVLQJLQFOXGHVDSLYRWDOVLQJOHDUP3KDVH6WXG\3;$ZLWKVXEMHFWV
WKDW GHPRQVWUDWHGHIILFDF\DQGVDIHW\6LHJHOVHH6HFWLRQ+HUHWKHGRVLQJ
VFKHGXOHLVVOLJKWO\PRGLILHGWRVWHSXSFDUILO]RPLEIURPWRPJPRQ&\FOH'D\
LQVWHDGRI&\FOH'D\WRVSHFLI\LQIXVLRQRYHUPLQXWHVDQGWRLQFOXGH
FRDGPLQLVWUDWLRQRIORZGRVHGH[DPHWKDVRQHRUDOO\DWPJZHHNO\3DSDGRSRXORV
7KHVWHSXSRIFDUILO]RPLERQ&\FOH'D\KDVEHHQDSSURYHGE\WKH86)'$IRUWKH
WUHDWPHQWRIPXOWLSOHP\HORPDLQSDWLHQWVZKRKDYHUHFHLYHGDWOHDVWSULRUWKHUDSLHV
LQFOXGLQJERUWH]RPLEDQGDQ,0L'DQGKDYHGHPRQVWUDWHGGLVHDVHSURJUHVVLRQRQRUZLWKLQ
GD\VRIFRPSOHWLRQRIWKHODVWWKHUDS\.\SUROLV3UHVFULELQJ,QIRUPDWLRQ7KH
FDUILO]RPLEGRVLQJVFKHGXOHXVHGLQWKLVVWXG\LVXVHGLQWKHRQJRLQJJOREDOSKDVH
VWXG\³$5DQGRPL]HG2SHQODEHO3KDVH6WXG\LQ6XEMHFWVZLWK5HODSVHGDQG
5HIUDFWRU\0XOWLSOH0\HORPD5HFHLYLQJ&DUILO]RPLELQ&RPELQDWLRQZLWK


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
'H[DPHWKDVRQH&RPSDULQJ2QFHZHHNO\YHUVXV7ZLFHZHHNO\&DUILO]RPLE'RVLQJ´
$PJHQ
678'<5$7,21$/(
&OLQLFDOGDWDWRGDWHGHPRQVWUDWHWKDWFDUILO]RPLEKDVFOLQLFDODFWLYLW\LQSDWLHQWVZLWK
PXOWLSOHP\HORPD
2IQRWHVWXG\3;$ZDVDPXOWLFHQWHUVWXG\FRQGXFWHGLQWKH86DQG&DQDGD
ZKLFKHYDOXDWHGWKHHIILFDF\DQGVDIHW\RIFDUILO]RPLEPRQRWKHUDS\LQVXEMHFWVZLWK
UHODSVHGDQGUHIUDFWRU\PXOWLSOHP\HORPD6LHJHO6XEMHFWVZHUHUHTXLUHGWRKDYHKDG
WUHDWPHQWZLWKSULRUOLQHVRIWKHUDS\LQFOXGLQJERUWH]RPLEDQGDQ,0L'HLWKHU
WKDOLGRPLGHRUOHQDOLGRPLGHDUHVSRQVHWRDWOHDVWRQHSULRUOLQHDQGGLVHDVHWKDWZDV
UHIUDFWRU\WRWKHPRVWUHFHQWWKHUDS\7KHPHGLDQQXPEHURISULRUUHJLPHQVIRUWKLVVWXG\
SRSXODWLRQZDVUDQJHDQGWKHPHGLDQWLPHIURPGLDJQRVLVRIPXOWLSOHP\HORPD
XQWLOHQUROOPHQWLQ6WXG\$ZDV\HDUV
6XEMHFWVUHFHLYHG,9FDUILO]RPLERQ'D\VDQGRIGD\F\FOHVDWDGRVHRI
PJPIRU&\FOHLQFUHDVHGWRPJPIRUVXEVHTXHQWWUHDWPHQWF\FOHV6XEMHFWV
UHFHLYHGSUHPHGLFDWLRQZLWKPJGH[DPHWKDVRQHWKURXJK&\FOHDQGFDUILO]RPLEZDV
LQIXVHGRYHUWRPLQXWHV
7KHSULPDU\HQGSRLQWZDVRYHUDOOUHVSRQVHUDWH2552YHUDOOUHVSRQVHUDWHZDVGHILQHGDV
VWULQJHQWFRPSOHWHUHVSRQVHV&5FRPSOHWHUHVSRQVH&5YHU\JRRGSDUWLDOUHVSRQVH
9*35RUSDUWLDOUHVSRQVH35DFFRUGLQJWRWKH,QWHUQDWLRQDO0\HORPD:RUNLQJ*URXS
8QLIRUP5HVSRQVH&ULWHULD,0:*85&'XULH
7KH255ZLWKFDUILO]RPLEPRQRWKHUDS\LQVWXG\3;$ZDV
FRQILGHQFHLQWHUYDO>&,@DQGWKHSURSRUWLRQRISDWLHQWVZKRDFKLHYHGD
PLQLPDOUHVSRQVH05RUEHWWHULHFOLQLFDOEHQHILWUDWH>&%5@ZDV
&,,PSRUWDQWO\WKHPHGLDQGXUDWLRQRIUHVSRQVH'25ZDVPRQWKV
&,DQGWKHPHGLDQGXUDWLRQRIFOLQLFDOEHQHILW'&%ZDVPRQWKV
&,GHPRQVWUDWLQJDUREXVWDQGGXUDEOHUHVSRQVHWRFDUILO]RPLEWKHUDS\
0HGLDQ26ZDVPRQWKV&,


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 24 of 151 
 
Confidential 
12 April  2018 
Carfilzomib treatment was generally well tolerated by this population of patients with 
advanced and heavily pre-treated multiple myeloma. 
This Phase 3 study (20140242 [CFZ005]), was originally designed to employ the same exact 
treatment regimen as that in study PX-171-003A1 to determine the magnitude and duration 
of response in relapsed and refractory multiple myeloma patients in China.  However, 
multiple myeloma treatment has evolved and the protocol has been modified to evaluate 
carfilzomib given in accordance with current practice.  Specifically:  (a) carfilzomib will be 
given in combination with low dose dexamethasone (Kd), (b) carfilzomib will be infused 
over 30 minutes, and (c) after initial treatment with 20 mg/m2 carfilzomib on Cycle 1 Days 1 
and 2, carfilzomib will be raised to therapeutic dosing of 27 mg/m2 beginning on Cycle 1 
Day 8, in agreement with US FDA labelling.  
Using a proteasome inhibitor in combination with low dose dexamethasone is a common 
clinical practice, and is anticipated to confer improved efficacy and tolerability as compared 
to single agent carfilzomib (Lendvai, 2014; Papadopoulos, 2015).  In China, bortezomib, a 
proteasome inhibitor introduced before carfilzomib, is recommended for use in combination 
with dexamethasone for multiple myeloma patients (Guidelines on the Diagnosis and 
Management of Multiple Myeloma in China, 2013). Though carfilzomib is generally very 
well-tolerated, patients can experience dyspnea and fever during treatment.  Tolerance 
improves when carfilzomib is infused over 30 minutes, rather than 2 to 10 minutes (Kortuem 
and Stewart, 2013).  Thirty-minute infusions of carfilzomib yield equivalent proteasome 
inhibition as do shorter infusions (Papadopoulos, 2015), and will be used here.   
To facilitate evaluation of response data, Multiple Myeloma disease response is assessed 
following the International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC; Durie, 2006, Rajkumar, 2011; Kumar, 2016
CCI
). The primary endpoint in 
this trial is ORR after each subject has had the opportunity to receive at least 6 cycles 
of therapy, with response as determined by review of subject data by an Independent 
Review Committee, following the IMWG-URC. 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 25 of 151 
 
Confidential 
12 April  2018 
In summary, carfilzomib 20/27 mg/m2 is an approved regimen for relapsed and refractory 
multiple myeloma in the United States.  Its activity has been demonstrated in the 
PX-171-003-A1 study (n = 266) with an ORR of 23%.  Its safety profile has been 
characterized across phase 1/2 studies (n = 598), and an estimated 20,000 patients have been 
treated with this regimen in the post-marketing setting.  The ORR of Kd is estimated to be 
approximately 30% in relapsed and refractory multiple myeloma patients.  Here, carfilzomib 
20/27 mg/m2 in combination with low dose dexamethasone will be evaluated in China. 
2 STUDY OBJECTIVES 
 PRIMARY OBJECTIVES 
The primary objective of this study is to evaluate the ORR after at least 6 cycles of Kd in 
subjects with multiple myeloma who have previously received an alkylating agent or 
anthracycline, bortezomib and an IMiD, have relapsed after 2 or more lines of therapy, and 
are refractory to the most recently received therapy.  Overall response rate is defined as the 
proportion of subjects with a best overall response of sCR, CR, VGPR, or PR.  The ORR will 
be determined using best overall response as assessed by the Independent Review Committee 
(IRC) per IMWG-URC (Durie, 2006; Rajkumar, 2011; Kumar, 2016). 
 SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• To evaluate ORR after at least 6 cycles of Kd using investigator assessment of response 
• To evaluate ORR after at least 12 cycles of Kd  
• 
CCI
To estimate Clinical Benefit Rate (CBR, defined as the proportion of subjects with a best 
overall response of MR or better) after at least 6 cycles and after at least 12 cycles 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
x 7RHVWLPDWH'XUDWLRQRI5HVSRQVH'25
x 7RHVWLPDWH'XUDWLRQRI&OLQLFDO%HQHILW'&%
x 7RHVWLPDWH3URJUHVVLRQ)UHH6XUYLYDO3)6
x 7RHVWLPDWH2YHUDOO6XUYLYDO26
x 7RHVWLPDWHWLPHWRUHVSRQVH775
x 7RFKDUDFWHUL]HSKDUPDFRNLQHWLFV3.LQDVXEVHWRIVXEMHFWV

(;3/25$725<2%-(&7,9(6
7KHH[SORUDWRU\REMHFWLYHVRIWKLVVWXG\DUH
x 7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRIUHVSRQVH
x 7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRIUHVSRQVH
x 7RHVWLPDWH&%5DIWHUDWOHDVWDQGDIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$
x
7RHVWLPDWH'25'&%3)6DQG775XVLQJ25&$

678'<'(6,*1
7KLV3KDVHVWXG\ZLOOEHFRQGXFWHGDVDPXOWLFHQWHURSHQODEHOVLQJOHDUPVWXG\DW
DSSUR[LPDWHO\FHQWHUVLQ&KLQD7KHVWXG\LVGHVLJQHGWRHYDOXDWHWKHHIILFDF\RI
FDUILO]RPLELQFRPELQDWLRQZLWKORZGRVHGH[DPHWKDVRQHLQVXEMHFWVZLWKPXOWLSOHP\HORPD
ZKRKDYHSUHYLRXVO\UHFHLYHGDQDON\ODWLQJDJHQWRUDQWKUDF\FOLQHERUWH]RPLEDQGDQ,0L'
UHODSVHGIROORZLQJRUPRUHWKHUDSLHVDQGDUHUHIUDFWRU\WRWKHPRVWUHFHQWO\UHFHLYHG
WKHUDS\
7UHDWPHQWF\FOHVDUHHYHU\GD\V,Q&\FOHVXEMHFWVZLOOUHFHLYHFDUILO]RPLEPJP
LQIXVLRQRQ'D\VDQG,IZHOOWROHUDWHGGHILQHGDVDEVHQFHRIDQ\WUHDWPHQWUHODWHG
DGYHUVHHYHQW>$(@UHTXLULQJGRVHUHGXFWLRQGHOD\RUWKHGRVHWREHKHOGLQ&\FOH>VHH
6HFWLRQ@WKHGRVHZLOOHVFDODWHWRPJPWREHJLYHQ&\FOH'D\DQGRQZDUG
'H[DPHWKDVRQHPJZLOOEHJLYHQWRVXEMHFWVRQ'D\VDQGRQD
VFKHGXOHRIHYHU\GD\V2QGD\VZKHQFDUILO]RPLELVDGPLQLVWHUHGWKHGH[DPHWKDVRQHLV
WREHJLYHQPLQXWHVWRKRXUVSULRUWRFDUILO]RPLE


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
6XEMHFWVZLOOUHFHLYHWUHDWPHQWXQWLOGLVHDVHSURJUHVVLRQXQDFFHSWDEOHWR[LFLW\LQLWLDWLRQRI
QHZDQWLP\HORPDWKHUDS\RUGLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWIRUDQ\RWKHUUHDVRQ
ZKLFKHYHURFFXUVILUVW
'RVHUHGXFWLRQVRIFDUILO]RPLEDQGGH[DPHWKDVRQHZLOOEHSHUPLWWHGSHUSURWRFROJXLGHOLQHV
VHH6HFWLRQ
3KDUPDFRNLQHWLFDQDO\VHVZLOOEHFKDUDFWHUL]HGLQDVXEVHWRIDSSUR[LPDWHO\VXEMHFWVDW
VHOHFWHGVLWHV6XEMHFWVZKRGRQRWSURYLGHDOOUHTXLUHG3.DVVHVVPHQWVDW&\FOH'D\
DQG&\FOH'D\ZLOOEHUHSODFHG
7<3('(6,*12)678'<
7KHGHVLJQVFKHPDIRUWKLVRSHQODEHOVLQJOHDUPVWXG\LVSUHVHQWHGLQ)LJXUH
)LJXUH6WXG\'HVLJQ$QG7UHDWPHQW6FKHPD


$EEUHYLDWLRQV&%5 FOLQLFDOEHQHILWUDWH'25 GXUDWLRQRIUHVSRQVH'&% GXUDWLRQRIFOLQLFDOEHQHILW
(&2* (DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS3HUIRUPDQFH6WDWXV,0L' LPPXQRPRGXODWRU\GUXJ
1 QXPEHU255 RYHUDOOUHVSRQVHUDWH26 RYHUDOOVXUYLYDO3)6 SURJUHVVLRQIUHHVXUYLYDO
3. SKDUPDFRNLQHWLFV775 7LPHWR7UHDWPHQW5HVSRQVH


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
0,1,0,=,1*%,$6

5DQGRPL]DWLRQ
1RWDSSOLFDEOHWKLVLVDVLQJOHDUPVWXG\

%OLQGLQJ
1RWDSSOLFDEOHWKLVLVDQRSHQODEHOVWXG\
(1'2)678'<
3ULPDU\&RPSOHWLRQ7KHWLPHZKHQDOOVXEMHFWVKDYHKDGWKHRSSRUWXQLW\WRFRPSOHWHDW
OHDVWF\FOHVRI.GRUKDYHZLWKGUDZQIURPVWXG\WUHDWPHQW
(QGRI6WXG\7KUHH\HDUVDIWHUODVWVXEMHFWLQLWLDWHVWUHDWPHQWRUZKHQDOOVXEMHFWVKDYH
ZLWKGUDZQFRQVHQWRUGLHGZKLFKHYHURFFXUVILUVW

68%-(&76(/(&7,21
$WRWDORIDSSUR[LPDWHO\VXEMHFWVDUHSODQQHGIRUWKLVVWXG\
,1&/86,21&5,7(5,$
6XEMHFWVPXVWPHHWDOORIWKHIROORZLQJLQFOXVLRQFULWHULDWREHHOLJLEOHIRUVWXG\HQUROOPHQW
 0XOWLSOHP\HORPD
 6XEMHFWVPXVWKDYHPHDVXUDEOHGLVHDVHGHILQHGDVRUPRUHRIWKHIROORZLQJ
D 6HUXP0SURWHLQJG/
E 8ULQH0SURWHLQPJKRXUV
F ,QVXEMHFWVZLWKRXWPHDVXUDEOHVHUXPRUXULQH0SURWHLQVHUXPIUHHOLJKWFKDLQ
6)/&!PJ/LQYROYHGOLJKWFKDLQDQGDQDEQRUPDONOUDWLR
 6XEMHFWVPXVWKDYHEHHQUHVSRQVLYHLHDFKLHYHGD05RUEHWWHUWRDWOHDVWRIWKHLU
SULRUWUHDWPHQWUHJLPHQV
 5HIUDFWRU\WRWKHPRVWUHFHQWO\UHFHLYHGWKHUDS\5HIUDFWRU\GLVHDVHGHILQHGDV
UHVSRQVHWRRUSURJUHVVLQJGXULQJWKHUDS\RUZLWKLQGD\VDIWHUODVWWKHUDS\
 6XEMHFWVPXVWKDYHUHFHLYHGSULRUUHJLPHQV,QGXFWLRQWKHUDS\DQGVWHPFHOO
WUDQVSODQWPDLQWHQDQFHZLOOEHFRQVLGHUHGDVUHJLPHQDVGHVFULEHGLQ
6HFWLRQ


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 29 of 151 
 
Confidential 
12 April  2018 
6. Subjects must have received prior treatment with bortezomib and an IMiD 
7. Subjects must have received an alkylating agent or anthracycline alone or in 
combination with other myeloma treatments (this may include high-dose melphalan as 
part of the conditioning regimen prior to stem cell transplant) 
8. Males and females ≥ 18 years of age 
9. Life expectancy of more than 3 months 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2 
11. Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal (ULN), 
and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 times 
the ULN 
12. Absolute neutrophil count (ANC) ≥ 1,000/mm3, hemoglobin ≥ 8.0 g/dL, and platelet 
count ≥ 50,000/mm3 
• Subjects should not have received platelet transfusions for at least 1 week prior to 
obtaining the screening platelet count 
• Screening ANC should be independent of granulocyte-colony stimulating factor  
(G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) support 
for ≥ 1 week and pegylated G-CSF for ≥ 2 weeks 
• Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per 
institutional guidelines is allowed; however, most recent RBC transfusion may not 
have been done within 7 days prior to obtaining screening hemoglobin 
13. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min.  Calculated CrCl 
should be performed by using a widely accepted equation (e.g., the Cockcroft and Gault 
formula: [(140 – Age) × Mass (kg) / (72 × Creatinine mg/dL)]; multiply result by 0.85 
if female) 
14. Left ventricular ejection fraction (LVEF) ≥ 40%; 2-dimentional (2-D) transthoracic 
echocardiogram (ECHO) is the preferred method of evaluation; multiple gated 
acquisition scan (MUGA) is acceptable if ECHO is not available 
15. Written informed consent in accordance with national, local, and institutional guidelines 
16. Female subjects of child-bearing potential (FCBP) must have a negative serum 
pregnancy test within 7 days prior to first dose of carfilzomib and agree to use an 
effective method of contraception during and for 30 days following last dose of 
carfilzomib (more frequent pregnancy tests may be conducted if required per local 
regulations).  This protocol defines a FCBP as a sexually mature woman who:  1) has 
not undergone a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or 
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months).   


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
 0DOHVXEMHFWVPXVWXVHDQHIIHFWLYHEDUULHUPHWKRGRIFRQWUDFHSWLRQGXULQJWKHVWXG\
DQGIRUGD\VIROORZLQJWKHODVWGRVHRIFDUILO]RPLELIVH[XDOO\DFWLYHZLWKD)&%3
0DOHVXEMHFWVPXVWQRWGRQDWHVSHUPGXULQJWUHDWPHQWDQGIRUDQDGGLWLRQDOGD\V
DIWHUODVWGRVHRIFDUILO]RPLE0DOHVXEMHFWVZLWKSUHJQDQWSDUWQHUVPXVWSUDFWLFH
VH[XDODEVWLQHQFHRUXVHDFRQGRPGXULQJYDJLQDOVH[
(;&/86,21&5,7(5,$
6XEMHFWVPHHWLQJDQ\RIWKHIROORZLQJH[FOXVLRQFULWHULDZLOOQRWEHHOLJLEOHWRHQUROOLQWKLV
VWXG\

:DOGHQVWU|P¶VPDFURJOREXOLQHPLDRULPPXQRJOREXOLQ0,J0PXOWLSOHP\HORPD
 6XEMHFWVZKRIDLOHGWRDFKLHYHDWOHDVWDFRQILUPHG05RQDQ\RIWKHLUSULRUUHJLPHQV
 6XEMHFWVZLWKQRQVHFUHWRU\PXOWLSOHP\HORPDGHILQHGDVJG/0SURWHLQLQVHUXP
DQGPJKRXU0SURWHLQLQXULQHDQG6)/&PJ/LQYROYHGOLJKWFKDLQ
 *OXFRFRUWLFRLGWKHUDS\SUHGQLVRQH!PJGD\RUHTXLYDOHQWZLWKLQZHHNVSULRUWR
&\FOH'D\
 32(06V\QGURPHSRO\QHXURSDWK\RUJDQRPHJDO\HQGRFULQRSDWK\PRQRFORQDO
SURWHLQDQGVNLQFKDQJHV
 3ODVPDFHOOOHXNHPLD!î/FLUFXODWLQJSODVPDFHOOVE\VWDQGDUGGLIIHUHQWLDO
 &KHPRWKHUDS\ZLWKDSSURYHGRULQYHVWLJDWLYHDQWLFDQFHUWKHUDSHXWLFVLQFOXGLQJVWHURLG
WKHUDS\ZLWKLQWKHZHHNVSULRUWR&\FOH'D\
 5DGLDWLRQWKHUDS\RULPPXQRWKHUDS\LQWKHZHHNVSULRUWR&\FOH'D\ORFDOL]HG
UDGLDWLRQWKHUDS\ZLWKLQZHHNSULRUWR&\FOH'D\
 3DUWLFLSDWLRQLQDQLQYHVWLJDWLRQDOWKHUDSHXWLFVWXG\ZLWKLQZHHNVRUZLWKLQGUXJ
KDOIOLYHV7òSULRUWR&\FOH'D\ZKLFKHYHUWLPHLVJUHDWHU

3ULRUWUHDWPHQWZLWKFDUILO]RPLE
 0DMRUVXUJHU\ZLWKLQZHHNVEHIRUH&\FOH'D\
 &RQJHVWLYHKHDUWIDLOXUH>&+)@1HZ<RUN+HDUW$VVRFLDWLRQ&ODVV,,,WR,9
V\PSWRPDWLFLVFKHPLDFRQGXFWLRQDEQRUPDOLWLHVXQFRQWUROOHGE\FRQYHQWLRQDO
LQWHUYHQWLRQ6XEMHFWVFDQQRWKDYHH[SHULHQFHGDP\RFDUGLDOLQIDUFWLRQZLWKLQ
PRQWKVSULRUWR&\FOH 'D\
 8QFRQWUROOHGK\SHUWHQVLRQDVXVWDLQHGV\VWROLFEORRGSUHVVXUH!PP+JDQGRU
GLDVWROLF%3!PP+J
 $FXWHDFWLYHLQIHFWLRQUHTXLULQJV\VWHPLFHLWKHULQWUDYHQRXVRURUDODQWLELRWLFV
DQWLYLUDOVRUDQWLIXQJDOVWKHWUHDWPHQWPXVWEHFRPSOHWHGDWOHDVWZHHNVSULRUWR
&\FOH 'D\


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 31 of 151 
 
Confidential 
12 April  2018 
15. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients 
with hepatitis B surface antigen or core antibody receiving and responding to antiviral 
therapy directed at hepatitis B: these patients are allowed; Note: patients who are 
HepB surface antigen negative at screening, or who are receiving interferon alfa-2a 
(IFN) or Peginterferon alfa-2a  (PEG-IFN) and have Hepatitis B Virus (HBV) DNA 
< 2000 International Units (IU) at screening, or, are receiving a nucleos(t)ide 
analog and have HBV DNA below Lower Limit of Normal (LLN) at screening are 
eligible 
16. Non-hematologic malignancy within the past 3 years except: 
a. Adequately treated basal cell or squamous cell skin cancer, 
b. Carcinoma in situ of the cervix, or 
c. Prostate cancer < Gleason Score 6 with stable prostate-specific antigen 
17. Subjects with treatment-related myelodysplastic syndrome  
18. Significant neuropathy (Grade 3, 4, or Grade 2 with pain) at the time of baseline 
evaluation 
19. Subjects in whom the required program of fluid hydration is contraindicated, e.g., due 
to pre-existing pulmonary, cardiac, or renal impairment 
20. Subjects with known or suspected amyloidosis 
21. Subjects with pleural effusions requiring thoracentesis 
22. Subjects with ascites requiring paracentesis 
23. Any clinically significant medical disease or condition, that in the investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent 
24. Female subjects who are pregnant or lactating, or planning to become pregnant during 
treatment and for an additional 30 days after discontinuing carfilzomib. 
25. Serious psychiatric or medical conditions that could interfere with treatment  
5 
SUBJECT SCREENING 
A signed and dated informed consent form (ICF) will be obtained before any screening 
procedures are performed.  All subjects who sign consent will be assigned a unique study 
number.  This number will be used to identify the subject throughout the clinical study and 
must be used on all study documentation related to that subject.   
Evaluations obtained as part of routine medical care and performed prior to informed consent 
may be used in place of the study-specific evaluations, provided they meet the time windows 
described in Section 9.2.1. Subjects will acknowledge and agree to the possible use of this 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 32 of 151 
 
Confidential 
12 April  2018 
information for the study by giving informed consent.  The screening period for a particular 
subject commences at the point at which the subject signs the ICF, and must be completed 
within 21 days. 
6 SUBJECT ENROLLMENT 
Only subjects who fulfill all eligibility criteria will be allowed to enroll into the study.  The 
investigator is responsible for reviewing the subject’s information before enrollment to 
ensure his or her eligibility.  
Study sites that do not enroll a single subject within the first 3 months of opening the study 
may be subject to study site closure at the discretion of the sponsor.   
7 STUDY DRUG 
 CARFILZOMIB 
7.1.1 Physical Description 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-
1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-
2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  
The molecular formula is C40H57N5O7 and the molecular weight is 719.91.  It specifically 
functions as an inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads 
to the accumulation of protein substrates within the cell and induction of apoptosis.   
7.1.2 Formulation 
Carfilzomib will be provided as a lyophilized powder which, when reconstituted, contains a 
2 mg/mL isotonic solution of carfilzomib Free Base in  mM sodium citrate buffer (pH  ) 
containing  % (w/v) sulfobutylether-β-cyclodextrin (SBE-β-CD, Captisol). 
7.1.3 How Supplied 
C
CI
Carfilzomib is supplied as a lyophilized parenteral product in single-use vials packaged in 
multi-vial cartons.  Institutional pharmacies will be supplied with open stock vials with 
full-disclosure labels.  Reordering clinical drug supplies will be managed through the 
CC
I
C
CI


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
,QWHUDFWLYH9RLFH5HFRJQLWLRQ6\VWHPRU,QWHUDFWLYH:HE5HFRJQLWLRQ6\VWHPGHWDLOVDUH
SURYLGHGLQWKH,QYHVWLJDWLRQDO3URGXFW,QVWUXFWLRQ0DQXDO,3,0
'(;$0(7+$621(
'H[DPHWKDVRQHLVDFRPPHUFLDOO\DYDLODEOHGUXJ7KHGHVFULSWLRQKRZVXSSOLHGDQG
VWRUDJHLQVWUXFWLRQVIRUGH[DPHWKDVRQHDUHIRXQGLQWKHSUHVFULELQJLQIRUPDWLRQ6LWHVDUH
DGYLVHGWRUHIHUWRWKHSUHVFULELQJLQIRUPDWLRQIRULQIRUPDWLRQWKDWLVVSHFLILFWRWKHEUDQGRU
IRUPXODWLRQRIWKHGUXJSURGXFWWKH\DUHXVLQJ2UDORU,9GH[DPHWKDVRQHPD\EHXWLOL]HG
SHUVLWH¶VVWDQGDUGSUDFWLFH
678'<'58*$&&2817$%,/,7<
7KHVSRQVRURUGHVLJQHHDQGWKHLQYHVWLJDWRUZLOOPDLQWDLQUHFRUGVRIHDFKVKLSPHQWRI
LQYHVWLJDWLRQDOSURGXFW,38SRQUHFHLSWRI,3WKHGHVLJQDWHGUHFLSLHQWDWWKHVWXG\VLWHZLOO
LQVSHFWWKHVKLSPHQWYHULI\WKHQXPEHUDQGFRQGLWLRQRIWKHYLDOVDQGSUHSDUHDQLQYHQWRU\
RUGUXJDFFRXQWDELOLW\UHFRUG7KHUHFRUGVZLOOGRFXPHQWVKLSPHQWGDWHVEDWFKQXPEHUV
SURGXFWSUHVHQWDWLRQTXDQWLW\RIYLDOVFRQWDLQHGLQWKHVKLSPHQWDQGGLVSHQVDWLRQWR
LQGLYLGXDOVXEMHFWVXVLQJWKHVXEMHFWLGHQWLILFDWLRQQXPEHU
5HIHUWRWKH,3,0IRUDGGLWLRQDOGHWDLOV

'26$*($1'75($70(17$'0,1,675$7,21
3UHWUHDWPHQWDQGWUHDWPHQWDGPLQLVWUDWLRQGHWDLOVDUHRXWOLQHGEHORZLQ6HFWLRQ
'RVHPRGLILFDWLRQVIRUWR[LFLW\DUHGHVFULEHGLQ6HFWLRQ'HWDLOVRQGUXJGHVFULSWLRQ
IRUPXODWLRQVWRUDJHDQGDFFRXQWDELOLW\RIDOOVWXG\GUXJVDUHGHVFULEHGLQWKH,3,0
*(1(5$/,16758&7,216)25$'0,1,675$7,21

2UDODQG,QWUDYHQRXVK\GUDWLRQ
,QWUDYHQRXVK\GUDWLRQZLOOEHJLYHQLPPHGLDWHO\SULRUWRDQGIROORZLQJFDUILO]RPLE
DGPLQLVWUDWLRQGXULQJ&\FOHDQGDWWKHLQYHVWLJDWRU¶VGLVFUHWLRQLQ&\FOHDQGKLJKHU,I
XULFDFLGLVHOHYDWHGDW&\FOH'D\WKHQWKHUHFRPPHQGHG,9K\GUDWLRQVKRXOGEH
UHSHDWHGIRUDOORI&\FOHDQGDWWKHLQYHVWLJDWRU¶VGLVFUHWLRQLQFRQMXQFWLRQZLWK
VXEVHTXHQWF\FOHV7KLVZLOOFRQVLVWRIWRP/,9QRUPDOVDOLQHRURWKHUDSSURSULDWH


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 34 of 151 
 
Confidential 
12 April  2018 
IV fluid.  The goal of the hydration program is to maintain robust urine output  
(e.g., ≥ 2 L/day).  Subjects should be monitored periodically during this period for evidence 
of fluid overload.  In subjects considered to be at risk for tumor lysis syndrome (TLS) at 
completion of Cycle 1, hydration should be continued into Cycle 2, if clinically indicated.  
Subjects in whom this program of oral and IV fluid hydration is contraindicated, e.g., due to 
pre-existing pulmonary, cardiac, or renal impairment, will not be eligible to participate in the 
clinical trial. 
In addition, refer to Section 8.3.1 for optional medications including allopurinol (or other 
approved uric acid-lowering agent) for patients considered to be at high risk for TLS.  
Patients should be well hydrated to reduce risk of TLS and decline in renal function; refer to 
Section 8.4.3 for safety guidance regarding TLS. 
8.1.2 
Carfilzomib Administration 
Information regarding drug description, formulation, storage, and accountability of 
carfilzomib is provided in Section 7 and in the IPIM.  
Carfilzomib is administered as an IV infusion over approximately 30 minutes (± 5 minutes).  
Note:  On days of PK sampling (Cycle 1 Day 1 and Cycle 2 Day 1), carfilzomib must be 
administered over 30 ± 1 minutes.  Subjects should have a dedicated line for drug 
administration whenever possible, and PK samples may not be collected from the same line 
that is used for carfilzomib administration.  The dedicated infusion line or the existing 
infusion line (when a dedicated line is not available) must be flushed as specified in the 
IPIM.   
Each dose will consist of carfilzomib administered on a mg/m2 basis, and should be based on 
the subject’s actual calculated body surface area (BSA) at baseline.  Subjects with a 
BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA (Mosteller 1987). 
Carfilzomib administration may be performed ± 2 days from the scheduled administration 
day.  Every effort should be made to maintain consecutive dosing days.  Anticipated 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
WUHDWPHQWGHOD\VRIJUHDWHUWKDQGD\VPXVWEHGLVFXVVHGZLWKWKHVWXG\PHGLFDOPRQLWRURU
GHVLJQHH3URFHGXUHVIRUGRVHUHGXFWLRQVDQGDGMXVWPHQWVDUHVXPPDUL]HGLQ6HFWLRQ

'H[DPHWKDVRQH$GPLQLVWUDWLRQ
'H[DPHWKDVRQHPJZLOOEHDGPLQLVWHUHGRQ'D\VDQGRQD
GD\F\FOH1RWH'D\VDQGGRVLQJPD\EHGD\VIURPWKHVFKHGXOHG
DGPLQLVWUDWLRQGD\(YHU\HIIRUWVKRXOGEHPDGHWRPDLQWDLQFRQVHFXWLYHGRVLQJGD\V
,WZLOOEHJLYHQDWOHDVWPLQXWHVEXWQRPRUHWKDQKRXUVSULRUWRFDUILO]RPLELQIXVLRQ
2QQRQFOLQLFGD\V32GH[DPHWKDVRQHPD\EHVHOIDGPLQLVWHUHGDWKRPH
3URFHGXUHVIRUGRVHUHGXFWLRQVDQGDGMXVWPHQWVDUHVXPPDUL]HGLQ6HFWLRQ
'26(02',),&$7,21*8,'(/,1(6
,QWKHHYHQWRIDSRVVLEOHGUXJUHODWHG$(WKHLQYHVWLJDWRUZLOOWRWKHEHVWRIKLVKHUDELOLW\
DVVHVVLWVUHODWLRQVKLSWRFDUILO]RPLEDQGRUGH[DPHWKDVRQH
)RUF\FOHVZKHUH'D\LVGHOD\HGWKHHQWLUHF\FOHVKRXOGVKLIWWRDFFRPPRGDWHWKHGHOD\
,IDPLGF\FOHGRVHLVPLVVHGWKDWGRVLQJGD\VKRXOGEHVNLSSHGDQGQRWPDGHXS
,IFDUILO]RPLEGRVLQJLVSHUPDQHQWO\VWRSSHGGXHWRWR[LFLW\SHUGRVHPRGLILFDWLRQJXLGHOLQHV
OLVWHGLQ6HFWLRQGH[DPHWKDVRQHGRVLQJZLOODOVREHVWRSSHGDQGWKHVXEMHFWDVVHVVHG
IRUGLVHDVHVWDWXVSHUSURWRFROVSHFLILHGGLVHDVHUHVSRQVHFULWHULDDQGIROORZHGSHUSURWRFRO
VSHFLILHGJXLGHOLQHV6HFWLRQSULRUWRLQLWLDWLQJQHZDQWLP\HORPDWKHUDSLHV

&DUILO]RPLE'RVH0RGLILFDWLRQ*XLGHOLQHV
'RVHUHGXFWLRQJXLGHOLQHVIRUFDUILO]RPLELQFOXGHJXLGHOLQHVZKHUHWKHGRVHRIFDUILO]RPLELV
GHFUHDVHGEDVHGRQWKHREVHUYHGWR[LFLW\$GPLQLVWUDWLRQRIFDUILO]RPLEZLOOEHGLVFRQWLQXHG
LQWKHHYHQWRIDWUHDWPHQWUHODWHGWR[LFLW\WKDWLQWKHRSLQLRQRIWKHLQYHVWLJDWRUZDUUDQWV
GLVFRQWLQXDWLRQ([FHSWLRQVWRWKHGRVHPRGLILFDWLRQJXLGHOLQHVDUHSHUPLWWHGZLWKSULRU
ZULWWHQDSSURYDOIURPWKHVWXG\PHGLFDOPRQLWRURUGHVLJQHH
7UHDWPHQWJXLGHOLQHVIRUVSHFLILFWR[LFLWLHVDUHRXWOLQHGLQ6HFWLRQ,IDVXEMHFWUHTXLUHV
DKROGRIWKHUDS\IRUPRUHWKDQFRQVHFXWLYHZHHNVGXHWRXQUHVROYHGWR[LFLW\WKHVXEMHFW


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 36 of 151 
 
Confidential 
12 April  2018 
should be removed from study treatment and followed for survival and disease progression.  
Exceptions to this should be discussed with the study medical monitor or designee.   
A maximum of 2 dose reductions are allowed (Table 1) if the carfilzomib dose is reduced 
during the previous cycle, the reduced dose level will be continued on Day 1 of the new 
cycle.  If the reduced dose level is well tolerated for a complete cycle, the subject may, at the 
investigator’s discretion, be rechallenged at the dose prior to the reduction at the start of the 
next cycle.   
Table 1:  Dose Decrements for Carfilzomib 
Starting Dose 
Reduced Carfilzomib Doses 
First Dose Reduction 
Dose –1 
Second Dose Reduction 
Dose –2 
20 mg/m2 
15 mg/m2 
11 mg/m2 
27 mg/m2  
20 mg/m2 
15 mg/m2 
Note:  Infusions remain as 30-minute infusions during dose reduction(s). 
 
8.2.1.1 Missed Doses 
Missed doses will not be replaced during a cycle.   
8.2.1.2 Changes in Body Surface Area 
Dose adjustments do not need to be made for weight gains/losses of ≤ 20%.  Study subjects 
with a BSA of > 2.2 m2 will receive a maximal dose of 44 mg of carfilzomib (at the 
20 mg/m2 dose level) or 59 mg of carfilzomib (at the 27 mg/m2 dose level).  
8.2.2 
Carfilzomib:  Guidelines for Treatment-Emergent Toxicities 
Guidelines for the management of hematologic and non-hematologic treatment emergent 
toxicities in subjects receiving carfilzomib are summarized in Table 2 and Table 3, 
respectively.  For conditions that do not require dose reduction, refer to Section 8.2.4. 
For both hematologic and non-hematologic treatment-emergent toxicities, no more than 
2 dose reductions will be permitted in an individual subject in the study; if toxicity continues, 
the subject should discontinue study treatment and begin follow-up (Section 9.2.16).   


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 37 of 151 
 
Confidential 
12 April  2018 
Table 2: Guidelines for Hematologic Treatment Emergent Toxicities  
in Carfilzomib Patients 
Hematologic Toxicity 
Recommended Action 
Thrombocytopenia 
When platelets first 
fall to ≤ 30 × 109/L 
If platelets 10–30 × 109/L 
without evidence of bleeding 
Continue at same dose*. 
If evidence of bleeding or 
platelets < 10 × 109/L 
Hold dose until platelets return to 
≥ 10 × 109/L and/or bleeding is 
controlled, then resume at 
same dose. 
For each subsequent drop to  
≤ 30 × 109/L 
If platelets 10–30 × 109/L 
without evidence of bleeding 
Continue at same dose. 
If evidence of bleeding or 
platelets < 10 × 109/L 
Hold dose until platelets return to 
≥ 10 × 109/L and/or bleeding is 
controlled, then resume at 
1 dose decrement. 
Neutropenia 
When ANC first falls to  
< 0.5 × 109/L 
If ANC < 0.5 × 109/L 
Hold dose until ANC returns to 
≥ 0.5 × 109/L, then resume at same 
dose.* 
For each subsequent drop to  
 < 0.5 × 109/L 
If ANC < 0.5 × 109/L 
Hold dose until ANC returns to 
≥ 0.5 × 109/L, then resume at 1 dose 
decrement. 
Neutropenic fever 
If < 1 × 109/L and single 
temperature > 38.3ºC OR 
temperature > 38.0 ºC for more 
than 1 hour 
Hold dose until ANC returns to 
baseline grade, then resume at same 
dose. 
ANC = absolute neutrophil count * If the first fall in platelet count or in ANC is observed before D8C1, 
then administer the protocol-specified 27 mg/m2 on D8C1 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 38 of 151 
 
Confidential 
12 April  2018 
Table 3: Guidelines for Non-hematologic Treatment Emergent Toxicities  
in Carfilzomib Patients 
Nonhematologic Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Actiona 
Tumor Lysis 
Syndrome  
3 or more of the following: 
increase in creatinine of ≥ 50% 
increase in uric acid of ≥ 50% 
increase in phosphate of ≥ 50% 
increase in potassium of ≥ 30% 
decrease in calcium  
OR 
increase in LDH of ≥ 2-fold from 
baseline 
Hold carfilzomib until all abnormalities in 
serum chemistries have resolved; resume at 
same doseb 
Infection  
Grade 3 or 4 
Hold carfilzomib. Once infection is 
controlled and the subject is without 
infection-related symptoms, and if ANC 
> 0.5 × 109/L, resume at full dose. If ANC 
<  0.5 × 109/L, follow hematologic toxicities 
dose reduction guidelines. 
Neuropathy 
Grade 2 treatment-emergent with 
pain, or Grade 3  
Hold carfilzomib until resolved to ≤ Grade 2 
without pain; then resume at 1 dose decrement 
 
Grade 4  
Discontinue 
 
Dyspnea 
Grade 3 or 4 
Hold carfilzomib until resolution to baseline, 
then resume at 1 dose decrement  
 
Renal Dysfunction 
Serum creatinine 
clearance < 15 mL/min (or CrCl 
decreases to ≤ 50% of baseline), or 
need for dialysis 
Hold carfilzomib and continue monitoring 
renal function 
If attributable to carfilzomib, resume when 
renal function has recovered to within 25% of 
baseline, resume at 1 dose level reduction 
If not attributable to carfilzomib, dosing may 
be resumed at the discretion of the treating 
physician 
If tolerated, reduced dose may be raised to the 
previous dose at the discretion of the treating 
physician.  For patients on dialysis receiving 
carfilzomib, the dose is to be administered 
after dialysis 
 
Page 1 of 3 
Footnotes defined on last page of the table. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 39 of 151 
 
Confidential 
12 April  2018 
Table 3: Guidelines for Non-hematologic Treatment Emergent Toxicities  
in Carfilzomib Patients 
Nonhematologic Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Actiona 
Elevation in Liver 
Function Tests 
≥ Grade 3 (AST, ALT, or total 
bilirubin) 
Hold carfilzomib until all abnormalities in 
liver functions resolve to baseline.  Resume 
carfilzomib at 1 dose decrement.   
Congestive Heart 
Failure 
N/A 
Any subject with symptoms of congestive 
heart failure, whether or not drug related, must 
have the dose held 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 6 weeks, the subject will be withdrawn 
from all study treatment 
Hypertensive crisis 
Hypertensive urgency defined as 
sustained or persistent 
SBP ≥ 180 mmHg or 
DBP ≥ 110 mmHg.  Hypertensive 
emergency with values as before 
and evidence of end organ 
damage. 
Hold carfilzomib until resolution to baselinec 
and restart at 1 dose decrement. 
 
Pulmonary toxicity 
Interstitial lung disease, acute 
respiratory failure, ARDS 
Hold carfilzomib until resolution to baseline 
and restart at 1 dose decrement. 
 
Pulmonary 
Hypertension 
Presence of mean pulmonary 
arterial pressure ≥ 25 mmHg at rest 
Hold carfilzomib until resolution to baseline 
and restart at 1 dose decrement 
 
Posterior 
Reversible 
Encephalopathy 
Syndrome 
Headaches, altered mental status, 
seizures, visual loss, and 
hypertension 
If PRES is suspected, hold 
carfilzomib.  Consider evaluation with 
neuroradiological imaging for onset of visual 
or neurological symptoms suggestive of 
PRES.  If the diagnosis of PRES is excluded, 
carfilzomib administration may resume if 
clinically appropriate. 
 
Page 2 of 3 
Footnotes defined on last page of the table. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 40 of 151 
 
Confidential 
12 April  2018 
Table 3: Guidelines for Non-hematologic Treatment Emergent Toxicities  
in Carfilzomib Patients 
Nonhematologic Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Actiona 
Thrombotic 
Microangiopathy 
Fever, microangiopathic hemolytic 
anemia, renal failure, 
thrombocytopenia, neurological 
manifestations 
If the diagnosis is suspected, stop carfilzomib 
and manage per standard of care including 
plasma exchange as clinically appropriate.  If 
the diagnosis is excluded, carfilzomib can be 
restarted.  
 
Other 
Nonhematologic 
Toxicity 
Assessed as carfilzomib-related 
and ≥ Grade 3 
Hold dose until toxicity resolves to ≤ Grade 1 
or baseline; restart at 1 dose decrement 
 
 
 
  
 
 
 
Page 3 of 3 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; ARDS = acute respiratory distress 
syndrome; AST = aspartate aminotransferase; CrCl = creatinine clearance; DPB = diastolic blood pressure; 
LDH = lactate dehydrogenase; PRES = posterior reversible encephalopathy; SBP = systolic blood pressure. 
a 
The maximum allowed interruption of carfilzomib is 6 consecutive weeks. 
b    If the Tumor Lysis Syndrome laboratory finding is observed before D8C1, administer the 
protocol-specified 27 mg/m2 when dosing is resumed. 
c      For grade 3 hypertension, baseline refers to an average SBP < 140 mmHg or DPB < 90 mmHg on   
appropriate antihypertensive therapy. 
 
Please refer to Section 8.2.4 for additional conditions that do NOT require dose reductions. 
8.2.3 
Dexamethasone Toxicities and Treatment 
Guidelines for dexamethasone dose modifications are summarized in Table 4 and Table 5.  In 
the event that carfilzomib is permanently discontinued, dexamethasone should also be 
discontinued. 
Two dose reduction levels are defined for dexamethasone, as illustrated in Table 4 below. 
Table 4: Dose Decrements for Dexamethasone 
Nominal 
Dose 
Reduced Dexamethasone Doses 
Dose –1  
Dose –2 
20 mg  
12 mg 
8 mg 
In the event of additional dexamethasone-related dose-limiting toxicity, dexamethasone will 
be permanently discontinued after 2 dose reductions.  At the investigator’s discretion, 
dexamethasone may be tapered prior to complete discontinuation.  If the dexamethasone dose 
is reduced during the previous cycle, the reduced dose level will be continued on day 1 of the 
new cycle.  If the reduced dose level is well tolerated for a complete cycle, the patient may, 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 41 of 151 
 
Confidential 
12 April  2018 
at the investigator’s discretion, be rechallenged with the dose level used prior to the 
reduction, at the start of the next cycle. 
Table 5: Treatment Guidelines for Dexamethasone-related Toxicity 
Body System  
Symptom  
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
Grade 1–2 (requiring 
medical management) 
Continue dexamethasone at same dose and treat with 
therapeutic doses of H2 blockers, or proton pump 
inhibitor.  May consider adding sucralfate or other 
antiulcer treatment as clinically indicated.  If symptoms 
persist despite above measures, decrease dexamethasone 
dose by 1 dose level. 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
≥ Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement along with 
concurrent therapy with H2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite above measures, 
discontinue dexamethasone permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
General disorders 
Edema > Grade 3 (> 30% 
limb discrepancy in 
volume; gross deviation 
from normal anatomic 
contour; limiting self-care 
activities of daily living 
(ADL) 
Hold dexamethasone until symptoms return to baseline.  
Diuretics as needed, and restart dexamethasone at 1 dose 
decrement; if edema persists despite above measures, 
decrease dose another level.  Discontinue dexamethasone 
permanently if symptoms persist despite second 
reduction. 
Psychiatric 
Disorders 
Confusion or mood 
alteration > Grade 2 
(interfering with function ± 
interfering with activities of 
daily living) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement.  If symptoms 
persist despite above measures, reduce by another dose 
decrement. 
Musculoskeletal 
Muscle weakness > Grade 
2 (symptomatic and 
interfering with function ± 
interfering with activities of 
daily living) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement. If weakness 
persists, decrease dose by 1 more dose level.  Discontinue 
dexamethasone permanently if symptoms persist. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ Grade 3 
(fasting glucose > 250 
mg/dL) 
Hold dexamethasone until glucose is < Grade 2 
(< 250 mg/dL) and treat with insulin or other 
hypoglycemic agents as needed.  If uncontrolled despite 
above measures, decrease dose by 1 dose level until ≤ 
Grade 2 (< 250 mg/dL) 
All Other 
Other nonhematologic 
toxicity ≥ Grade 3 felt 
related to dexamethasone 
Hold dexamethasone dose. Resume at 1 dose decrement 
when toxicity has resolved to Grade 2 or less or to 
baseline.  If toxicity recurs, hold dexamethasone dose 
until toxicity has resolved to Grade 2 or less or to baseline 
and resume dexamethasone dose by 1 more dose 
decrement.  If toxicity recurs despite 2 dose decrements, 
discontinue dexamethasone permanently. 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO

&RQGLWLRQV1RW5HTXLULQJ'RVH5HGXFWLRQ
7KHIROORZLQJFRQGLWLRQVDUHH[FHSWLRQVWRWKHDERYHJXLGHOLQHV&DUILO]RPLEDQG
GH[DPHWKDVRQHGRQRWQHHGWREHVNLSSHGRUZLWKGUDZQLQWKHIROORZLQJFDVHV
x *UDGHQDXVHDYRPLWLQJRUGLDUUKHDXQOHVVSHUVLVWLQJPRUHWKDQGD\VDIWHU
DGHTXDWHWUHDWPHQWZLWKDQWLHPHWLFVRUDQWLGLDUUKHDODJHQWV
x *UDGHIDWLJXHXQOHVVSHUVLVWLQJIRU!GD\V
x $Q\JUDGHDQHPLDRUO\PSKRSHQLD
x $ORSHFLD
&21&20,7$170(',&$7,216
$FRQFRPLWDQWPHGLFDWLRQLVGHILQHGDVDQ\SUHVFULSWLRQRURYHUWKHFRXQWHUSUHSDUDWLRQ
LQFOXGLQJYLWDPLQVVXSSOHPHQWVDQG7UDGLWLRQDO&KLQHVH0HGLFLQHV$OOFRQFRPLWDQW
PHGLFDWLRQVPXVWEHUHFRUGHGRQWKHVXEMHFW¶VFDVHUHSRUWIRUP&5)IURPLQIRUPHG
FRQVHQWWRGD\VIROORZLQJWKHODVWGRVHRIVWXG\GUXJRULQLWLDWLRQRIQHZDQWLP\HORPD
WKHUDS\ZKLFKHYHUFRPHVILUVW%ORRGRUEORRGSURGXFWVDUHQRWFRQVLGHUHGFRQFRPLWDQW
PHGLFDWLRQVDQGPXVWEHUHFRUGHGRQWKHDSSURSULDWH&5)

5HTXLUHGDQG2SWLRQDO&RQFRPLWDQW0HGLFDWLRQV
$QWLYLUDO3URSK\OD[LV
9DODF\FORYLURUHTXLYDOHQWDQWLYLUDOLVDUHTXLUHGFRQFRPLWDQWPHGLFDWLRQ
9DODF\FORYLUPJRUDOO\GDLO\RUHTXLYDOHQWDQWLYLUDOVKRXOGFRQWLQXHIRUWKHGXUDWLRQRI
WUHDWPHQW$QWLYLUDOSURSK\OD[LVLVUHFRPPHQGHGWREHLQLWLDWHGDWOHDVWKRXUVEHIRUH
WKHILUVWGRVHRIFDUILO]RPLE
0\FRVWDWLQRURUDOIOXFRQD]ROHWRSUHYHQWRUDOWKUXVKLVRSWLRQDODQGPD\EHJLYHQDWWKH
LQYHVWLJDWRU¶VGLVFUHWLRQ
$OORSXULQRORURWKHUDSSURYHGXULFDFLGORZHULQJDJHQWLQSDWLHQWVDWKLJKULVNIRU7/6GXH
WRKLJKWXPRUEXUGHQPD\EHSUHVFULEHGDWWKHLQYHVWLJDWRU¶VGLVFUHWLRQ*OXFRFRUWLFRLGV
PJRUDOSUHGQLVRQHRUHTXLYDOHQWSHUZHHNDUHSHUPLWWHGIRUQRQPDOLJQDQWFRQGLWLRQV
HJDVWKPDLQIODPPDWRU\ERZHOGLVHDVHHWFDVQHHGHG
6XEMHFWVPD\UHFHLYHDQWLHPHWLFVDQGDQWLGLDUUKHDODJHQWVDVQHFHVVDU\0\HORLGJURZWK
IDFWRUVHJ*&6)PD\EHXVHGLIQHXWURSHQLDRFFXUVLQDFFRUGDQFHZLWK$PHULFDQ


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 43 of 151 
 
Confidential 
12 April  2018 
Society of Clinical Oncology Guidelines (Smith 2006), but should not be given 
prophylactically.  Subjects may receive RBC transfusions, erythropoietic stimulating agents, 
or platelet transfusions if clinically indicated in accordance with institutional guidelines.  
Subjects may receive bisphosphonates. 
Palliative radiation for pain management is permitted with the written approval of the study 
medical monitor or designee. 
8.3.2 
Excluded Concomitant Medications 
Concurrent therapy with a marketed or investigational anticancer therapeutic (including 
steroids at a higher dose than this protocol specifies) or radiation to large marrow reserves for 
either a palliative or therapeutic intent is not allowed.  If a patient requires radiation 
therapy and wishes to remain on study, the radiation plan must be shared and written 
approval of the study medical monitor must be obtained prior to the initiation of 
radiation therapy. Additionally, alternative anticancer therapy including Chinese herbal 
medicine with curative intent (other than that administered in the study), or other 
investigational agents are not allowed prior to confirmed progressive disease (PD). 
8.3.3 
Additional Considerations Regarding Concomitant Medications 
In an in vitro human microsome system, carfilzomib demonstrated direct, time-dependent 
inhibition of cytochrome CYP3A4/5 activity (Yang 2012).  Carfilzomib did not induce 
human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes.  Carfilzomib was 
primarily metabolized via peptidase and epoxide hydrolase activities.  Cytochrome P450–
mediated mechanisms played a minor role in the overall metabolism of carfilzomib.  The PK 
profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome 
P450 inhibitors and inducers.  Carfilzomib showed marginal inhibitory effects on 
P-glycoprotein (P-gp) in a Caco-2 monolayer system, but was determined to be a P-gp 
substrate.  Given that carfilzomib is administrated IV and is extensively metabolized, the PK 
profile of carfilzomib is unlikely to be affected by P-gp inhibitors or inducers. 
A clinical study of 17 subjects using PO midazolam as a CYP3A probe demonstrated that the 
PK of midazolam were unaffected by concomitant carfilzomib administration.  Carfilzomib 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
LVQRWH[SHFWHGWRLQKLELW&<3$DFWLYLWLHVDQGRUDIIHFWWKHH[SRVXUHWR&<3$
VXEVWUDWHV
6$)(7<*8,'$1&()25,19(67,*$7256

,QIXVLRQ5HDFWLRQVDQG$GYHUVH(YHQWV([SHULHQFHG:LWKLQD'D\RI'RVLQJRI
&DUILO]RPLE
7UXHLQIXVLRQUHDFWLRQVKDYHEHHQUHSRUWHGEXWDUHUDUH6KRXOGDQLQIXVLRQUHDFWLRQRFFXU
JOXFRFRUWLFRLGV,9IOXLGVYDVRSUHVVRUVR[\JHQEURQFKRGLODWRUVDQGDFHWDPLQRSKHQDUHWR
EHDYDLODEOHIRULPPHGLDWHXVHDQGLQVWLWXWHGDVPHGLFDOO\LQGLFDWHG$GYHUVHHYHQWVWKDW
KDYHEHHQFRPPRQO\REVHUYHGZLWKLQDGD\RIFDUILO]RPLEDGPLQLVWUDWLRQLQFOXGHPLOGIHYHU
FKLOOVG\VSQHDDQGRUULJRUVRFFXUULQJLQWKHHYHQLQJIROORZLQJWKHILUVWGD\RILQIXVLRQ
GXULQJWKHILUVWF\FOHRIWKHUDS\7KLVFDQEHDVVRFLDWHGZLWKDQLQFUHDVHLQVHUXPFUHDWLQLQH
OHYHORQWKHVXEVHTXHQWGD\5HIHUWRWKH&&6,IRUGHWDLOHGLQIRUPDWLRQ

5HQDO)XQFWLRQ
*UDGHDQGUHYHUVLEOHLQFUHDVHVLQVHUXPFUHDWLQLQHKDYHEHHQUHSRUWHGLQVXEMHFWVWUHDWHG
FDUILO]RPLERQFOLQLFDOWULDOV5HQDOLQVXIILFLHQF\KDVEHHQUHSRUWHGOHVVIUHTXHQWO\,WLVQRW
NQRZQLIWKHUHLVDFOHDUDVVRFLDWLRQEHWZHHQUHQDOIDLOXUHDQGFDUILO]RPLE,Q3KDVH
VWXGLHVFDVHVRIUHQDOIDLOXUHZHUHFRQIRXQGHGE\GRFXPHQWHGRUVXVSHFWHG7/6
VHSVLVLQIHFWLRQVOLJKWFKDLQGLVHDVHDQGGLVHDVHSURJUHVVLRQ5HQDOIXQFWLRQZLOOEH
PRQLWRUHGSULRUWRHDFKGRVH5HIHUWR7DEOHIRUJXLGDQFHUHJDUGLQJGRVHUHGXFWLRQLQ
VXEMHFWVZLWKFRPSURPLVHGUHQDOIXQFWLRQDQGWKH&&6,IRUDGGLWLRQDOGHWDLOV

7XPRU/\VLV6\QGURPH
6XVSHFWHGRUGRFXPHQWHG7/6KDVEHHQREVHUYHGLQVRPHVXEMHFWVWUHDWHGZLWKFDUILO]RPLE
HDUO\LQWKH3KDVHVWXGLHVZKLFKUHVXOWHGLQWKHLQVWLWXWLRQRI7/6SURSK\OD[LVJXLGHOLQHV
6XEMHFWVZLWKKLJKWXPRUEXUGHQRUFRPSURPLVHGUHQDOIXQFWLRQHJ,QWHUQDWLRQDO6WDJLQJ
6\VWHP6WDJH,,,,,RUUDSLGO\LQFUHDVLQJ0SURWHLQRUOLJKWFKDLQVRUFRPSURPLVHGUHQDO
IXQFWLRQ>&U&OP/PLQXWH@PD\EHDWHOHYDWHGULVNDQGPXVWEHFORVHO\PRQLWRUHGDQG
XULFDFLGOHYHOVQRUPDOL]HGSULRUWRLQLWLDWLRQRIWUHDWPHQWLIDSSURSULDWH,QWUDYHQRXV
K\GUDWLRQPXVWEHJLYHQWRDOOVXEMHFWVLQ&\FOHSUHPHGLFDWLRQZLWKDOORSXULQRORURWKHU
DSSURYHGXULFDFLGORZHULQJDJHQWLVRSWLRQDO)ROORZLQJ&\FOHSUHFDUILO]RPLE,9


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 45 of 151 
 
Confidential 
12 April  2018 
hydration is only required if indicated by the subject’s condition and/or risk factors, and the 
reason for hydration must be documented on the CRF.  Refer to the CCSI for detailed 
information. 
8.4.4 
Thrombocytopenia and Neutropenia 
Carfilzomib has been associated with thrombocytopenia.  The thrombocytopenia pattern is 
cyclical with nadirs following the second dose each week and typically recovering prior to 
the initiation of the next treatment, similar to that observed with Bortezomib.  The severity of 
thrombocytopenia is related to the pretreatment platelet counts.  Transfusions may be 
considered.  The incidence of significant bleeding is < 5%.  At minimum, platelet counts are 
to be monitored on Days 1, 8, and 15 of each cycle.  Severe neutropenia has been reported 
and may occur during treatment but is uncommon.  Please refer to dose modification 
recommendations for hematologic toxicity in Table 2.   
8.4.5 
Cardiac Disorders 
Safety data reported from single-arm Phase 2 studies of carfilzomib in heavily pretreated 
subjects has shown acute development or exacerbation of CHF and new onset of decreased 
left ventricular function.  Death due to cardiac arrest has occurred within a day of carfilzomib 
administration (< 1%).  Subjects with risk factors for or evidence of existing heart disease are 
to be closely monitored throughout their treatment with carfilzomib.  A follow-up ECHO is 
to be conducted in patients who develop clinically significant CHF or clinically important 
signs/symptoms indicative of decreased ventricular function.  Carfilzomib must be held if 
CHF develops or appears to be exacerbated by treatment (refer to Table 3), and may be 
resumed once the symptoms resolve.   
Dyspnea may or may not occur in association with cardiac disorders.  Subjects who 
experience dyspnea are to be evaluated for the presence of associated conditions and 
management should be tailored to the appropriate treatment for the underlying disorder.  
Refer to the CCSI for detailed information.  


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 46 of 151 
 
Confidential 
12 April  2018 
8.4.6 
Gastrointestinal Events 
Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation, sometimes 
requiring the use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement is to be 
administered to prevent dehydration.  Routine premedication with medications to treat nausea 
and vomiting is not required.   
8.4.7 
Hepatic Impairment 
Three cases of hepatic failure (including 2 cases that were fatal, with both cases occurring in 
the context of progressive disease [PD]) and 1 case of veno-occlusive disease have been 
reported with the use of carfilzomib at the time of finalization of this protocol, at which time 
more than 2000 subjects have received carfilzomib in Onyx-sponsored studies.  Non-serious 
and serious (Grades 1 to 3) elevations of serum transaminase levels have been reported 
infrequently.  The use of carfilzomib has not been characterized in subjects with moderate or 
severe hepatic impairment.  See Table 3 for dose reduction information related to hepatic 
toxicities.  Refer to the CCSI for detailed information. 
8.4.8 
Pulmonary Events 
Dyspnea was reported in 35% of patients treated on carfilzomib Phase 2 clinical trials, was 
predominantly Grade 1 or Grade 2 in severity, transient, and did not require intervention.  
Grade 3 events occurred in 5% of subjects; no Grade 4 events, and one Grade 5 event was 
reported.  Grade 3 or 4 dyspnea, especially if occurring within a day of carfilzomib dosing, is 
to be evaluated immediately and appropriate medical management given. 
Pulmonary hypertension was reported in 2% of subjects in Phase 2 studies, and was 
≥ Grade 3 in < 1% of subjects.  In most cases, insufficient diagnostic evidence was available 
to definitively confirm the diagnosis of pulmonary hypertension, and the cases reported 
occurred primarily in the context of CHF.  Refer to the CCSI for detailed information. 
8.4.9 
Posterior reversible encephalopathy syndrome 
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in 
patients receiving carfilzomib.  Posterior reversible encephalopathy syndrome is a rare, 
neurological disorder, which can present with seizure, headache, lethargy, confusion, 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 47 of 151 
 
Confidential 
12 April  2018 
blindness, altered consciousness, and other visual and neurological disturbances, along with 
hypertension, and the diagnosis is confirmed by neuro-radiological imaging.  Carfilzomib 
should be discontinued if PRES is suspected. 
8.4.10 
Thrombotic microangiopathy 
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and 
haemolytic uraemic syndrome (TTP/HUS) have been reported in patients who received 
carfilzomib.  Some of these events have been fatal.  Monitor for signs and symptoms of 
TTP/HUS.  If the diagnosis is suspected, treatment should be interrupted. If diagnosis of 
TTP/HUS is excluded, carfilzomib can be restarted.  
8.4.11 
Venous thrombosis 
Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary 
embolism with fatal outcomes, have been reported in patients who received carfilzomib.  
Patients with known risk factors for thromboembolism, including prior thrombosis, should be 
closely monitored.  Action should be taken to try to minimise all modifiable risk factors (e.g., 
smoking, hypertension, and hyperlipidaemia).  Caution should be used in the concomitant 
administration of other agents that may increase the risk of thrombosis (e.g., erythropoietic 
agents or hormone replacement therapy).  Patients and physicians are advised to be observant 
for the signs and symptoms of thromboembolism.  Patients should be instructed to seek 
medical care if they develop symptoms such as shortness of breath, chest pain, haemoptysis, 
arm or leg swelling or pain.  Thromboprophylaxis should be considered based on an 
individual benefit/risk assessment.   
9 
STUDY PROCEDURES 
Study-specific procedures are described below in Section 9.1.  The schedule of study 
assessments is outlined in Section 9.2 and tabulated in Appendix A. 
Appropriate written informed consent must be obtained before any study-specific tests may 
be performed.   


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
'(6&5,37,212)678'<63(&,),&352&('85(6

0HGLFDO+LVWRU\
0HGLFDOKLVWRU\ZLOOLQFOXGHUHFRUGLQJRIVLJQLILFDQWPHGLFDOFRQGLWLRQVSULRUFDQFHU
VXUJHU\UDGLDWLRQWKHUDS\WUDQVSODQWWREDFFRKLVWRU\\HDUVRIWREDFFRXVHSDFNVSHUGD\RI
FLJDUHWWHVDOFRKROKLVWRU\FXUUHQWQXPEHURIDOFRKROLFGULQNVSHUZHHNDQGQHXURSDWK\
KLVWRU\

0XOWLSOH0\HORPD+LVWRU\DQG3ULRU/LQHVRI7KHUDS\$VVHVVPHQW
6XEMHFWVPXVWKDYHFRQILUPHGDQGYHULILDEOHGLDJQRVLVRIPXOWLSOHP\HORPDDQGGRFXPHQWHG
UHODSVHDIWHURUPRUHWKHUDSLHVIRUPXOWLSOHP\HORPD3ULRUWKHUDSLHVPXVWKDYHLQFOXGHG
DQDON\ODWLQJDJHQWRUDQWKUDF\FOLQHERUWH]RPLEDQGDQ,0L':KHQGRFXPHQWLQJSULRU
WKHUDSLHVIRUPXOWLSOHP\HORPDWKHIROORZLQJJXLGHOLQHVVKRXOGEHXVHG
x $QHZOLQHRIWKHUDS\LVFRQVLGHUHGWRVWDUWZKHQDSODQQHGFRXUVHRIWKHUDS\LV
PRGLILHGWRLQFOXGHRWKHUWUHDWPHQWDJHQWVDORQHRULQFRPELQDWLRQDVDUHVXOWRI
ODFNRIDGHTXDWHUHVSRQVH3'HYHQLIWKHOHYHORISURJUHVVLRQKDVQRW\HWPHW
,0:*FULWHULDIRU3'UHODSVHRUWR[LFLW\$QHZWKHUDS\LVDOVRFRQVLGHUHGWRVWDUW
ZKHQDSODQQHGSHULRGRIREVHUYDWLRQRIIWKHUDS\LVLQWHUUXSWHGE\DQHHGIRU
DGGLWLRQDOOLQHVRIWKHUDS\IRUWKHGLVHDVH
x $QLQFUHDVHLQWUHDWPHQWDGPLQLVWUDWLRQZLWKWKHLQWHQWLRQRIUHFDSWXULQJUHVSRQVHLQ
DSDWLHQWZLWKHYLGHQFHRIGLVHDVHSURJUHVVLRQRQWKDWOLQHRIWKHUDS\LVFRQVLGHUHGD
QHZWKHUDS\
([DPSOHVRIDOLQHRIWKHUDS\LQFOXGH
x ,QGXFWLRQWKHUDS\DQGVWHPFHOOWUDQVSODQWIROORZHGE\SODQQHGPDLQWHQDQFHWKHUDS\
SURYLGHGWKHUHLVQRLQWHUYHQLQJ3'
x ,QGXFWLRQWKHUDS\IROORZHGE\PDLQWHQDQFHWKHUDS\SURYLGHGWKHUHLVQRLQWHUYHQLQJ
3'


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 49 of 151 
 
Confidential 
12 April  2018 
Investigators are responsible for maintaining documentation of prior lines of multiple 
myeloma therapy. 
9.1.3 
Vital Signs 
Vital signs will include:  heart rate, blood pressure, respiratory rate, and temperature.  The 
subject should be in a supine position in a rested and calm state for at least 5 minutes before 
blood pressure assessments are conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position possible (this request is 
recommended in all following assessments).  The position selected for a subject should be 
the same that is used throughout the study and documented on the vital signs CRF.  
9.1.4 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group performance status grades and descriptions are 
tabulated in Appendix C.   
9.1.5 
Complete and Routine Physical Examinations 
A complete physical examination should include:  examination of cardiovascular and 
respiratory systems, abdominal examination, neurologic physical exam, weight, BSA, and 
height (height measurement will be performed only at screening physical examination).  
Body surface area is determined by a standard formula such as the Mosteller Formula:  BSA 
(m²) = ([Height (cm) × Weight (kg)]/ 3600)½ (Mosteller 1987).   
A routine physical examination should include examination of cardiovascular and respiratory 
systems. 
9.1.6 
Electrocardiogram 
Twelve-lead electrocardiograms (ECGs) including corrected QT interval (QTc; representing 
the corrected duration of ventricular electrical activity) will be performed.  
Electrocardiograms will be required in all subjects at screening and at the end of treatment 
only.   


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 50 of 151 
 
Confidential 
12 April  2018 
9.1.7 
Echocardiogram 
A 2-D transthoracic ECHO to assess LVEF will be performed at Screening.  If transthoracic 
ECHO is not available, MUGA will be acceptable. 
9.1.8 
Laboratory Evaluation 
Laboratory tests, including hematology, blood chemistries, and coagulation tests will be 
performed as outlined in Section 9.2.1 and 9.2.16 and the Schedule of Assessments 
(Appendix A).  Unscheduled or additional laboratory samples may be collected and analyzed 
if immediate results are necessary for management of treatment emergent AEs or dosing 
determination.   
9.1.8.1 Chemistry 
The chemistry panel to be used is displayed below in Table 6 Chemistry panels will be 
performed at the local laboratory. 
Table 6: Laboratory Tests:  Chemistry Panel 
Chemistry Panel  
Albumin 
Glucose 
Alkaline Phosphatase 
LDH 
ALT 
Magnesium 
AST 
Phosphorus 
Bicarbonate or Total CO2 
Potassium 
BUN 
Sodium 
Calcium 
Total Bilirubin  
Chloride 
Total Protein 
Creatinine 
Uric Acid 
Abbreviations:  ALT= alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea 
nitrogen, LDH = lactate dehydrogenase. 
9.1.8.2 Hematology 
Table 7 displays the hematology tests that will be conducted.  Hematology tests will be 
performed at the local laboratory. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 51 of 151 
 
Confidential 
12 April  2018 
Table 7: Laboratory Tests:  Hematology 
Hematology Panel 
Hemoglobin 
Hematocrit 
WBCs with complete manual or automated differentiala to include: 
• Total neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
RBCs 
Platelet count 
Abbreviations:  RBCs = red blood cells, WBCs = white blood cells. 
a  Absolute or percent counts will be acceptable. 
9.1.8.3 Coagulation Panel 
Coagulation panel will be performed at baseline, at the local laboratory (see Table 8). 
Table 8: Laboratory Tests:  Coagulation Panel 
Coagulation Panel 
PT 
aPTT or PTT 
 INR 
Abbreviations:  PT = Prothrombin time, aPTT = activated partial thromboplastin time, INR = 
international normalized ratio 
9.1.9 
Pregnancy Evaluation and Contraception Considerations 
For FCBPs, a serum pregnancy test that is confirmed negative is required for eligibility.  This 
protocol defines a FCBP as a sexually mature woman who:  1) has not undergone a 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
In addition to the pregnancy test conducted for eligibility, a serum or urine pregnancy test 
must be confirmed negative on Day 1 of each cycle prior to dosing and at end of therapy 
(EOT).  More frequent pregnancy tests may be conducted if required per local regulations.   
Pregnancy testing will be done at the local laboratory. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 52 of 151 
 
Confidential 
12 April  2018 
9.1.10 
Multiple Myeloma Disease Assessments  
9.1.10.1 Plasmacytoma Evaluations 
All subjects are required to have a clinical assessment in consideration of formal 
plasmacytoma evaluation at screening.  Further evaluation for extramedullary plasmacytoma 
evaluation is required at screening only if a lesion is suspected clinically.  The baseline 
plasmacytoma evaluation may consist of palpation, ultrasound, computed tomography (CT) 
scan, magnetic resonance imaging (MRI), or positron emission tomography with diagnostic 
CT (PET/CT). Bone scintigraphy is not an acceptable method of plasmacytoma imaging. 
At baseline, the greatest diameter, and the greatest orthogonal cross diameter must be 
measured.  If an extramedullary plasmacytoma is detected at Screening, imaging evaluation 
must be repeated during treatment only if required to confirm a new response of PR or better, 
a new response of CR or better, or to confirm PD, per the IMWG response criteria 
(Durie, 2006; Rajkumar, 2011) (Appendix E).  The same technique should be employed for 
each measurement of plasmacytoma dimensions.  Bi-dimensional lesion measurements must 
be performed and recorded in the designated CRF. 
 
9.1.10.2 Skeletal Survey 
 
Skeletal survey by plain radiography will include lateral radiograph of the skull, 
anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, 
femora, and humeri. Skeletal survey may be done by X-ray, CT, CT/PET, or MRI.  Bone 
scintigraphy is not an acceptable method of skeletal imaging.   The skeletal survey will be 
conducted at screening and will be repeated if worsening clinical symptoms suggest PD, or 
as clinically indicated. 
 
9.1.10.3 Bone Marrow Aspirate and/or Biopsy 
 
All subjects will have a baseline bone marrow aspirate and/or biopsy done and evaluated 
locally for percent plasma cell involvement.  Multiple myeloma-specific interphase 
Fluorescent In Situ Hybridization (FISH) testing is optional.   


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
$ERQHPDUURZDVSLUDWHDQGRUELRSV\HYDOXDWHGORFDOO\LVUHTXLUHGWRFRQILUPDODERUDWRU\
UHVSRQVHRI&5RUV&5
 'LVHDVH5HVSRQVHDQG3URJUHVVLRQ$VVHVVPHQWV
6XEMHFWVZLOOEHHYDOXDWHGE\WKHLQYHVWLJDWRUIRUGLVHDVHUHVSRQVHDFFRUGLQJWRWKH
,0:*85&DVVHVVPHQWSDUDPHWHUVDVRXWOLQHGLQ$SSHQGL[(RQ'D\RI&\FOHVDQG
KLJKHUWKURXJKWR(27DQGGXULQJ$FWLYH)ROORZXS'XULH5DMNXPDU.XPDU
0LQLPDOUHVSRQVHZLOODOVREHDVVHVVHG.XPDU$SSHQGL[)7KHIROORZLQJ
FOLQLFDOUHVSRQVHDVVHVVPHQWVZLOOEHFRPSOHWHGDWWKHSURWRFROVSHFLILHGWLPHSRLQWV
/DERUDWRU\$VVHVVPHQWVRI'LVHDVH6FUHHQLQJ
$OOVXEMHFWVPXVWKDYH63(3VHUXPLPPXQRIL[DWLRQHOHFWURSKRUHVLV6,)(6)/&EHWD
PLFURJOREXOLQVHUXPFDOFLXPTXDQWLWDWLYHLPPXQRJOREXOLQVDQGKRXUXULQHFROOHFWLRQ
IRU83(3DQGXULQHLPPXQRIL[DWLRQHOHFWURSKRUHVLV8,)(DWEDVHOLQH127(83(3ZLWK
LPPXQRIL[DWLRQRQDKRXUFROOHFWLRQLVUHTXLUHG1RVXEVWLWXWHPHWKRGLVDFFHSWDEOH
,IPXOWLSOHGLVHDVHDVVHVVPHQWPHDVXUHPHQWVDUHDYDLODEOHEHIRUHLQLWLDWLRQRIWKHUDS\
WKHPHDVXUHPHQWFORVHVWWR&\FOH'D\ZLOOEHXVHGDVEDVHOLQH.XPDU
/DERUDWRU\DVVHVVPHQWVRIGLVHDVHOLVWHGDERYHZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\
)RUGHWDLOVRIFROOHFWLRQSOHDVHUHIHUWRWKHVWXG\&HQWUDO/DERUDWRU\0DQXDO
/DERUDWRU\$VVHVVPHQWVRI'LVHDVH±'XULQJ7UHDWPHQW3HULRGDQG$FWLYH
)ROORZ8S
'D\&\FOHVDQG+LJKHU(27DQG$FWLYH)ROORZ8S
x 6HUXP0SURWHLQ6XEMHFWVZLWKVHUXPSRVLWLYHIRU0SURWHLQOHYHOVPHDVXUHGE\63(3
!JG/DWEDVHOLQH±PXVWKDYH63(3DQG6,)(GRQHRQ'D\RIHDFKF\FOHGD\V
IURP&\FOHDQGEH\RQGDW(27DQGGXULQJ$FWLYH)ROORZXS63(3DQG6,)(ZLOOEH
SHUIRUPHGDWWKHFHQWUDOODERUDWRU\
x 8ULQH0SURWHLQ$OOVXEMHFWVPXVWKDYHDKRXUXULQHIRU83(3DQG8,)(GRQHRQ
GD\RIHDFKF\FOHGD\VIURP&\FOHDQGEH\RQGDW(27DQGGXULQJDFWLYH
IROORZXS83(3DQG8,)(ZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\
x 6HUXPDQG8ULQH0SURWHLQ6XEMHFWVZLWKERWKVHUXPDQGXULQHSRVLWLYHIRU0SURWHLQ
OHYHOV!JG/LQVHUXPDQG!PJKRXUVLQXULQHDWEDVHOLQH±PXVWKDYHERWK
63(36,)(DQGDKRXUXULQHIRU83(3DQG8,)(GRQHRQ'D\RIHDFKF\FOH


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
GD\VIURP&\FOHDQGEH\RQGDW(27DQGGXULQJ$FWLYH)ROORZXS7KHVHWHVWV
ZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\
x 6HUXPIUHHOLJKWFKDLQV$OOVXEMHFWVPXVWKDYH6)/&DVVD\GUDZQDW6FUHHQLQJDQG
(276XEMHFWVZLWKJG/VHUXP0SURWHLQDQGPJKRXUVXULQH0SURWHLQDW
EDVHOLQHPXVWKDYH6)/&GUDZQRQGD\RIHDFKF\FOHGD\VIURP&\FOHRQZDUGV
DW(27DQGGXULQJ$FWLYH)ROORZXS6XEMHFWVLQ&5PXVWKDYH6)/&GUDZQ6)/&
WHVWZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\
x 6HUXPFDOFLXPPXVWEHWHVWHGRQDOOVXEMHFWVDWWKHFHQWUDOODERUDWRU\RQGD\GD\V
RI&\FOHVDQGKLJKHUDW(27DQGGXULQJ$FWLYH)ROORZXS
5HVSRQVH$VVHVVPHQWV
,QDGGLWLRQWRWKHDERYHGHVFULEHGDVVHVVPHQWVRIPXOWLSOHP\HORPDGLVHDVHPDUNHUOHYHOVLQ
VHUXPDQGXULQHWKHIROORZLQJUHVSRQVHDVVHVVPHQWVDUHUHTXLUHGWRFRQILUPDOOUHVSRQVH
FDWHJRULHV359*35&5V&505
x 7ZRFRQVHFXWLYHODERUDWRU\DVVHVVPHQWVRI0SURWHLQOHYHOVHUXPDQGRUXULQHGUDZQ
DWDQ\WLPHEHIRUHWKHVWDUWRIQHZRIISURWRFROP\HORPDWKHUDS\1RPLQLPXP
LQWHUYDOLVUHTXLUHGIRU63(36,)(6)/&LWFDQEHGRQHRQWKHVDPHGD\KRZHYHU
WRFRQILUPUHVSRQVHRUSURJUHVVLYHGLVHDVHGLVFUHWHVDPSOHVDUHUHTXLUHGWHVWLQJ
FDQQRWEHEDVHGRQWKHVSOLWWLQJRIDVLQJOHVDPSOH
x $SODVPDF\WRPDHYDOXDWLRQLISUHVHQWDWEDVHOLQHDUHGXFWLRQLQWKHVL]HRI
SODVPDF\WRPDVLVUHTXLUHGWRFRQILUPDQHZUHVSRQVHRI35RUEHWWHUWREHGRQHZLWKLQ
ZHHNVRIILUVWODERUDWRU\HYLGHQFHRI35RUEHWWHU'LVDSSHDUDQFHRISODVPDF\WRPDLV
UHTXLUHGWRFRQILUPDQHZUHVSRQVHRI&5RUEHWWHUWREHGRQHZLWKLQZHHNVRIILUVW
ODERUDWRU\HYLGHQFHRI&5RUEHWWHU
x 1RNQRZQHYLGHQFHRISURJUHVVLYHRUQHZERQHOHVLRQVRQVNHOHWDOVXUYH\LIUDGLRJUDSKLF
VWXGLHVDUHSHUIRUPHGDIWHUEDVHOLQHKRZHYHUUDGLRORJ\H[DPLQDWLRQLVQRWD
VFKHGXOHGDVVHVVPHQWDIWHUEDVHOLQHXQOHVVFOLQLFDOO\LQGLFDWHG
,QDGGLWLRQWKHIROORZLQJDVVHVVPHQWVDUHUHTXLUHGWRFRQILUPD9*35RUEHWWHU
x 8,)(LQVXEMHFWVEHLQJIROORZHGE\VHUXP0SURWHLQRU6)/&HYHQLI83(3DQG8,)(
ZHUHQRWPHDVXUDEOHDWEDVHOLQH7KLVWHVWZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\$
UHSHDWFRQILUPDWRU\8,)(LVUHTXLUHGWRDOORZFODVVLILFDWLRQRIUHVSRQVH


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
,QDGGLWLRQWRDOORIWKHDERYHWKHIROORZLQJDVVHVVPHQWVDUHUHTXLUHGWRFRQILUPD&5RU
V&5
x 6)/&DVVD\DQGFRQILUPDWRU\6)/&$QRUPDOțȜUDWLRLVUHTXLUHGWRFRQILUPDV&5
7KLVWHVWZLOOEHSHUIRUPHGDWWKHFHQWUDOODERUDWRU\
x 6,)(DQG8,)(PXVWEHUHSHDWHGDQGEHQHJDWLYHWRFRQILUP&5RUV&5UHJDUGOHVVRI
WKHOHYHORIEDVHOLQH0SURWHLQLQWKHVHUXPRUXULQH7KHVHWHVWVZLOOEHGRQHDWWKH
FHQWUDOODERUDWRU\
x %RQHPDUURZDVSLUDWHDQGRUELRSV\LVUHTXLUHGWRFRQILUPODERUDWRU\HYLGHQFHRI&5RU
V&5$SSHQGL[(%RQHPDUURZELRSV\PXVWEHGRQHZLWKLQZHHNVRIFRQILUPDWRU\
ODERUDWRU\HYLGHQFHRI&5RUV&5DQGZLOOEHHYDOXDWHGDWWKHORFDOSDWKRORJ\ODERUDWRU\
x 'RFXPHQWGLVDSSHDUDQFHRIDQ\VRIWWLVVXHSODVPDF\WRPDVLISUHVHQWDWEDVHOLQH
3URJUHVVLYH'LVHDVH
3URJUHVVLYHGLVHDVHUHTXLUHVFRQVHFXWLYHODERUDWRU\DVVHVVPHQWVRI0SURWHLQOHYHOEHIRUH
FODVVLILFDWLRQDVUHODSVHRUGLVHDVHSURJUHVVLRQDQGRUWKHLQVWLWXWLRQRIDQ\QHZWKHUDS\
7KHVHWHVWVZLOOEHGRQHDWWKHFHQWUDOODERUDWRU\

$GYHUVH(YHQWV
)RUDOOVXEMHFWVDOO$(VUHJDUGOHVVRIFDXVDOLW\PXVWEHUHFRUGHGLQWKHGHVLJQDWHG&5)
IURPWKHILUVWGRVHRI,3WKURXJKGD\VIROORZLQJWKHODVWGRVHRIDOOVWXG\GUXJVRU
LQLWLDWLRQRIQHZDQWLP\HORPDWKHUDS\ZKLFKHYHUFRPHVILUVW

&RQFRPLWDQW0HGLFDWLRQV
$OOFRQFRPLWDQWPHGLFDWLRQVPXVWEHUHFRUGHGLQWKHGHVLJQDWHG&5)IURPLQIRUPHGFRQVHQW
WRGD\VIROORZLQJWKHODVWGRVHRIDOOVWXG\GUXJVRULQLWLDWLRQRIQHZDQWLP\HORPD
WKHUDS\ZKLFKHYHUFRPHVILUVW

3KDUPDFRNLQHWLF0HDVXUHPHQWV
%ORRGVDPSOHVZLOOEHFROOHFWHGDWVHOHFWHGVLWHVWRPHDVXUHSODVPDFRQFHQWUDWLRQRI
FDUILO]RPLE7KH3.VDPSOLQJWLPHVDUHRXWOLQHGEHORZLQ 7DEOH
1RWH2QGD\VRI3.VDPSOLQJ&\FOH'D\DQG&\FOH'D\FDUILO]RPLEPXVWEH
DGPLQLVWHUHGRYHUPLQXWHV


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
7DEOH %ORRG6DPSOH&ROOHFWLRQIRU3KDUPDFRNLQHWLFV
%ORRG6DPSOH&ROOHFWLRQ
7RPHDVXUHSODVPDFRQFHQWUDWLRQRIFDUILO]RPLE
&\FOH
'D\V
7LPLQJRI6DPSOH&ROOHFWLRQ
DQG

x 3UHGRVHZLWKLQPLQXWHVEHIRUHWKHVWDUWRIFDUILO]RPLELQIXVLRQ
x PLQXWHVSRVWVWDUWRIFDUILO]RPLELQIXVLRQ
x ,PPHGLDWHO\ZLWKLQPLQXWHVEHIRUHWKHHQGRILQIXVLRQ
x $WDQGPLQXWHVPLQXWHVIRUDOOWLPHSRLQWVDQGDQG
KRXUVPLQXWHVIRUDOOWLPHSRLQWVDIWHUWKHHQGRIFDUILO]RPLE
LQIXVLRQ
1RWH&DUILO]RPLEPXVWEHDGPLQLVWHUHGRYHUPLQXWHVRQGD\VRI3.VDPSOLQJ
6&+('8/(2)678'<$66(660(176
6FUHHQLQJDVVHVVPHQWVHOLJLELOLW\WHVWVDQGDOOSURWRFROUHTXLUHGDVVHVVPHQWVDORQJZLWK
WKHLUFKURQRORJ\DUHWDEXODWHGLQ$SSHQGL[$7KHWLPLQJRIDOOVWXG\DVVHVVPHQWVLV
SURYLGHGEHORZLQ6HFWLRQVWKURXJK6HFWLRQ

6FUHHQLQJ$VVHVVPHQWV
7KH6FUHHQLQJSHULRGIRUDSDUWLFXODUVXEMHFWFRPPHQFHVRQFHWKHVXEMHFWVLJQVLQIRUPHG
FRQVHQW$XQLTXHVXEMHFWQXPEHUZLOOEHXVHGWRLGHQWLI\WKHVXEMHFWWKURXJKRXWWKHFOLQLFDO
VWXG\DQGPXVWEHXVHGRQDOOVWXG\GRFXPHQWDWLRQUHODWHGWRWKDWVXEMHFWGDWDIRUVFUHHQ
IDLOXUHVZLOOEHFDSWXUHG
7KHIROORZLQJVFUHHQLQJDVVHVVPHQWVPXVWEHSHUIRUPHGEHWZHHQ'D\V±DQG±
x :ULWWHQLQIRUPHGFRQVHQWWREHVLJQHGEHIRUHDQ\SURWRFROVSHFLILFWHVWVRUSURFHGXUHV
DUHFRQGXFWHG
x 2EWDLQPHGLFDOKLVWRU\LQFOXGLQJSULRUFDQFHUVXUJHU\UDGLRWKHUDS\WUDQVSODQWWREDFFR
KLVWRU\\HDUVRIWREDFFRXVHSDFNVSHUGD\RIFLJDUHWWHVDQGDOFRKROKLVWRU\FXUUHQW
QXPEHURIDOFRKROLFGULQNVSHUZHHNQHXURSDWK\KLVWRU\DQG(&2*
x 'RFXPHQWPXOWLSOHP\HORPDWUHDWPHQWKLVWRU\
x 3HUIRUPFRPSOHWHSK\VLFDOH[DPLQDWLRQLQFOXGLQJQHXURORJLFDVVHVVPHQWDQG
SODVPDF\WRPDDVVHVVPHQW
x 2EWDLQKHLJKWZHLJKWDQG%6$
x 0HDVXUHEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUH


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 57 of 151 
 
Confidential 
12 April  2018 
• Perform 12-lead ECG including QTc interval 
• 2-D ECHO.  Multiple gated acquisition scan is acceptable if ECHO is not available.  
Repeat ECHO only required for subjects who develop clinically significant CHF.  Note:  
Study does not need to be repeated if previously done within 30 days of informed consent 
• Obtain blood sample for chemistry panel (Table 6)  Note:  Tests do not need to be 
repeated if performed prior to informed consent but within 21 days prior to Cycle 1 Day 1  
• Obtain blood sample for hematology panel (Table 7)  Note:  Tests do not need to be 
repeated if performed prior to informed consent but within 21 days prior to Cycle 1 Day 1 
• Obtain blood sample for coagulation tests (PT, aPTT or PTT and INR) (Table 8).  Note:  
Tests do not need to be repeated if performed prior to informed consent but within 21 
days prior to Cycle 1 Day 1 
• Perform serum pregnancy test within 7 days of first dose for FCBP 
• Obtain blood for SPEP, SIFE, SFLC, quantitative immunoglobulins, beta-2 
microglobulin, and serum calcium.  Obtain 24-hour urine sample for UPEP and UIFE and 
urine immunofixation.  NOTE:  UPEP with UIFE (on a 24-hour collection) is required.  
No substitute method is acceptable 
• Perform bone marrow biopsy and/or aspirate, documenting percent plasma cells in the 
marrow.  Performing FISH is preferred but optional.  Note:  Bone marrow assessment 
does not need to be repeated if it is conducted within 30 days of informed consent. 
• Obtain skeletal survey.  Note: skeletal assessment does not need to be repeated if done 
within 30 days of informed consent  
• Record concomitant medications 
• Determine eligibility according to Inclusion/Exclusion criteria (see Section 4) 
9.2.2 
Cycle 1 Days -2 and -1 
• Consider oral hydration for patients with high tumor burden and a risk of TLS.  See 
Section 8.1.1 for additional details.  Antiviral prophylaxis is recommended to be 
initiated at least 24 hours before the first dose of carfilzomib. 
Cycle 1 Day 1 
The following assessments must be completed on Cycle 1 Day 1 (defined as first day of 
dosing): 
• Obtain weight, and BSA 
• Perform physical examination 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing  
• Urine or serum pregnancy test must be confirmed negative prior to Cycle 1 Day 1 dose  


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 58 of 151 
 
Confidential 
12 April  2018 
• Obtain blood sample for chemistry up to 1 day prior to Cycle 1 Day 1 and review results 
prior to carfilzomib dose  
• Obtain blood sample for hematology panel up to 1 day prior to Cycle 1 Day 1 and review 
results prior to carfilzomib dose 
• In subjects participating in the PK sub-study, obtain serial blood samples.  
See Section 9.3 and Appendix B for additional details.   
• Administer IV hydration predose 
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 20 mg/m2 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Administer IV hydration postdose 
• Record AEs 
• Record concomitant medications  
9.2.3 
Cycle 1 Day 2 
The following assessments must be completed on Cycle 1 Day 2: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry  
• Administer IV hydration pre carfilzomib dose  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib dose 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Administer IV hydration postdose 
• Record AEs 
• Record changes in concomitant medications 
9.2.4 
Cycle 1 Day 8 
If 20 mg/m2 carfilzomib is well tolerated (defined as absence of any treatment-related AE 
requiring dose reduction or delay), the dose will be escalated to 27 mg/m2 on Cycle 1 Day 8 
and thereafter. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 59 of 151 
 
Confidential 
12 April  2018 
The following assessments must be completed on Cycle 1 Day 8: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing  
• Obtain blood sample for serum chemistry (review results up to 1 day prior to carfilzomib 
dosing) 
• Obtain blood sample for hematology panel (review results up to 1 day prior to 
carfilzomib dosing) 
• Administer IV hydration predose 
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib dose 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is complete) 
• Administer IV hydration postdose 
• Record AEs 
• Record changes in concomitant medications 
9.2.5 
Cycle 1 Day 9 
The following assessments must be completed on Cycle 1 Day 9: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry  
• Administer IV hydration predose  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib dose 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Administer IV hydration postdose 
• Record AEs 
• Record changes in concomitant medications 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 60 of 151 
 
Confidential 
12 April  2018 
9.2.6 
Cycle 1 Day 15 
The following assessments must be completed on Cycle 1 Day 15: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain blood sample for serum chemistry (review results up to 1 day prior to carfilzomib 
dosing) 
• Obtain blood sample for hematology (review results up to 1 day prior to carfilzomib 
dosing) 
• Administer IV hydration predose  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Administer IV hydration postdose 
• Record AEs 
• Record changes in concomitant medications 
9.2.7 
Cycle 1 Day 16 
The following assessments must be completed on Cycle 1 Day 16: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry  
• Administer IV hydration predose  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate post dose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Administer IV hydration postdose 
• Record AEs 
• Record changes in concomitant medications 
9.2.8 
Cycle 1 Days 22 and 23 
Administer dexamethasone.  Oral dexamethasone may be self-administered at home. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 61 of 151 
 
Confidential 
12 April  2018 
9.2.9 
Cycle 2 (and Higher) Day 1  
Please note that though disease assessment laboratories are drawn on day 1 of each cycle, the 
results of disease assessment labs will not be reported until several days later.  Initiation of a 
cycle may begin while the results of disease assessment laboratories for that cycle are 
pending. 
Response assessments based upon the laboratory results are to be made once the disease 
assessment laboratory results become available, following guidelines in Appendix E.  All 
response assessments require confirmation with 2 consecutive assessments to confirm 
response or progression (Durie, 2006, Rajkumar, 2011; Kumar, 2016). 
The following assessments must be completed on Day 1 of Cycle 2 and higher: 
• Obtain weight and BSA 
• Perform routine physical examination 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Urine or serum pregnancy test must be confirmed negative prior to start of each cycle of 
therapy for FCBP 
• Obtain blood sample for chemistry panel (review results up to 1 day prior to carfilzomib 
dosing)* 
• Obtain blood sample for hematology panel (review results up to 1 day prior to 
carfilzomib dosing) 
• Obtain disease response assessment as outlined in Section 9.1.10.4.2 (± 3-day window, 
response labs must be drawn prior to administration of Kd) 
• If a subject has entered a PR or better or a CR or better, and had a plasmacytoma at 
baseline, a plasmacytoma evaluation (using the modality used at baseline) must be done 
to classify response. 
• If a subject has entered a CR or better, a bone marrow aspirate and/or biopsy is required 
to confirm response 
• In subjects participating in the PK sub-study, obtain serial blood samples (Cycle 2).  
See Section 9.3 and Appendix B for additional details.   
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 62 of 151 
 
Confidential 
12 April  2018 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid is elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 
9.2.10 
Cycle 2 (and Higher) Day 2 
The following assessments must be completed on Day 2 of Cycle 2 and higher: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry*  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 
9.2.11 
Cycle 2 (and Higher) Day 8 
The following assessments must be completed on Day 8 of Cycle 2 and higher: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain blood sample for serum chemistry (review results up to 1 day prior to carfilzomib 
dosing)* 
• Obtain blood sample for hematology panel (review results up to 1 day prior to 
carfilzomib dosing) 
• Administer dexamethasone 30 minutes to 4  hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 63 of 151 
 
Confidential 
12 April  2018 
9.2.12 
Cycle 2 (and Higher) Day 9 
The following assessments must be completed on Day 9 of Cycle 2 and higher: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry*  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood Pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 
9.2.13 
Cycle 2 (and Higher) Day 15 
The following assessments must be completed on Day 15 of Cycle 2 and higher: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain blood sample for serum chemistry (review results up to 1 day prior to carfilzomib 
dosing)* 
• Obtain blood sample for hematology panel (review results up to 1 day prior to 
carfilzomib dosing) 
• Administer dexamethasone 30 minutes to 4  hours prior to carfilzomib  
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 64 of 151 
 
Confidential 
12 April  2018 
9.2.14 
Cycle 2 (and Higher) Day 16 
The following assessments must be completed on Day 16 of Cycle 2 and higher: 
• Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior 
to carfilzomib dosing 
• Obtain optional blood sample for serum chemistry*  
• Administer dexamethasone 30 minutes to 4 hours prior to carfilzomib 
• Administer carfilzomib dose 
• Repeat blood pressure and heart rate postdose (between 5 and 60 minutes after 
carfilzomib infusion is completed) 
• Record AEs 
• Record changes in concomitant medications 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated 
for all of Cycle 2, and, at the investigator’s discretion, in conjunction with subsequent cycles. 
9.2.15 
Cycle 2 (and Higher) Days 22 and 23 
Administer dexamethasone.  Oral dexamethasone may be self-administered at home. 
9.2.16 
End of Treatment Assessment (within 30 days of Treatment discontinuation) 
Patients may withdraw from study treatment at any time.  Reasons for discontinuation 
include:  Adverse event, pregnancy, withdrawal by subject, and progressive disease. 
A patient who develops progressive disease per IMWG-URC (Durie, 2006; 
Rajkumar, 2011; Kumar, 2016) must discontinue study treatment.  Any patient who misses 
more than 6 consecutive weeks of study treatment must discontinue study treatment.  The 
reason for discontinuation of study treatment will be documented in the CRF. 
The following EOT assessments must be completed within 30 days of treatment 
discontinuation and prior to initiation of any new antimyeloma therapy: 
• Obtain weight and ECOG 
• Perform complete physical examination, including neurologic assessment 
• Measure blood pressure, heart rate, respiratory rate, and temperature  
• Urine or serum pregnancy test must be confirmed negative in FCBP  
• Obtain blood sample for chemistry panel  
• Obtain blood sample for hematology panel 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
x 2EWDLQGLVHDVHUHVSRQVHDVVHVVPHQWODEVDVRXWOLQHGLQ6HFWLRQ
x 2EWDLQEHWDPLFURJOREXOLQDQGTXDQWLWDWLYHLPPXQRJOREXOLQV
x 5HFRUG$(V
x 5HFRUGFKDQJHVLQFRQFRPLWDQWPHGLFDWLRQV
x 2EWDLQ(&*DVGHVFULEHGLQ6HFWLRQ
3+$50$&2.,1(7,&6$03/,1*6&+('8/(
%ORRGVDPSOHVZLOOEHFROOHFWHGIURPDVXEVHWRIVXEMHFWVIRU3.DQDO\VLVRQ&\FOH'D\
DQG&\FOH'D\DWWKHIROORZLQJWLPHSRLQWV $SSHQGL[%
x 3UHGRVHZLWKLQPLQXWHVRILQLWLDWLRQRIFDUILO]RPLELQIXVLRQ
x PLQXWHVSRVWVWDUWRIFDUILO]RPLELQIXVLRQ
x ,PPHGLDWHO\ZLWKLQPLQXWHVEHIRUHWKHHQGRIFDUILO]RPLELQIXVLRQ
x $WDQGPLQXWHVPLQXWHVIRUDOOWLPHSRLQWVDQGDQGKRXUV
PLQXWHVIRUDOOWLPHSRLQWVDIWHUWKHHQGRIFDUILO]RPLELQIXVLRQ
)2//2:±839,6,76

$FWLYH)ROORZXS
$OOVXEMHFWVZKRGLVFRQWLQXHVWXG\WUHDWPHQWIRUUHDVRQVRWKHUWKDQ3'ZLOOEHIROORZHGLQ
DFWLYHIROORZXSHYHU\ZHHNVGD\VILUVWYLVLWVKRXOGEHZHHNVDIWHU(27YLVLWIRU
GLVHDVHSURJUHVVLRQXQWLOFRQILUPHG3'ZLWKGUDZDORIFRQVHQWIRUIXUWKHUSDUWLFLSDWLRQORVV
WRIROORZXSLQLWLDWLRQRIQHZQRQSURWRFRODQWLP\HORPDWKHUDS\GHDWKRUVWXG\
FORVXUH'XULQJDFWLYHIROORZXSVXEMHFWVZLOOEHHYDOXDWHGHYHU\ZHHNVGD\V
0XOWLSOHP\HORPDGLVHDVHDVVHVVPHQWZLOOEHSHUIRUPHGZLWKODERUDWRU\HYDOXDWLRQVDV
VSHFLILHGLQ6HFWLRQ3K\VLFDODQGODERUDWRU\DVVHVVPHQWVZLOOEHSHUIRUPHGDV
FOLQLFDOO\LQGLFDWHG


/RQJ7HUP6XUYLYDO)ROORZXS
$IWHUGLVHDVHSURJUHVVLRQ RULQLWLDWLRQRIQHZQRQSURWRFRODQWLP\HORPDWKHUDS\
VXEMHFWVZLOOEHIROORZHGHYHU\PRQWKVZHHNVIRUVXUYLYDOIRUXSWR\HDUVIURPVWDUW


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 66 of 151 
 
Confidential 
12 April  2018 
of study treatment, or until the subject has withdrawn consent for further participation, is lost 
to follow up, has died, or the sponsor makes the decision to close the study. 
10 STUDY DISCONTINUATION 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or 
is unable to continue further study participation.  Subject data up to withdrawal of 
consent will be included in the analysis of the study, and where permitted, publically 
available data can be included after withdrawal of consent.  The investigator is to 
discuss with the subject appropriate procedures for withdrawal from the study, and 
must document the subject’s decision to withdraw in the subject’s medical records.  
Subjects who withdraw from treatment will be monitored for AEs as described in Section 11 
and Appendix D (National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI-CTCAE], version 4.03).    
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly. 
Subjects may withdraw from the study at any time.   
The sponsor may elect to discontinue the study at any time. 
The investigator may discontinue study treatment for any of the following reasons: 
• Disease progression (PD must be verified with 1 set of confirmatory labs  
• Unacceptable toxicity 
• Subject noncompliance with study procedures, including use of non-protocol therapies 
• Requirement for alternative therapy 
• Intercurrent illness or worsening of a chronic condition 
Subjects who discontinue therapy will be followed for survival and disease status 
(if discontinuation is prior to progression). 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
,IWKHUHDVRQIRUZLWKGUDZDOLVDQ$(WKHVXEMHFWZLOOEHIROORZHGE\WKHLQYHVWLJDWRUDV
GHVFULEHGLQ6HFWLRQXQWLOVXFKHYHQWVUHVROYHVWDELOL]HDQGDFFRUGLQJWRWKH
LQYHVWLJDWRU¶VMXGJPHQWWKHUHLVQRQHHGIRUIXUWKHUVDIHW\IROORZXS
,IDVXEMHFWLVZLWKGUDZQIRU3'WKHGDWHRIWKHODERUDWRU\WHVWRUSURFHGXUHLQGLFDWLQJ
GLVHDVHSURJUHVVLRQZLOOEHXVHGDVWKHGDWHRI3'
5HDVRQVIRUFRPSOHWHZLWKGUDZDOIURPWKHVWXG\WUHDWPHQWDQGDOOIROORZXSEHIRUH
GRFXPHQWDWLRQRIVXEMHFWGHDWKLQFOXGH
x :LWKGUDZDORIFRQVHQWE\VXEMHFWIRUDOOVWXG\SURFHGXUHV
x /RVWWRIROORZXS
x 6SRQVRUGHFLVLRQWRWHUPLQDWHWKHVWXG\
 $'9(56((9(176$1'6(5,286$'9(56((9(176
$'9(56((9(175(3257,1*

'HILQLWLRQV
$Q$(LVDQ\XQWRZDUGPHGLFDORFFXUUHQFHLQDVWXG\VXEMHFWDGPLQLVWHUHGDQLQYHVWLJDWLRQDO
SURGXFWVUHJDUGOHVVRIWKHFDXVDOUHODWLRQVKLSZLWKWUHDWPHQW
$Q$(WKHUHIRUHFDQEHDQ\XQIDYRUDEOHDQGXQLQWHQGHGVLJQLQFOXGLQJODERUDWRU\ILQGLQJ
V\PSWRPRUGLVHDVHWHPSRUDOO\DVVRFLDWHGZLWKSDUWLFLSDWLRQLQDQLQYHVWLJDWLRQDOVWXG\
ZKHWKHURUQRWFRQVLGHUHGGUXJUHODWHG,QDGGLWLRQWRQHZHYHQWVDQ\LQFUHDVHLQWKH
VHYHULW\RUIUHTXHQF\RIDSUHH[LVWLQJFRQGLWLRQWKDWRFFXUVDIWHUWKHVXEMHFWUHFHLYHVWKHILUVW
GRVHRIFDUILO]RPLELVFRQVLGHUHGDQ$(7KLVLQFOXGHVDQ\VLGHHIIHFWLQMXU\WR[LFLW\RU
VHQVLWLYLW\UHDFWLRQ$OOUHSRUWHG$(VZLOOEHFRGHGXVLQJWKHFXUUHQWYHUVLRQRI0HGLFDO
'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$
:KHQHYHUSRVVLEOHWKH1&,&7&$(YHUVLRQVKRXOGEHXVHGWRGHVFULEHWKHHYHQWDQG
IRUDVVHVVLQJWKHVHYHULW\RI$(V)RU$(VQRWDGHTXDWHO\DGGUHVVHGLQWKH1&,&7&$(
YHUVLRQ7DEOHEHORZVKRXOGEHXVHG


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
7DEOH 7R[LFLW\*UDGLQJIRU$GYHUVH(YHQWV1RW&RYHUHGLQWKH1&,&7&$(
9HUVLRQ
6HYHULW\
'HVFULSWLRQ
*5$'(±0LOG
$V\PSWRPDWLFRUPLOGV\PSWRPVFOLQLFDORUGLDJQRVWLFREVHUYDWLRQV
RQO\LQWHUYHQWLRQQRWLQGLFDWHG
*5$'(±0RGHUDWH
0LQLPDOORFDORUQRQLQYDVLYHLQWHUYHQWLRQLQGLFDWHGOLPLWLQJ
DJHDSSURSULDWHLQVWUXPHQWDODFWLYLWLHVRIGDLO\OLYLQJ$'/
*5$'(±6HYHUH
0HGLFDOO\VLJQLILFDQWEXWQRWLPPHGLDWHO\OLIHWKUHDWHQLQJ
KRVSLWDOL]DWLRQRUSURORQJDWLRQRIKRVSLWDOL]DWLRQLQGLFDWHG
GLVDEOLQJOLPLWLQJVHOIFDUH$'/
*5$'(±/LIHWKUHDWHQLQJ
/LIHWKUHDWHQLQJFRQVHTXHQFHVXUJHQWLQWHUYHQWLRQLQGLFDWHG
*5$'(±)DWDO
'HDWK
$Q$(RUVXVSHFWHGDGYHUVHUHDFWLRQLVFRQVLGHUHG³XQH[SHFWHG´LILWLVQRWOLVWHGLQWKH
FXUUHQW&&6,RUSUHVFULELQJLQIRUPDWLRQIRUDPDUNHWHGFRPSRXQGRULVQRWOLVWHGDWWKH
VSHFLILFLW\RUVHYHULW\WKDWKDVEHHQREVHUYHG$GYHUVHHYHQWVRUVXVSHFWHGDGYHUVHUHDFWLRQV
WKDWDUHPHQWLRQHGLQWKH&&6,DVRFFXUULQJZLWKDFODVVRIGUXJVRUDVDQWLFLSDWHGIURPWKH
SKDUPDFRORJLFDOSURSHUWLHVRIWKHGUXJEXWDUHQRWVSHFLILFDOO\PHQWLRQHGDVRFFXUULQJZLWK
SDUWLFXODUVWXG\GUXJDUHFRQVLGHUHG³XQH[SHFWHG´)RUH[DPSOHDQHYHQWPRUHVSHFLILFRU
PRUHVHYHUHWKDQGHVFULEHGLQWKH&&6,ZRXOGEHFRQVLGHUHG³XQH[SHFWHG´$Q\FRQGLWLRQ
ODERUDWRU\DEQRUPDOLW\RUSK\VLFDOILQGLQJZLWKDQRQVHWGDWHSULRUWRWKHVXEMHFWUHFHLYLQJ
WKHILUVWGRVHRIFDUILO]RPLELVFRQVLGHUHGWREHSUHH[LVWLQJLQQDWXUHDQGSDUWRIWKHVXEMHFW¶V
PHGLFDOKLVWRU\
$EQRUPDOODERUDWRU\ILQGLQJVVKRXOGEHUHSRUWHGDV$(VLIPHGLFDOLQWHUYHQWLRQRUFRUUHFWLYH
DFWLRQHJWUDQVIXVLRQVLQLWLDWLRQRIDQWLELRWLFVRURWKHUWUHDWPHQWUHJLPHQVK\GUDWLRQ
VWXG\GUXJSODFHGRQKROGLVUHTXLUHGRUWKHHYHQWLVGHHPHGFOLQLFDOO\VLJQLILFDQWE\WKH
WUHDWLQJSK\VLFLDQ
&$86$/,7<
$VXVSHFWHGDGYHUVHUHDFWLRQPHDQVDQ\$(IRUZKLFKWKHUHLVUHDVRQDEOHSRVVLELOLW\WKDW
FDUILO]RPLERUGH[DPHWKDVRQHFDXVHGWKH$(³5HDVRQDEOHSRVVLELOLW\´PHDQVWKDWWKHUHLV
HYLGHQFHWRVXJJHVWDFDXVDOUHODWLRQVKLSEHWZHHQWKHGUXJDQGWKH$($QDGYHUVHUHDFWLRQ
PHDQVDQ\$(FDXVHGE\DGUXJ7KHUHODWLRQVKLSRIWKH$(WRWKHVWXG\GUXJVKRXOG
DVVHVVHGXVLQJWKHIROORZLQJFULWHULD


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
<(67KHHYHQWLVVXVSHFWHGWREHUHODWHGLI
x 7KHUHLVDFOLQLFDOO\SODXVLEOHWLPHVHTXHQFHEHWZHHQWKH$(RQVHWDQGDGPLQLVWUDWLRQRI
VWXG\WUHDWPHQWDQGRU
x 7KHUHLVDELRORJLFDOO\SODXVLEOHPHFKDQLVPIRUWKHVWXG\WUHDWPHQWWRFDXVHRUFRQWULEXWH
WRWKH$(DQGRU
x 7KHHYHQWLPSURYHVRUGLPLQLVKHVXSRQZLWKGUDZDORIWKHVWXG\GUXJZLWKRXWWKH
LQLWLDWLRQRIDQ\VSHFLILFWUHDWPHQWIRUWKHHYHQWGHFKDOOHQJHDQGRUUHFXUVRUZRUVHQV
ZLWKUHFKDOOHQJHZKHQFOLQLFDOO\IHDVLEOHDQGRU
x 7KH$(FDQQRWEHUHDVRQDEO\DWWULEXWHGWRFRQFXUUHQWRUXQGHUO\LQJLOOQHVVRWKHUGUXJV
RUSURFHGXUHV
127KHHYHQWLVQRWVXVSHFWHGWREHUHODWHGLI
x 7KH$(LVPRUHOLNHO\WREHH[SODLQHGE\WKHVXEMHFW¶VFOLQLFDOVWDWHXQGHUO\LQJGLVHDVH
FRQFRPLWDQWPHGLFDOVWXG\RUQRQVWXG\SURFHGXUHDQGRU
x 7KHWLPHRFFXUUHQFHRIWKH$(LVQRWUHDVRQDEO\UHODWHGWRDGPLQLVWUDWLRQRIVWXG\
WUHDWPHQWDQGRU
x 7KHHYHQWLVQRWUHODWHGWRWKHLQYHVWLJDWLRQDOSURGXFWV
$'9(56((9(1765(3257,1*352&('85(6

*HQHUDO
$OO$(VHJDQ\QHZHYHQWRUZRUVHQLQJLQVHYHULW\RUIUHTXHQF\RIDSUHH[LVWLQJ
FRQGLWLRQRUODERUDWRU\ILQGLQJZLWKDQRQVHWGDWHDIWHUWKHVXEMHFWUHFHLYHVWKHILUVWGRVHRI
FDUILO]RPLEPXVWEHSURPSWO\GRFXPHQWHGRQWKH$(&5)'HWDLOVRIWKHHYHQWPXVWLQFOXGH
VHYHULW\UHODWLRQVKLSWRVWXG\GUXJVGXUDWLRQDFWLRQWDNHQDQGRXWFRPH:KHQHYHU
SRVVLEOHUHSRUWLQJVSHFLILFGLDJQRVLVLVSUHIHUUHGZKHQUHSRUWLQJ$(VLQWKH$(&5)UDWKHU
WKDQUHSRUWLQJLQGLYLGXDOVLJQVDQGV\PSWRPV
$OO$(VZLOOEHFROOHFWHGIURPWKHWLPHWKHVXEMHFWUHFHLYHVWKHILUVWGRVHRIFDUILO]RPLE
WKURXJKGD\VDIWHUUHFHLYLQJWKHODVWGRVHRIFDUILO]RPLERUXQWLOLQLWLDWLRQRIDQHZ
DQWLFDQFHUWKHUDS\DIWHUUHFHLYLQJWKHODVWGRVHRIFDUILO]RPLEZKLFKHYHUFRPHVILUVW,I
LQLWLDWLRQRIQHZDQWLFDQFHUWKHUDS\RFFXUVZLWKLQGD\VIROORZLQJWKHODVWGRVHRIVWXG\
GUXJVWKHGDWHRIQHZDQWLFDQFHUWKHUDS\ZLOOEHUHFRUGHGRQWKHDSSURSULDWH&5)
7KHLQYHVWLJDWRUPXVWDVVHVVZKHWKHUWKH$(LVSRVVLEO\UHODWHGWRFDUILO]RPLERUWR
GH[DPHWKDVRQH7KLVUHODWLRQVKLSLVLQGLFDWHGE\D³\HV´RU³QR´UHVSRQVHWRWKHTXHVWLRQ


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 70 of 151 
 
Confidential 
12 April  2018 
“Is there a reasonable possibility that the event may have been caused by a study 
activity/procedure”?  Please refer to Section 11.2 for causality assessment. 
All AE severity changes will be recorded on the AE CRF as separate events.  
All AEs that are considered related to study drug and all serious adverse events (SAEs) 
regardless of relationship to study drug must be followed to resolution or stabilization if 
improvement is not expected.  Adverse events which completely resolve and then recur 
should be recorded as a new AE.  For subjects who complete the EOT visit less than 30 days 
following the last dose of study drug, a follow-up of ongoing AEs should be attempted by 
telephone and documented in the subject’s source file.  Adverse events continuing at 30 days 
after the last dose of study treatment should have a comment in the source file by the 
investigator that the event has stabilized or is not expected to improve. 
The investigator is responsible for evaluating all AEs, obtaining supporting source 
documents, and determining that documentation of the event is adequate.  The investigator 
may delegate these duties to sub-investigators and must ensure that these sub-investigators 
are qualified to perform these duties under the supervision of the investigator. 
11.3.2 
Disease Progression 
Discontinuation of treatment due to progression of disease should be recorded on the 
treatment discontinuation CRF as “Disease Progression.”  Disease progression will be 
documented in an eCRF intended to capture PD information and will be analyzed as a 
study endpoint. Signs and symptoms related to disease progression (eg, pathologic 
fracture in a subject with progressive multiple myeloma) should be reported in the 
appropriate eCRF as an AE or as an SAE (if the event in question meets the criteria for 
seriousness). Verbatim terms such as “disease progression,” “progressive disease,” etc. 
should not be reported as AEs or SAEs unless the investigator considers the progression 
to be atypical, accelerated, or caused by the study drug. Similarly deaths occurring as a 
result of disease progression should be reported on the eCRF intended to capture death 
information and should not be reported as SAEs. Additional details of the event (such as 
the contributory causes of death) should be reported on the Death CRF. 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
6(5,286$'9(56((9(176'(),1,7,216
$Q6$(LVDQ$(WKDWPHHWVRQHRUPRUHRIWKHIROORZLQJFULWHULD
x 'HDWK
x /LIHWKUHDWHQLQJH[SHULHQFHGHILQHGDVDQ\DGYHUVHH[SHULHQFHWKDWSODFHVWKHVXEMHFWLQ
WKHYLHZRIWKHVSRQVRURULQYHVWLJDWRUDWLPPHGLDWHULVNRIGHDWKDWWKHWLPHRI
RFFXUUHQFHLHLWGRHVQRWLQFOXGHDUHDFWLRQWKDWKDGLWRFFXUUHGLQDPRUHVHYHUHIRUP
PLJKWKDYHFDXVHGGHDWK
x 5HTXLUHVLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIDQH[LVWLQJKRVSLWDOL]DWLRQH[FHSW
VFKHGXOHGKRVSLWDOL]DWLRQVIRUDQRQDFXWHXQUHODWHGFDXVHVXFKDVHOHFWLYHVXUJHU\
x 5HVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\LHVXEVWDQWLDOGLVUXSWLRQLQD
VXEMHFW¶VDELOLW\WRFRQGXFWQRUPDODFWLYLWLHVRIGDLO\OLYLQJ
x ,VDFRQJHQLWDODQRPDO\ELUWKGHIHFWLQWKHRIIVSULQJRIDQH[SRVHGIHPDOHVXEMHFWRU
RIIVSULQJRIDIHPDOHSDUWQHURIDPDOHVXEMHFW
x ,PSRUWDQWPHGLFDOHYHQWVWKDWPD\QRWUHVXOWLQGHDWKEHOLIHWKUHDWHQLQJRUUHTXLUH
KRVSLWDOL]DWLRQPD\EHFRQVLGHUHGD6$(ZKHQEDVHGXSRQDSSURSULDWHPHGLFDO
MXGJPHQWMHRSDUGL]HVWKHVXEMHFWDQGPD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWR
SUHYHQWRQHRIWKHRXWFRPHVOLVWHGLQWKLVGHILQLWLRQ
6(5,286$'9(56((9(175(3257,1*$1''2&80(17$7,21
5(48,5(0(176
7KHLQYHVWLJDWRULVUHVSRQVLEOHIRUHQVXULQJWKDWDOO6$(VREVHUYHGE\WKHLQYHVWLJDWRURU
REVHUYHGE\WKHVXEMHFWWKDWRFFXUDIWHUVLJQLQJWKH,&)WKURXJKGD\VDIWHUWKHODVWGRVHRI
FDUILO]RPLERULQLWLDWLRQRIQHZDQWLP\HORPDWKHUDS\DUHUHFRUGHGLQWKHVXEMHFWV¶
PHGLFDOUHFRUGDQGDUHUHSRUWHGWRWKHVSRQVRU
6SRQVRU*OREDO3DWLHQW6DIHW\PXVWEHQRWLILHGRIWKHRFFXUUHQFHRIDQ\6$(ZLWKLQKRXUV
RIWKHLQYHVWLJDWRUGHVLJQHHRUVLWHSHUVRQQHO¶VNQRZOHGJHRIWKHHYHQW7KH6$(ZLOOEH
UHSRUWHGE\FRPSOHWLQJDQGVXEPLWWLQJWKH6$(UHSRUWIRUP6HH$SSHQGL[-IRUWKH6$(
FRQWLQJHQF\IRUPLQWKHHYHQWWKDWHOHFWURQLFGDWDFDSWXUH('&LVXQDYDLODEOH3OHDVHUHIHU
WRWKH6$(5HSRUWLQJ*XLGHOLQHVLQWKHVWXG\UHIHUHQFHPDQXDO
1HZLQIRUPDWLRQUHODWLQJWRDSUHYLRXVO\UHSRUWHG6$(PXVWEHVXEPLWWHGWRWKHVSRQVRU
$OOQHZLQIRUPDWLRQIRU6$(VPXVWEHVHQWWRVSRQVRU*OREDO3DWLHQW6DIHW\ZLWKLQKRXUV
IROORZLQJNQRZOHGJHRIWKHQHZLQIRUPDWLRQ7KHLQYHVWLJDWRUPD\EHDVNHGWRSURYLGH
DGGLWLRQDOIROORZXSLQIRUPDWLRQZKLFKPD\LQFOXGHDGLVFKDUJHVXPPDU\RUH[WUDFWVIURP


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
WKHPHGLFDOUHFRUG,QIRUPDWLRQSURYLGHGDERXWWKH6$(PXVWEHFRQVLVWHQWZLWKWKDW
UHFRUGHGRQWKH(YHQW&5)
7KHUHLVQRUHTXLUHPHQWWRPRQLWRUVWXG\VXEMHFWVIRU6$(VIROORZLQJWKHSURWRFROUHTXLUHG
UHSRUWLQJSHULRGRUDIWHUWKHHQGRIVWXG\+RZHYHUWKHVH6$(VFDQEHUHSRUWHGWRWKH
VSRQVRULILQYHVWLJDWRUVEHFRPHDZDUHRIVXFKHYHQWV,I6$(VDUHUHSRUWHGWKHLQYHVWLJDWRU
LVWRUHSRUWWKHPWR6SRQVRU*OREDO3DWLHQW6DIHW\ZLWKLQKRXUVIROORZLQJWKH
LQYHVWLJDWRU¶VNQRZOHGJHRIWKHHYHQW
6HULRXVDGYHUVHHYHQWVUHSRUWHGRXWVLGHRIWKHSURWRFROUHTXLUHGUHSRUWLQJSHULRGZLOOEH
FDSWXUHGZLWKLQWKHVDIHW\GDWDEDVHDVFOLQLFDOWULDOFDVHVIRUWKHSXUSRVHVRIH[SHGLWHG
UHSRUWLQJ
7KHLQYHVWLJDWRUPXVWDVVHVVZKHWKHUWKH6$(LVSRVVLEO\UHODWHGWRDQ\VWXG\PDQGDWHG
DFWLYLW\RUSURFHGXUH7KHUHODWLRQVKLSLVLQGLFDWHGE\D³\HV´RU³QR´UHVSRQVHWRWKH
TXHVWLRQ³,VWKHUHDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWPD\KDYHEHHQFDXVHGE\DVWXG\
DFWLYLW\SURFHGXUH´"
7KHLQYHVWLJDWRULVUHVSRQVLEOHIRUQRWLI\LQJWKH,QVWLWXWLRQDO5HYLHZ%RDUG,5%RU
,QGHSHQGHQW(WKLFV&RPPLWWHHV,(&LQDFFRUGDQFHZLWKORFDOUHJXODWLRQVRIDOO6$(V
7KHVSRQVRUPD\UHTXHVWDGGLWLRQDOVRXUFHGRFXPHQWDWLRQSHUWDLQLQJWRWKH6$(IURPWKH
LQYHVWLJDWLRQDOVLWH,IDVXEMHFWLVSHUPDQHQWO\ZLWKGUDZQIURPWKHVWXG\GXHWRD6$(WKLV
LQIRUPDWLRQPXVWEHLQFOXGHGLQWKH(YHQW&5)
7KHVSRQVRULVUHVSRQVLEOHIRUQRWLI\LQJWKHDSSURSULDWHJOREDOKHDOWKDXWKRULWLHVRI6$(V
ZKHQUHTXLUHGDQGLQDFFRUGDQFHZLWKDSSOLFDEOHODZVDQGUHJXODWLRQV
35(*1$1&<$1'%5($67)((',1*5(3257,1*
3UHJQDQF\RFFXUULQJLQDIHPDOHVXEMHFWZKLOHHQUROOHGLQWKLVWULDOWKURXJKGD\VDIWHUWKH
ODVWGRVHRIFDUILO]RPLEUHFHLYHGRULQDPDOHVXEMHFW¶VSDUWQHUZKLOHHQUROOHGLQWKLVFOLQLFDO
WULDOWKURXJKGD\VDIWHUWKHODVWGRVHRIFDUILO]RPLEUHFHLYHGDOWKRXJKQRWFRQVLGHUHGDQ
6$(PXVWEHUHSRUWHGWR6SRQVRU*OREDO3DWLHQW6DIHW\ZLWKLQKRXUVRIWKHLQYHVWLJDWRU
GHVLJQHHRUVLWHSHUVRQQHOOHDUQLQJRIWKHHYHQWRQD3UHJQDQF\1RWLILFDWLRQ:RUNVKHHW


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
$SSHQGL[,,IWKHVXEMHFWLVSUHJQDQWDOOVWXG\WUHDWPHQWPXVWEHGLVFRQWLQXHG
LPPHGLDWHO\DQGWKHSUHJQDQF\PXVWEHUHSRUWHGWRWKHLQYHVWLJDWRUZLWKLQKRXUV7KH
VSRQVRUZLOOUHTXHVWFRQVHQWWRREWDLQSUHJQDQF\DQGELUWKRXWFRPHLQIRUPDWLRQ
,QWKHHYHQWRIDSUHJQDQF\LQWKHSDUWQHURIDPDOHVXEMHFWWKHSUHJQDQWSDUWQHUZLOOEH
DVNHGWRFRPSOHWHDQLQIRUPHGFRQVHQWDXWKRUL]DWLRQIRUPIRUWKHSUHJQDQWSDUWQHUSULRUWR
WKHFROOHFWLRQRIDQ\SUHJQDQF\GDWD
,IWKHRXWFRPHRIWKHSUHJQDQF\PHHWVDQ6$(FULWHULRQHJVSRQWDQHRXVDERUWLRQ
VWLOOELUWKQHRQDWDOGHDWKRUIHWDORUQHRQDWDOFRQJHQLWDODQRPDO\WKHLQYHVWLJDWRUZLOOUHSRUW
WKH6$(WKURXJKWKHXVXDOSURFHVVHV
,IDIHPDOHVXEMHFWEUHDVWIHHGVZKLOHWDNLQJFDUILO]RPLEUHSRUWWKHODFWDWLRQFDVHWR6SRQVRU
*OREDO3DWLHQW6DIHW\ZLWKLQKRXUVRIWKHLQYHVWLJDWRU¶VNQRZOHGJHRIWKHHYHQW5HSRUWD
ODFWDWLRQFDVHRQWKH/DFWDWLRQ1RWLILFDWLRQ:RUNVKHHW$SSHQGL[,7KHVSRQVRUZLOO
UHTXHVWDXWKRUL]DWLRQWRREWDLQKHDOWKLQIRUPDWLRQIRUERWKWKHPRWKHUDQGWKHLQIDQW
 67$7,67,&$/&216,'(5$7,216
7KLVVHFWLRQGHVFULEHVWKHVWDWLVWLFDODQDO\VLVWKDWZLOOEHHPSOR\HGIRUDVVHVVLQJHDFKRIWKH
HIILFDF\DQGVDIHW\HQGSRLQWVFRQVLGHUHGLQWKHWULDO6SHFLILFVRIWKHDQDO\VHVZLOOEH
SURYLGHGLQWKH6WDWLVWLFDO$QDO\VLV3ODQ6$3$Q\RWKHUFKDQJHVPDGHWRWKHSODQQHG
DQDO\VHVDIWHUWKHSURWRFRODQG6$3KDYHEHHQILQDOL]HGDORQJZLWKDQH[SODQDWLRQDVWR
ZKHQDQGZK\WKH\RFFXUUHGZLOOEHGHVFULEHGLQWKH&OLQLFDO6WXG\5HSRUWLQZKLFKDQ\
SRVWKRFH[SORUDWRU\DQDO\VHVDOVRZLOOEHFOHDUO\LGHQWLILHG
678'<(1'32,176

3ULPDU\(QGSRLQW
7KHSULPDU\HQGSRLQWRIWKLVVWXG\LV
x 2YHUDOOUHVSRQVHUDWHDIWHUDWOHDVWF\FOHVRI.GEDVHGRQEHVWUHVSRQVHDVVHVVPHQWE\
WKH,5&
x 7KH255LVGHILQHGDVWKHSURSRUWLRQRIVXEMHFWVZLWKDEHVWRYHUDOOUHVSRQVHSHU
,0:*85&FULWHULD'XULH5DMNXPDU.XPDU$SSHQGL[(RI
V&5&59*35RU35


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 74 of 151 
 
Confidential 
12 April  2018 
12.1.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
• ORR after at least 6 cycles of Kd based on response assessed by the investigator 
• ORR after at least 12 cycles of Kd based on both investigator and IRC assessment of best 
response 
• CBR after at least 6 cycles and after at least 12 cycles, based on IRC and investigator 
assessments of best response.  Clinical benefit rate is defined as the proportion of subjects 
with the best overall response of MR or better (Durie, 2006; Rajkumar 2011; Kumar, 
2016) (Appendix E and Appendix F) 
• Duration of response, defined as the time from first evidence of PR or better to disease 
progression or death due to any cause based on both investigator and IRC response 
assessments 
• Duration of clinical benefit, defined as the time from first evidence of MR or better to 
disease progression or death due to any cause based on both investigator and IRC 
response assessments 
• Progression-free survival, defined as the time from first dose to the earlier of disease 
progression or death due to any cause based on both investigator and IRC response 
assessments 
• Overall survival, defined as the time from first dose to the date of death (due to 
any cause) 
• Time to response, defined as the time from the start of study treatment until the start of 
the first confirmed response (PR or greater) based on both investigator and IRC response 
assessments 
• Pharmacokinetics of carfilzomib 
12.1.3 
Exploratory Endpoints: 
Efficacy endpoints related to response and disease progression will be determined based 
on a validated computer algorithm (ORCA) are: 
• ORR after at least 6 cycles of Kd and after at least 12 cycles 
• CBR after at least 6 cycles and after at least 12 cycles 
• Duration of response 
• Duration of clinical benefit 
• Progression-free survival  
• Time to response 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 75 of 151 
 
Confidential 
12 April  2018 
 DETERMINATION OF SAMPLE SIZE 
CCI
This study will enroll approximately 120 subjects with relapsed and refractory multiple 
myeloma.CCI
CCI


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 76 of 151 
 
Confidential 
12 April  2018 
 ANALYSIS POPULATION 
The Safety Population is defined as all enrolled patients who received at least 1 dose of 
carfilzomib.  The Safety Population will be the primary population for all efficacy and safety 
data presented.   
 PLANNED ANALYSES 
12.4.1 Primary Analysis 
Primary analysis will be performed when all of the enrolled subjects have received at least 
6 cycles of Kd or have discontinued treatment with Kd. 
12.4.2 Final Analysis 
Final analysis will be performed when all of the enrolled subjects have received at least 
CCI
12 cycles of Kd or have discontinued the treatment with Kd.   


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
6WXG\WUHDWPHQWVZLOOEHDGPLQLVWHUHGXQWLOGLVHDVHSURJUHVVLRQXQDFFHSWDEOHWR[LFLW\RU
GLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWIRUDQ\RWKHUUHDVRQZKLFKHYHURFFXUVILUVW'RVH
UHGXFWLRQVRIFDUILO]RPLEDQGGH[DPHWKDVRQHZLOOEHSHUPLWWHGSHUSURWRFROJXLGHOLQHV
8SRQGLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWIRUUHDVRQVRWKHUWKDQGLVHDVHSURJUHVVLRQVXEMHFWV
ZLOOEHIROORZHGDVGHVFULEHGLQ6HFWLRQ
$IWHUGLVHDVHSURJUHVVLRQHDFKVXEMHFWZLOOEHIROORZHGDVGHVFULEHGLQ6HFWLRQ

(VWLPDWHG6WXG\'XUDWLRQ
(QUROOPHQWLVH[SHFWHGWREHFRPSOHWHGDSSUR[LPDWHO\PRQWKVDIWHURSHQLQJ
7KHGXUDWLRQRIVFUHHQLQJIRUHDFKVXEMHFWLVDSSUR[LPDWHO\GD\V7KHGXUDWLRQRI
WUHDWPHQWZLOOYDU\IRUHDFKVXEMHFWZLWKDQDSSUR[LPDWHO\PRQWKHVWLPDWHGPHGLDQ
GXUDWLRQRIWUHDWPHQW3DWLHQWVZLOOEHIROORZHGXQWLOZLWKGUDZDORIFRQVHQWGHDWKORVVWR
IROORZXSRUWKHVSRQVRUPDNHVDGHFLVLRQWRFORVHWKHVWXG\ZKLFKHYHURFFXUVILUVW
(VWLPDWHGVWXG\GXUDWLRQLVDERXWPRQWKV

,QGHSHQGHQW5HYLHZ&RPPLWWHH
7KHPHPEHUVKLSFULWHULDDQGRSHUDWLRQDOGHWDLOVRIWKH,5&ZLOOEHGHVFULEHGLQWKH,5&
FKDUWHU7KH,5&ZLOOFHQWUDOO\UHYLHZWKHGLVHDVHUHODWHGODERUDWRU\WHVWVDQGSODVPDF\WRPD
DVVHVVPHQWV7KHRXWFRPHVGHWHUPLQHGE\WKH,5&ZLOOVHUYHDVWKHSULPDU\GDWDVRXUFHIRU
WKHSULPDU\DQDO\VLVIRU255,5&5HVSRQVHVZLOOEHDVVHVVHGXVLQJWKH,0:*85&
'XULH.XPDU$SSHQGL[(DQGPLQLPDOUHVSRQVHZLOOEHHYDOXDWHG
IROORZLQJ,0:*85&.XPDU$SSHQGL[)
67$7,67,&$/0(7+2'6

(IILFDF\$QDO\VHV
7KHDQDO\VLVRIDOOHIILFDF\HQGSRLQWVZLOOEHEDVHGRQWKH6DIHW\3RSXODWLRQ


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 78 of 151 
 
Confidential 
12 April  2018 
12.5.1.1 Primary Efficacy Analysis 
Overall response rate after at least 6 cycles of Kd, defined as the proportion of subjects with 
the best overall response of PR or better, will be determined along with the corresponding 
95% exact binomial.  Responses will be assessed by the IRC according to the IMWG-URC 
criteria (ORR6-IRC) (Durie, 2006; Rajkumar, 2011; Kumar, 2016).  
12.5.1.2 Secondary Efficacy Analyses 
Overall response rate (after at least 6 cycles of Kd), based on the investigator’s assessment of 
best response according to IMWG-URC criteria (Durie, 2006; Rajkumar, 2011; Kumar, 
2016) (Appendix E) will be determined along with the corresponding 95% exact binomial. 
Overall response rate (after at least 12 cycles of Kd), based on both IRC and investigator 
assessment of best overall response will be determined along with the corresponding 95% 
exactly binomial. 
Clinical benefit rate, defined as the proportion of subjects with the best overall response (per 
the investigator) of MR or better, will be determined along with the 95% exact binomial CI.  
Minimal response will be defined according to IMWG criteria (Kumar, 2016;Appendix F).  
Clinical benefit rate will be calculated after at least 6 and after at least 12 cycles of therapy 
and determined for both investigator and IRC response assessments.   
Duration of response (DOR) is defined as the time from first evidence of PR or better to 
disease progression or death due to any cause.  Duration of response will be determined 
based on both investigator and IRC assessment.  Duration of response will be right-censored 
for subjects who achieve at least a PR based on the censoring conventions defined in  
Table 12 for PFS.  Duration of clinical benefit (DCB) is defined as the time from first 
evidence of MR or better to disease progression or death due to any cause.  Duration of 
clinical benefit will be right-censored for subjects who at least achieve at least an MR based 
on the censoring conventions defined in Table 12 for PFS.    
Progression-free survival (PFS) is defined as the time from first dose to the earlier of disease 
progression or death due to any cause.  Progression-free survival will be determined based on 
both investigator and IRC assessment of response.  For purposes of calculating PFS, the start 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 79 of 151 
 
Confidential 
12 April  2018 
date for PD is the date at which progression is first observed.  The duration of PFS will be 
right-censored for subjects who meet 1 of the conditions described in Table 12. For such 
subjects, the analysis of PFS will be right-censored according to the conventions described in 
Table 12.   
Table 12: Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first dose 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to start of 
new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease assessment 
visit 
Date of last disease assessment visit without 
documentation of PD that is before the first 
missed visit 
Censored 
Alive and without PD documentation  
Date of last disease assessment 
Censored 
Death or PD between planned 
disease assessments 
Date of death or first disease assessment 
showing PD, whichever occurs first 
Progressed 
Death before first disease assessment 
Date of death 
Progressed 
 
Overall survival (OS) is defined as the time from the first dose to the date of death due to any 
cause.  Subjects who are alive or lost to follow-up as of the data analysis cutoff date will be 
right-censored at the subject’s date of last contact (last known to be alive). If the date last 
known to be alive is after the data analysis cutoff date, the subject will be censored at 
the data analysis cutoff date. 
Analyses for all time-to-event secondary endpoints (DOR, DCB, PFS, and OS) will be 
performed using the Kaplan-Meier method, and calculated using both IRC and investigator 
response assessments.  Medians and other quartiles for each endpoint will be estimated in 
addition to the corresponding two-sided 95% CIs.  Duration of follow-up for PFS and OS 
will also be estimated according to the Kaplan-Meier estimate of potential follow-up also 
termed “reverse Kaplan-Meier” (Schemper 1996). 
Time to response is the time from the start of study treatment until the start of the first 
confirmed response (PR or greater) and will be determined based on both investigator and 
IRC assessment.  The mean, standard deviation, minimum, and maximum will be calculated 
for time to response. 


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
 ([SORUDWRU\(IILFDF\$QDO\VHV
(IILFDF\HQGSRLQWVUHODWHGWRUHVSRQVHDQGGLVHDVHSURJUHVVLRQGHWHUPLQHGE\25&$
ZLOOEHDQDO\]HGSHUWKHPHWKRGVGHVFULEHGLQ6HFWLRQDQG6HFWLRQ
6$)(7<$1$/<6,6
7KHDQDO\VLVRIDOOVDIHW\HQGSRLQWVZLOOEHEDVHGRQWKH6DIHW\3RSXODWLRQ
6DIHW\DQGWROHUDELOLW\DVVHVVPHQWVZLOOLQFOXGHH[WHQWRIH[SRVXUHWRVWXG\WUHDWPHQW$(V
LQFOXGLQJ6$(VODERUDWRU\YDOXHVYLWDOVLJQUHVXOWVDQG(&*V6DIHW\GDWDZLOOEH
H[DPLQHGRQDQRQJRLQJEDVLVWRHQVXUHVXEMHFWVDIHW\
([WHQWRIH[SRVXUHWRWKHVWXG\WUHDWPHQWZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFV
QXPEHUPHDQVWDQGDUGGHYLDWLRQPHGLDQDQGUDQJH3HUFHQWRIVXEMHFWVDQGQXPEHURI
F\FOHVZLWKGRVHVKHOGLHGHOD\HGRUPLVVHGDQGGRVHUHGXFWLRQVZLOOEHFDOFXODWHGE\
WUHDWPHQWJURXS
7UHDWPHQWHPHUJHQWDGYHUVHHYHQWVDUHGHILQHGDV$(VRFFXUULQJIURPWKHILUVWGRVHRIVWXG\
WUHDWPHQWWKURXJKGD\VDIWHUWKHODVWGRVHRIVWXG\WUHDWPHQWRULQLWLDWLRQRIQHZ
DQWLP\HORPDWKHUDS\ZKLFKHYHUFRPHVILUVW$GYHUVHHYHQWVZLOOEHVXPPDUL]HGE\
0HG'5$V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPIRUWKHQXPEHUDQGSHUFHQWDJHRIVXEMHFWV
ZKRH[SHULHQFHGWKHHYHQW$VXEMHFWUHSRUWLQJWKHVDPH$(PRUHWKDQRQFHZLOOEHFRXQWHG
RQO\RQFHZKHQFDOFXODWLQJZLWKLQDJLYHQV\VWHPRUJDQFODVVDQGZLWKLQDJLYHQ
V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPFRPELQDWLRQ)RUVXFKFDVHVWKHPD[LPXP1&,
&7&$(WR[LFLW\JUDGHDQGVWURQJHVWFDXVDOUHODWLRQVKLSWRVWXG\WUHDWPHQWIRUWKHHYHQWZLOO
EHXVHGLQWKHLQFLGHQFHFDOFXODWLRQV7UHDWPHQWHPHUJHQW$(VZLOOEHWDEXODWHGWRH[DPLQH
WKHLUIUHTXHQF\VHYHULW\DQGUHODWLRQVKLSWRVWXG\WUHDWPHQW$GGLWLRQDOVXPPDULHVZLOOEH
SURYLGHGIRU6$(VDQGHYHQWVUHVXOWLQJLQWKHSHUPDQHQWGLVFRQWLQXDWLRQRIWUHDWPHQW
$OO$(VZLOODOVREHLQFOXGHGLQLQGLYLGXDOVXEMHFWOLVWLQJV$GYHUVHHYHQWUHSRUWLQJZLOO
LQFOXGHLQFLGHQFHDQGVHYHULW\RIFRQJHVWLYHKHDUWIDLOXUHP\RFDUGLDOLQIDUFWLRQDFXWH
NLGQH\LQMXU\DGXOWUHVSLUDWRU\GLVWUHVVV\QGURPHSXOPRQDU\K\SHUWHQVLRQG\VSQHD
K\SHUWHQVLRQWKURPERHPEROLFHYHQWVWKURPERF\WRSHQLDKHSDWLFWR[LFLW\DQGWKURPERWLF
PLFURDQJLRSDWK\KHPRO\WLFXUHPLFV\QGURPH


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
/DERUDWRU\SDUDPHWHUVZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFVE\SRVWGRVHVKLIWV
UHODWLYHWREDVHOLQHDQGDVXPPDU\RIWKHLQFLGHQFHRIFOLQLFDOO\VLJQLILFDQWDEQRUPDOYDOXHV
IRUNH\ODERUDWRU\DQDO\WHV9LWDOVLJQUHVXOWVZLOODOVREHVXPPDUL]HGGHVFULSWLYHO\IRUHDFK
VFKHGXOHGSURWRFROWLPHSRLQW&KDQJHVZLOOEHFDOFXODWHGUHODWLYHWRWKHYDOXHVFROOHFWHGDW
%DVHOLQHGHILQHGDVWKHODVWDVVHVVPHQWWDNHQSULRUWRWKHILUVWGRVHRIVWXG\GUXJRQ'D\RI
&\FOH
7KHDQDO\VLVRIWKHORFDOO\SHUIRUPHG(&*VZLOOLQYROYHGHVFULSWLYHVWDWLVWLFV
3+$50$&2.,1(7,&$1$/<6(6
3KDUPDFRNLQHWLFGDWDDQDO\VLVVHWZLOOLQFOXGHDSSUR[LPDWHO\VXEMHFWVZKRUHFHLYHG
FDUILO]RPLEJLYHQDVDPLQXWH,9LQIXVLRQDQGKDYHDGHTXDWHFDUILO]RPLESODVPD
FRQFHQWUDWLRQYHUVXVWLPHGDWDIRUWKHHVWLPDWLRQRI3.SDUDPHWHUVE\DQRQFRPSDUWPHQWDO
DQDO\VLV,QGLYLGXDODQGPHDQSODVPDFRQFHQWUDWLRQYHUVXVWLPHGDWDZLOOEHWDEXODWHGDQG
SORWWHGIRUWKHVXEMHFWVSDUWLFLSDWLQJLQWKH3.SRUWLRQRIWKHVWXG\7KHIROORZLQJ3.
SDUDPHWHUVZLOOEHGHWHUPLQHGZKHQSRVVLEOHIRUFDUILO]RPLE
x 0D[LPXPSODVPDFRQFHQWUDWLRQ&PD[REVHUYHG
x 7LPHRIPD[LPXPSODVPDFRQFHQWUDWLRQ7PD[REVHUYHG
x $UHDXQGHUWKHSODVPDFRQFHQWUDWLRQWLPHFXUYHIURPWLPH]HURWRWLPHRIODVWTXDQWLILDEOH
FRQFHQWUDWLRQDQGWRLQILQLW\$8&ODVWDQG$8&UHVSHFWLYHO\
x 7HUPLQDOHOLPLQDWLRQKDOIOLIH7ò
x 3ODVPDFOHDUDQFH&/
x 9ROXPHRIGLVWULEXWLRQ9DUHD
x 9ROXPHRIGLVWULEXWLRQDWVWHDG\VWDWH9VV
x 0HDQUHVLGHQFHWLPH057
$OO3.SDUDPHWHUVZLOOEHFRPSXWHGXVLQJDFWXDOHODSVHGWLPHFDOFXODWHGUHODWLYHWRWKHVWDUW
RIGRVHDGPLQLVWUDWLRQ


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
 (7+,&$/$1'$'0,1,675$7,9(&216,'(5$7,216
&203/,$1&(67$7(0(17
7KLVVWXG\ZLOOEHFRQGXFWHGLQDFFRUGDQFHZLWKWKHSURWRFRODQGZLWK,&+*&3JXLGHOLQHV
DVZHOODVDOODSSOLFDEOHFRXQWU\DQGUHJLRQDOUHJXODWRU\UHTXLUHPHQWV7KHLQYHVWLJDWRULV
UHVSRQVLEOHIRUHQVXULQJWKDWWKLVSURWRFROWKHVLWH¶VLQIRUPHGFRQVHQWIRUPDQGDQ\RWKHU
LQIRUPDWLRQWKDWZLOOEHSUHVHQWHGWRSRWHQWLDOVXEMHFWVDUHUHYLHZHGDQGDSSURYHGE\WKH
DSSURSULDWH,5%RU,(&SULRUWRWKHHQUROOPHQWRIDQ\VWXG\VXEMHFWV
,167,787,21$/5(9,(: %2$5'25,1'(3(1'(17
(7+,&6&200,77((
7KHLQYHVWLJDWRUZLOOVXEPLWWKLVSURWRFROWKHLQIRUPHGFRQVHQW,%DQGDQ\RWKHUUHOHYDQW
VXSSRUWLQJLQIRUPDWLRQWRWKHDSSURSULDWH,5%RU,(&DQGWKHORFDOUHJXODWRU\DJHQF\IRU
UHYLHZDQGDSSURYDOSULRUWRVWXG\LQLWLDWLRQ
$PHQGPHQWVWRWKHSURWRFROPXVWDOVREHDSSURYHGE\WKH,5%,(&DQGWKHORFDOUHJXODWRU\
DJHQF\DVDSSURSULDWHSULRUWRWKHLPSOHPHQWDWLRQRIFKDQJHVLQWKLVVWXG\1RSURWRFRO
GHYLDWLRQVDUHDOORZHG+RZHYHUWKHLQYHVWLJDWRUPD\LPSOHPHQWDGHYLDWLRQIURPRUD
FKDQJHRIWKHSURWRFROWRHOLPLQDWHDQLPPHGLDWHKD]DUGVWRWKHVWXG\VXEMHFWVZLWKRXW
SULRU,5%,(&VSRQVRUDSSURYDOIDYRUDEOHRSLQLRQ$VVRRQDVSRVVLEOHWKHLPSOHPHQWHG
GHYLDWLRQRUFKDQJHWKHUHDVRQVIRULWDQGLIDSSURSULDWHWKHSURSRVHGSURWRFRODPHQGPHQW
VKRXOGEHVXEPLWWHGWRWKH,5%,(&VSRQVRU$Q\GHYLDWLRQVIURPWKHSURWRFROPXVWEHIXOO\
H[SODLQHGDQGGRFXPHQWHGE\WKHLQYHVWLJDWRU
,1)250('&216(17$1'+80$168%-(&73527(&7,21
1RLQYHVWLJDWRUPD\LQYROYHDKXPDQEHLQJDVDVXEMHFWLQUHVHDUFKXQOHVVWKHLQYHVWLJDWRU
KDVREWDLQHGWKHOHJDOO\HIIHFWLYHLQIRUPHGFRQVHQWRIWKHVXEMHFWRUWKHVXEMHFW¶VOHJDOO\
DXWKRUL]HGUHSUHVHQWDWLYH$QLQYHVWLJDWRUVKDOOVHHNVXFKFRQVHQWRQO\XQGHUFLUFXPVWDQFHV
WKDWSURYLGHWKHSURVSHFWLYHVXEMHFWRUWKHVXEMHFW¶VOHJDOO\DXWKRUL]HGUHSUHVHQWDWLYH
VXIILFLHQWRSSRUWXQLW\WRFRQVLGHUZKHWKHURUQRWWRSDUWLFLSDWHDQGWKDWPLQLPL]HWKH
SRVVLELOLW\RIFRHUFLRQRUXQGXHLQIOXHQFH7KHLQIRUPDWLRQWKDWLVJLYHQWRWKHVXEMHFWRUWKH
UHSUHVHQWDWLYHVKDOOEHLQDODQJXDJHXQGHUVWDQGDEOHWRWKHVXEMHFWRUUHSUHVHQWDWLYH


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
7KHVSRQVRURULWVGHVLJQDWHGUHSUHVHQWDWLYHZLOOSURYLGHWKHLQYHVWLJDWRUZLWKDVDPSOH,&)
/RFDODQGRULQVWLWXWLRQDOUHTXLUHPHQWVPD\UHTXLUHGLVFORVXUHRIDGGLWLRQDOLQIRUPDWLRQLQ
WKH,&)$Q\FKDQJHVWRWKH,&)PXVWEHVXEPLWWHGWRWKH6SRQVRURULWVGHVLJQDWHG
UHSUHVHQWDWLYHIRUDSSURYDOSULRUWRVXEPLVVLRQWRWKH,5%,(&7KH,5%,(&ZLOOUHYLHZ
WKH,&)IRUDSSURYDO$FRS\RIWKHDSSURYHGIRUPPXVWEHVXEPLWWHGWRWKH6SRQVRURULWV
GHVLJQDWHGUHSUHVHQWDWLYHSULRUWRLQLWLDWLRQRIWKHVWXG\%HIRUHLPSOHPHQWLQJDQ\VWXG\
SURFHGXUHLQIRUPHGFRQVHQWVKDOOEHGRFXPHQWHGLQWKHVXEMHFWFDVHKLVWRULHVDQGE\WKHXVH
RIDZULWWHQFRQVHQWIRUPDSSURYHGE\WKH,5%,(&DQGVLJQHGDQGGDWHGE\WKHVXEMHFWRU
WKHVXEMHFW¶VOHJDOO\DXWKRUL]HGUHSUHVHQWDWLYHDWWKHWLPHRIFRQVHQW$FRS\RIWKHVLJQHG
,&)ZLOOEHJLYHQWRWKHVXEMHFWRUVXEMHFW¶VOHJDOO\DXWKRUL]HGUHSUHVHQWDWLYH7KHRULJLQDO
VLJQHG,&)PXVWEHPDLQWDLQHGE\WKHLQYHVWLJDWRUDQGDYDLODEOHIRULQVSHFWLRQE\WKH
VSRQVRULWVGHVLJQDWHGUHSUHVHQWDWLYHRUUHJXODWRU\DXWKRULW\DWDQ\WLPH
',5(&7$&&(66726285&('$7$6285&('2&80(176$1'678'<
5(&25'6
7KHVWXG\ZLOOEHFDUULHGRXWLQNHHSLQJZLWKDSSOLFDEOHORFDOODZVDQGUHJXODWLRQV7KLV
PD\LQFOXGHDQLQVSHFWLRQE\VSRQVRUUHSUHVHQWDWLYHVGHVLJQHHVDQGRUUHJXODWRU\DXWKRULW\
UHSUHVHQWDWLYHVDWDQ\WLPH7KHLQYHVWLJDWRULQVWLWXWLRQPXVWDJUHHWRWKHLQVSHFWLRQRI
VWXG\UHODWHGUHFRUGVE\WKHUHJXODWRU\DXWKRULW\VSRQVRUUHSUHVHQWDWLYHVGHVLJQHHVDQGPXVW
DOORZGLUHFWDFFHVVWRVRXUFHGRFXPHQWVWRWKHUHJXODWRU\DXWKRULW\VSRQVRUUHSUHVHQWDWLYHV
GHVLJQHHV,5%,(&7KHLQYHVWLJDWRUPXVWDOORFDWHWLPHLQYHVWLJDWRUDQGVWXG\VWDIIWR
GLVFXVVILQGLQJVDQGUHOHYDQWLVVXHVZLWKWKHUHJXODWRU\DXWKRULW\VSRQVRUUHSUHVHQWDWLYHV
'$7$&2//(&7,21$1'+$1'/,1*
$VSDUWRIWKHUHVSRQVLELOLWLHVDVVXPHGE\SDUWLFLSDWLQJLQWKHVWXG\WKHLQYHVWLJDWRUDJUHHVWR
PDLQWDLQDGHTXDWHFDVHKLVWRULHVIRUWKHVXEMHFWVWUHDWHGDVSDUWRIWKHUHVHDUFKXQGHUWKLV
SURWRFRO7KHLQYHVWLJDWRUDJUHHVWRPDLQWDLQDFFXUDWH&5)VDQGVRXUFHGRFXPHQWDWLRQDV
SDUWRIWKHFDVHKLVWRULHV7KHVHVRXUFHGRFXPHQWVPD\LQFOXGHVXEMHFWGLDULHVODERUDWRU\
UHSRUWVDQGRWKHUGRFXPHQWV7KHVSRQVRUZLOOVXSSO\WKH&5)ZKLFKZLOOEHFRPSOHWHGLQ
(QJOLVK


2Q\[7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO1R&)=
&DUILO]RPLEIRU,QMHFWLRQ
3DJHRI
&RQILGHQWLDO
$SULO
'DWDFROOHFWLRQZLOOLQYROYHDGDWDFDSWXUHV\VWHPWRZKLFKRQO\DXWKRUL]HGSHUVRQQHOZLOO
KDYHDFFHVV
7KHLQYHVWLJDWRURUGHVLJQHHPXVWHQWHUDOOUHVXOWVFROOHFWHGGXULQJWKHFOLQLFDOVWXG\LQWR
&5)V*XLGHOLQHVIRUFRPSOHWLRQRI&5)VZLOOEHUHYLHZHGZLWKVWXG\VLWHSHUVRQQHODWWKH
VLWHLQLWLDWLRQYLVLWV,QYHVWLJDWRUVDUHUHVSRQVLEOHIRUDSSURYDORIWKHHQWHUHGFRUUHFWHGGDWD
'HWDLOHGLQVWUXFWLRQVPD\EHIRXQGLQWKHRWKHUVWXG\VSHFLILFGRFXPHQWV
$OOHQWULHVPDGHRQWKH&5)PXVWEHYHULILDEOHDJDLQVWVRXUFHGRFXPHQWV,QDGGLWLRQWR
SHULRGLFPRQLWRULQJRFFXUULQJZLWKLQWKHV\VWHPE\VWXG\PRQLWRUVSURJUDPPDWLFHGLW
FKHFNVDQGGDWDOLVWLQJVZLOOEHXVHGWRUHYLHZWKHGDWDIRUFRPSOHWHQHVVORJLFDQG
DGKHUHQFHWRVWXG\SURWRFRO$VDUHVXOWRIWKLVPRQLWRULQJDQGWKHVHFKHFNVTXHULHVPD\EH
HOHFWURQLFDOO\LVVXHGWRWKHFOLQLFDOVWXG\VLWHVDQGHOHFWURQLFDOO\UHVROYHGE\WKRVHVLWHV
$OOGDWDFROOHFWHGLQWKHFRQWH[WRIWKLVVWXG\ZLOOEHVWRUHGDQGHYDOXDWHGSHUUHJXODWRU\
UHTXLUHPHQWVDQGDSSOLFDEOHJXLGDQFHIRUHOHFWURQLFUHFRUGV$OVRGDWDZLOOEHVWRUHGDQG
HYDOXDWHGLQVXFKDZD\DVWRDVVXUHVXEMHFWFRQILGHQWLDOLW\LQDFFRUGDQFHZLWKWKHOHJDO
VWLSXODWLRQVDSSO\LQJWRFRQILGHQWLDOLW\RIGDWD6WXG\UHFRUGVHJFRSLHVRI&5)V
UHJXODWRU\GRFXPHQWVZLOOEHUHWDLQHGDWWKHVWXG\VLWHDORQJZLWKDGHTXDWHVRXUFH
GRFXPHQWDWLRQ7KHVWXG\ILOHDQGDOOVRXUFHGDWDVKRXOGEHUHWDLQHGXQWLOZULWWHQ
QRWLILFDWLRQLVJLYHQE\WKHVSRQVRURUGHVLJQHHIRUGHVWUXFWLRQ
&21),'(17,$/,7<
$OOUHFRUGVLGHQWLI\LQJWKHVXEMHFWZLOOEHNHSWFRQILGHQWLDODQGWRWKHH[WHQWSHUPLWWHGE\
WKHDSSOLFDEOHODZVDQGRUUHJXODWLRQVZLOOQRWEHPDGHSXEOLFO\DYDLODEOH
6XEMHFWQDPHVZLOOQRWEHVXSSOLHGWRWKHVSRQVRU2QO\WKHVXEMHFWQXPEHUZLOOEHUHFRUGHG
RQWKH&5),IWKHVXEMHFWQDPHDSSHDUVRQDQ\RWKHUGRFXPHQWHJSDWKRORJLVWUHSRUWRU
VWXG\PDWHULDOVHJELRSV\WLVVXHVOLGHVWKHQWKDWLQIRUPDWLRQPXVWEHGHOHWHGEHIRUHD
FRS\RIWKHGRFXPHQWLVVXSSOLHGWRWKHVSRQVRU6WXG\GDWDVWRUHGRQDFRPSXWHUZLOOEH
VWRUHGLQDFFRUGDQFHZLWKORFDOGDWDSURWHFWLRQODZV6XEMHFWVZLOOEHLQIRUPHGLQZULWLQJ
WKDWUHSUHVHQWDWLYHVRIWKHVSRQVRU,5%,(&RUUHJXODWRU\DXWKRULWLHVPD\LQVSHFWWKHLU
PHGLFDOUHFRUGVWRYHULI\WKHLQIRUPDWLRQFROOHFWHGDQGWKDWDOOSHUVRQDOLQIRUPDWLRQPDGH


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 85 of 151 
 
Confidential 
12 April  2018 
available for inspection will be handled in strictest confidence and in accordance with 
applicable local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 86 of 151 
 
Confidential 
12 April  2018 
14 REFERENCES 
American Cancer Society. Cancer facts and figures 2005. Atlanta: American Cancer Society 
2005. 
Arastu-Kapur S, Shenk K, Swinarski D, et al. Non-proteasomal targets of proteasome 
inhibitors bortezomib and carfilzomib. European Hematology Association 14th Congress 
2009; abstract 0939. 
Bladé J, Samson D, Reece D, et al. European Group for Blood and Marrow Transplant. 
Myeloma Subcommittee of the EBMT. Criteria for evaluating disease response and 
progression in subjects with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Br J Haematol. 1998;102(5):1115–23. 
Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005; 
16:481–488. 
Carfilzomib for Injection Investigator’s Brochure. 
Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007;67:6383-6391. 
Durie BG, Harousseau JL, Miguel JS, et al. International Myeloma Working Group. 
International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-
1473. Erratum in: Leukemia 2006;20(12):2220. Leukemia 2007; 21(5):1134. 
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: 
GLOBOCAN 2008. Int. J. Cancer. 2010;127,2893–2917. 
Ferlay K, Shin HR, Bray F, et al. Cancer incidence and mortality worldwide: IARC 
CancerBase No. 10 [Internet]: GLOBOCAN 2008 v2.0. Lyon, France: International Agency 
for Research on Cancer 2010. Available from: http://globocan.iarc.fr, accessed on 
14/Jan/2013. 
Guidelines on the Diagnosis and Management of Multiple Myeloma in China, 2013. 
Kortuem KM, Stewart AK. Carfilzomib. Blood, 2013. 121:893-897. 
Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible 
inhibitor of the ubiquitin proteasome pathway, against preclinical models of multiple 
myeloma. Blood. 2007;110:3281-3290. 
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple 
myeloma: changes in early mortality and outcomes in older patient. Leukemia. 
2014;28:1122-1128. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 87 of 151 
 
Confidential 
12 April  2018 
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma. Lancet Oncol 2016; 17:e328-46. 
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma: Criteria for assessment of multiple myeloma. Leukemia. 
2009;23:3–9. 
Kyprolis® (carfilzomib) for Injection [full prescribing information].  
South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2013. Available at: 
http://pi.amgen.com/united_states/kyprolis/kyprolis_pi.pdf 
Accessed 07 February 2015. 
Lendvai N, Hilden P, Devlin S, et al.  A phase 2 single-center study of carfilzomib 56 mg/m2 
with or without low dose dexamethasone in relapsed multiple myeloma. Blood 2014:124(6) 
899-906. 
Meregalli C, Canta A, Carozzi VA, et al. Bortezomib-induced painful neuropathy in rats: A 
behavioral, neurophysiological and pathological study in rats. European Journal of Pain, 
2010;14:343-50. 
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987; Oct 22; 
317(17):1098 (letter). 
Papadopoulos KP, Siegel DS, Vesole DH et al. Phase I study of 30-minute infusion of 
carfilzomib as single agent or in combination with low-dose dexamethasone in patients with 
relapsed and/or refractory multiple myeloma. J Clin Onc 2015;33:732-39. 
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1. Blood. 2011;117:4691-4695 
Schemper M, Stare J. Explained variation in survival analysis. Stat Med. 1996;15:1999–
2012. 
Siegel, DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-
003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120 (14) 
2817-25. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use 
of white blood cell growth factors: an evidence-based clinical practice guideline. 
J Clin Oncol. 2006;24(19):3187-3205. 
Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib resistant 
adenocarcinoma cells. PLoS One. 2011;6(12):e27996.  
Yang J, Wang, Z, Kirk C, et al. Pharmacokinetics, pharmacodynamics, metabolism, 
distribution, and excretion of carfilzomib in rats. Drug Metab Dispos. 2011;39:1873. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 88 of 151 
 
Confidential 
12 April  2018 
Yang J, Wang, Z, Kirk C, et al. Clinical pharmacokinetics, metabolism, and drug-drug 
interaction of carfilzomib. Drug Metab Dispos. 2012 Nov 1. [Epub ahead of print] 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 89 of 151 
 
Confidential 
12 April 2018 
APPENDIX A:  
SCHEDULE OF ASSESSMENTS 
Table 13: Schedule of Assessments for Subjects in Screening and Cycle 1 
Assessments 
Visit 
Screening 
Study Cycle 1 
Day –21 to 
–1 
Day 1  
Day 2 
Day 8 
Day 9 
Day 15 
Day 16 
Day 22 
Day 23 
Written Informed Consent 
× 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
× 
 
 
 
 
 
 
 
 
Medical Historya 
× 
 
 
 
 
 
 
 
 
Previous treatment history 
× 
 
 
 
 
 
 
 
 
Complete Physical Examination and ECOG 
× 
 
 
 
 
 
 
 
 
Height, Weight, and Body Surface Area 
× 
× 
 
 
 
 
 
 
 
Substance Historyb 
×q 
 
 
 
 
 
 
 
 
Routine Physical Evaluation 
 
× 
 
 
 
 
 
 
 
Blood Pressure, Heart Rate, Respiratory Rate and 
Temperaturec 
× 
× 
× 
× 
× 
× 
× 
 
 
12-lead Electrocardiogram, including QTc 
× 
 
 
 
 
 
 
 
 
2-D ECHOd 
× 
 
 
 
 
 
 
 
 
Pregnancy Teste (for FCBP, Day -7 to -1 and Day 1) 
(×) 
(×) 
 
 
 
 
 
 
 
Chemistry Panelf 
× 
× 
(×) 
× 
(×) 
× 
(×) 
 
 
Coagulation tests 
× 
 
 
 
 
 
 
 
 
Hematology Panelg 
× 
× 
 
× 
 
× 
 
 
 
Beta-2 microglobulin and quantitative immunoglobulins 
× 
 
 
 
 
 
 
 
 
IV Hydrationh 
 
× 
× 
× 
× 
× 
× 
 
 
Dexamethasone Dosingi 
 
× 
× 
× 
× 
× 
× 
× 
× 
Carfilzomib Dosingj 
 
× 
× 
× 
× 
× 
× 
 
 
Blood pressure, Heart Rate postdose 
 
× 
× 
× 
× 
× 
× 
 
 
Required Disease Assessment Labsk  
× 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy, Aspirate, FISHl 
× 
 
 
 
 
 
 
 
 
Skeletal Surveym 
× 
 
 
 
 
 
 
 
 
Plasmacytoma Evaluationn 
(if clinically indicated) 
(×) 
 
 
 
 
 
 
 
 
Adverse Eventso 
x 
× 
× 
× 
× 
× 
× 
 
 
Concomitant Medications 
× 
× 
× 
× 
× 
× 
× 
 
 
Pharmacokinetic Assessmentsp 
 
x 
 
 
 
 
 
 
 
Abbreviations: CRF = case report form;   ECHO = echocardiogram; ECOG = Easter Cooperative Oncology Group; FCBP = females of child bearing potential; 
FISH = fluorescence in situ hybridization; IV = intravenous; PO = orally; SFLC = serum-free light chain; SIFE = serum immunofixation electrophoresis; 
SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 90 of 151 
 
Confidential 
12 April 2018 
Footnotes to Table 13 
a. 
Medical history, including prior cancer surgery/radiotherapy, transplant and neuropathy history. 
b. Substance History:  Record number of alcoholic drinks per week, number of years of tobacco use, and number of packs of cigarettes smoked per day. 
c. 
Measure blood pressure, heart rate, respiratory rate, and temperature within 1 hour prior to dose of carfilzomib.   Blood pressure and heart rate will be 
measured 5 to 60 minutes after completing infusion.  The subject should be in a supine position in a rested and calm state for at least 5 minutes before 
blood pressure assessments are conducted.  If the subject is unable to be in the supine position, the subject should be in the most recumbent position 
possible (this request is recommended in all following assessments).  The position selected for a subject should be the same that is used throughout the 
study and documented on the vital signs CRF. 
d. ECHO is required during screening.  Multiple gated acquisition scan is acceptable if ECHO is not available.  The screening studies do not need to be 
repeated if previously done within 30 days of consent.  Repeat ECHO only required for subjects who develop clinically significant CHF. 
e. 
For FCBP, obtain serum pregnancy test within 7 days of first dose of carfilzomib.  Urine or serum pregnancy test must be confirmed negative locally on 
Day 1 of each cycle prior to dosing. 
f. 
Obtain chemistry panel (Table 6) up to 1 day prior to administration of carfilzomib on Days 1, 8, and 15.  A chemistry panel on Days 2, 9 and 16 is 
optional.  Results of local laboratory studies must be reviewed and deemed acceptable prior to administration of carfilzomib.  
g. Obtain hematology panel (Table 7) up to 1 day prior to administration of carfilzomib on Days 1, 8, and 15.  Results must be reviewed and deemed 
acceptable prior to administration of carfilzomib.  
h. IV hydration:  250–500 mL of normal saline (or other IV formulation) before and after each carfilzomib infusion is required during cycle 1  
i. 
Dexamethasone must be administered at least 30 minutes (but no more than 4 hours) prior to carfilzomib on Days 1, 2, 8, 9, 15, and 16.  On Days 22 and 
23, PO dexamethasone may be self-administered orally at home (± 2 days). 
j. 
Carfilzomib is administered at 20 mg/m2 in Cycle 1 Days 1 and 2; at 27 mg/m2 in Cycle 1 Days 8, 9, 15, and 16.  
k. See Section 9.1.10.4.2for required disease assessment labs (sent to central study laboratory).  Obtain blood for SPEP, SIFE, serum calcium, and SFLC 
and 24-hour urine sample for UPEP and UIFE.  NOTE:  UPEP with immunofixation (on a 24-hour collection) is required; no substitute method is 
acceptable.  Details can be found within the study procedures manual. 
l. 
Bone marrow biopsy and/or aspirate documenting percent marrow involvement.  FISH is optional at screening. The screening studies do not need to be 
repeated if previously done within 30 days of consent. 
m. Skeletal Survey does not need to be repeated if previously done within 30 days of consent.  Skeletal survey includes: lateral radiograph of the skull, 
anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri. 
n. All subjects are required to have a clinical assessment in consideration of formal plasmacytoma evaluation at screening (see Section 9.1.10.1 and 
Section 9.2.1).  If present at baseline, the plasmacytoma(s) should be monitored throughout the study, as clinically appropriate and in accordance with 
Section-9.1.10.4.3. 
o. Record all AEs from time of first administration of carfilzomib through 30 days post-last dose of study drug or initiation of a new anti-cancer therapy.  
Note:  All Serious Adverse Events (SAEs) should be collected after signing of the informed consent form (ICF).  Record concomitant medications from 
21 days before Day 1.  Any changes in the subject’s concomitant medications during the study, must be recorded on the CRF. 
p. Pharmacokinetic (PK) analyses will be characterized in a subset of approximately 15subjects at selected sites.  Subjects who do not provide all required 
PK assessments at Cycle 1 Day 1 and Cycle 2 Day 1 will be replaced.  See Section 9.1.13, Section 9.3, or Appendix B for more details. 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 91 of 151 
 
Confidential 
12 April 2018 
Table 14: Schedule of Assessments for Subjects in Cycles 2 and Higher 
Assessments 
Visit 
EOT/EWa 
Within 30 
days 
AFUl 
LTFUm 
Study Cycle 2+ 
Day 1 
Day 2 
Day 8 
Day 9 
Day 
15 
Day 16 
Day 22 
Day 23 
 
 
 
Complete Physical Examination 
 
 
 
 
 
 
 
 
× 
 
 
Weight and Body Surface Area 
× 
 
 
 
 
 
 
 
× 
 
 
Routine Physical Examination 
× 
 
 
 
 
 
 
 
 
 
 
ECOG 
 
 
 
 
 
 
 
 
× 
 
 
Blood Pressure, Heart Rate, Respiratory 
Rate, and Temperatureb 
× 
× 
× 
× 
× 
× 
 
 
× 
 
 
12-lead Electrocardiogram including QTc 
 
 
 
 
 
 
 
 
× 
 
 
Pregnancy Test (for FOCB)c 
(×) 
 
 
 
 
 
 
 
(×) 
 
 
Chemistry Paneld 
× 
(×) 
× 
(×) 
× 
(×) 
 
 
× 
 
 
Hematology Panele 
× 
 
× 
 
× 
 
 
 
× 
 
 
Beta-2 microglobulin and quantitative 
immunoglobulin 
 
 
 
 
 
 
 
 
× 
 
IV Hydrationf 
(×) 
(×) 
(×) 
(×) 
(×) 
(×) 
 
 
 
 
Dexamethasone Dosingg 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
Carfilzomib Dosingh 
× 
× 
× 
× 
× 
× 
 
 
 
 
 
Required Disease Response Assessment 
Labsi 
× 
 
 
 
 
 
 
 
× 
× 
 
Plasmacytoma Evaluationj 
If present at baseline and entered PR or 
better or CR or better 
(×) 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate and/or biopsy if 
patient has entered a new CR or sCR 
(×) 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsk 
× 
× 
× 
× 
× 
× 
 
 
× 
 
 
Concomitant Medications 
× 
× 
× 
× 
× 
× 
 
 
× 
 
 
Pharmacokinetic Assessmentsn 
x 
 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
× 
× 
Abbreviations:  AFU = active follow-up; CR = complete response; ECOG = Easter Cooperative Oncology Group; EOT = End of Treatment; EW = early 
withdrawal; FOCB = females of child-bearing potential; LTFU = long-term follow-up; PO = orally; sCR = stringent complete response; SFLC = serum-free light 
chain; SIFE = serum immunofixation electrophoresis; SPEP = serum protein electrophoresis; UIFE = urine immunofixation electrophoresis; UPEP = urine 
protein electrophoresis;  


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 92 of 151 
 
Confidential 
12 April 2018 
Footnotes to Table 14 
a. All EOT assessments must be performed within 30 days of treatment discontinuation and prior to initiation of any new anti-myeloma treatment.   
b. Measure blood pressure, heart rate, respiratory rate, and temperature within one hour prior to carfilzomib dose.  The subject should be in a supine 
position in a rested and calm state for at least 5 minutes before blood pressure assessments are conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position possible (this request is recommended in all following assessments).  The position 
selected for a subject should be the same that is used throughout the study and documented on the vital signs CRF.  Measure blood pressure and heart 
rate within 1 hour after completing carfilzomib infusion. 
c. 
Urine or serum pregnancy test must be confirmed negative locally on Day 1 of each cycle prior to dosing and at End of Treatment. 
d. Obtain chemistry panel (Table 6) up to 1 day prior to administration of carfilzomib on Days 1, 8, 15, and EOT.  Results of laboratory studies must be 
reviewed and deemed acceptable prior to administration of carfilzomib.  A chemistry panel on Days 2, 9, and 16 is optional. 
e. 
Obtain hematology panel (Table 7) up to 1 day prior to administration of carfilzomib on Days 1, 8, 15, and End of Treatment.  Results must be reviewed 
and deemed acceptable prior to administration of carfilzomib.  
f. 
If uric acid is elevated at Cycle 2 (and higher) Day 1, then the recommended IV hydration should be repeated for all of Cycle 2, and, at the investigator’s 
discretion, in conjunction with the subsequent cycles. 
g. Dexamethasone must be administered at least 30 minutes (but no more than 4 hours) prior to carfilzomib on Days 1, 2, 8, 9, 15, and 16.  On Days 22 and 
23, PO dexamethasone may be self-administered at home (± 2 days). 
h. Carfilzomib is administered at 27 mg/m2 for Cycle 2 and subsequent cycles on Days 1, 2, 8, 9, 15, and 16. 
i. 
See Section 9.1.10.4.2 for required labs.  Obtain blood for SPEP, SIFE, serum calcium, and SFLC and 24 hour urine sample for UPEP and UIFE.  
NOTE:  UPEP with immunofixation (on a 24-hour collection) is required; no substitute method is acceptable.  Details can be found within the study 
procedures manual. 
j. 
All subjects are required to have a plasmacytoma assessment at Screening (see Section 9.2.1).  If present at baseline, the plasmacytoma(s) should be 
monitored throughout the study, as clinically appropriate and in accordance with Section  9.1.10.4.3 
k. Record all AEs from first administration of carfilzomib through 30 days post-last dose of carfilzomib or initiation of a new anti-cancer therapy.  Note:  
All Serious Adverse Events (SAEs) should be collected after signing of the informed consent form (ICF).  Record concomitant medications from 21 
days before Day 1.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
l. 
AFU – Active follow-up occurs upon discontinuation of therapy in patients who do not have progression of disease.  AFU evaluations with disease 
response assessment labs are required every 4 weeks (± 4 days) until disease progression, death, or withdrawal of consent. 
m. LTFU - In long-term follow-up, upon progressive disease, subjects will be followed every 3 months (± 2 weeks) for survival for up to 3 years from start 
of study treatment. 
n. Pharmacokinetic (PK) analyses will be characterized in a subset of approximately 15 subjects at selected sites.  Subjects who do not provide all required 
PK assessments at Cycle 1 Day 1 and Cycle 2 Day 1 will be replaced.  See Section 9.1.13, Section 9.3, or Appendix B for more details. 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 93 of 151 
 
Confidential 
12 April 2018 
APPENDIX B: 
PHARMACOKINETIC SAMPLING SCHEDULE 
 
 
Pharmacokinetic Sampling Time points1 
Cycle 
Day 
Predose5 
5 min 
Post Start 
of Infusion 
End of 
Infusion2 
5 min 
End of 
Infusion3 
15 min 
End of 
Infusion3 
30 min 
End of 
Infusion3 
1 hour 
End of 
Infusion4 
2 hour 
End of 
Infusion4 
4 hour 
End of 
Infusion4 
1 
1 
× 
× 
× 
× 
× 
× 
× 
× 
× 
2 
1 
× 
× 
× 
× 
× 
× 
× 
× 
× 
* All timepoints are relative to the start and end of carfilzomib   
1. Carfilzomib must be administered over 30 ± 1 minutes on days of PK sampling 
2. Immediately (within 2 minutes) before end of infusion 
3. The 5, 15, and 30 minute sampling time points after the end of infusion have a window of ± 2 minutes 
4. The 1, 2, and 4 hour sampling time points after the end of infusion have a window of ± 5 minutes   
5. Within 15 minutes of starting the infusion   
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 94 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX C: 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all predisease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically 
strenuous but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 95 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX D: 
NATIONAL CANCER INSTITUTE 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI-CTCAE) 
GRADING SCALE 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the 
National Cancer Institute (NCI), Version 4.03 
 
Publish Date:  28 May 2009 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 96 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX E: 
INTERNATIONAL UNIFORM RESPONSE CRITERIA 
FOR MULTIPLE MYELOMA 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) 
Response 
Subcategory 
Multiple Myeloma Response Criteria 
sCR 
• Negative immunofixation on the serum and urine and  
• Disappearance of any soft tissue plasmacytomas and 
• < 5% plasma cells in bone marrow and  
• Normal SFLC ratio and  
• Absence of clonal plasma cells in bone marrow by 
immunohistochemistry or 2- to 4-color flow cytometry  
CR 
• Negative immunofixation on the serum and urine and  
• Disappearance of any soft tissue plasmacytomas and 
• < 5% plasma cells in bone marrow 
• In patients with measurable disease only by SFLC, normal SFLC 
ratio 
VGPR 
• Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or  
• ≥ 90% reduction in serum M-component with urine M-component 
< 100 mg per 24 hours 
• In patients with measurable disease only by SFLC, a decrease ≥ 90% 
in the difference between involved and uninvolved FLC levels 
PR 
• ≥ 50% reduction of serum M-protein and reduction in 24-hour 
urinary M-protein by ≥ 90% or to < 200 mg per 24 hours   
• If the serum and urine M-protein are not measurable, a decrease ≥ 
50% in the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria. 
•  
• In addition to the above criteria, if present at baseline, ≥ 50% 
reduction in the size of soft tissue plasmacytomas is also required.  
Stable 
Disease 
Not meeting criteria for CR, VGPR, PR, MR or PD 
(cont’d) 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 97 of 151 
 
 
Confidential 
12 April 2018 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) (cont’d) 
 PD 
• Increase of 25% from lowest response value in any of the 
following: 
o Serum M-component (absolute increase must be ≥ 0.5 
g/dL) and/or 
o Urine M-component (absolute increase must be ≥ 200 mg 
per 24 hours)  
o Only in patients without measurable serum and urine 
M-protein levels:  the difference between involved and 
uninvolved FLC levels (absolute increase must be 
>10 mg/dL) 
• Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in size of existing bone lesions 
or soft tissue plasmacytomas  
• Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL or 2.875 mmol/L) attributed solely to the plasma cell 
proliferative disorder* 
 
 
Abbreviations:  CR = complete response, FLC = free light chain, PD = progressive disease, PR = partial response, 
sCR = stringent complete response, SFLC = serum-free light chain, VGPR = very good partial response. 
All response categories (CR, sCR, VGPR, PR) require 2 consecutive laboratory assessments made  at any time 
before the institution of any new therapy (no minimum interval is required, it can be done the same day, 
however, to confirm response or progressive disease two discrete samples are required), as well as no 
known evidence of progressive or new bone lesions if radiographic studies were performed.  Radiographic 
studies are not required to satisfy these response requirements.  Bone marrow assessments are not required to be 
confirmed by repeat testing. 
Presence/absence of clonal cells is based upon the κ/λ ratio.  An abnormal κ/λ ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. 
Response criteria for all categories and subcategories of response except CR and VGPR are applicable only to 
patients that have “measurable” disease defined by at least one of SPEP ≥ 1 g/dL or UPEP ≥ 200 mg per 
24 hours; except for assessment of sCR, CR, or VGPR. 
Determination of PD while on study requires two consecutive assessments made at any time (no minimum 
interval is required, it can be done the same day, however, to confirm response or progressive disease two 
discrete samples are required)  before classification of PD and/or the institution of new therapy.  Serum M-
component increases of ≥ 1 g/dL from nadir are sufficient to define progression if nadir M-component is ≥ 5 
g/dL.     
*Development of hypercalcemia attributed soley to the plasma cell proliferative disorder is considered 
PD when confirmed with two consecutive assessments made at any time (Rajkumar, 2011). 
Plasmacytomas:  A definite increase in the size is defined as a ≥ 50% increase as measured serially by the sum 
of the products of the cross-diameters of the measurable lesion. A plasmacytoma is considered measurable if the 
longest diameter is at least 1 cm and the product of the cross diameters is at least 1 cm2.  Plasmacytomas of 
lesser size will be considered non-measurable. The requirement for bi-directional measurements applies only to 
plasmacytomas. The plasmacytoma specifications for PD are based on the sponsor’s interpretation of the 
IMWG-URC and practical considerations for study execution. 
Sources:  Durie 2006; Rajkumar 2011; Kumar, 2016. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 98 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX F: 
DEFINITION OF MINIMAL RESPONSE PER IMWG 
CRITERIA 
Minimal Response 
Response 
Subcategory 
Response Criteria 
MR 
25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-
hour urinary M-protein, which still exceeds 200 mg /24 hr  
 
If present at baseline, a >50% reduction in the size of soft tissue plasmacytomas is 
also required 
Abbreviations:  hr = hour(s), MR = minimal response.  
Sources: Kumar, 2016 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 99 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX G: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION 
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.      


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 100 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX H: 
SAMPLE DEXAMETHASONE 
PRESCRIBING INFORMATION 
 
http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase= 
renetnt&folderPath=/Prescribing+Information/PIs/Roxane/Dexamethasone/ 
Dexamethasone+Tablets+Solution+and+Intensol.pdf 
 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= 
Search.Overview&DrugName=DEXAMETHASONE 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 101 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX I:  PREGNANCY AND LACTATION NOTIFICATION WORKSHEETS 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 102 of 151 
 
 
Confidential 
12 April 2018 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 103 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX J:  SAE CONTINGENCY FORM 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 104 of 151 
 
 
Confidential 
12 April 2018 
 
 
 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 105 of 151 
 
 
Confidential 
12 April 2018 
 
 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 106 of 151 
 
 
Confidential 
12 April 2018 
 
 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 107 of 151 
 
 
Confidential 
12 April 2018 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 108 of 151 
 
 
Confidential 
12 April 2018 
APPENDIX K:  SUMMARY OF CHANGES 
SUMMARY OF CHANGES Superseding Amendment 1.0 - 12 April 2018 to Amendment 3 23 March 2018 
 
This summary of changes includes changes to the study synopsis and the body of the protocol to maintain consistency.   
Section(s) 
Changed from 
Changed to 
Rationale 
Title Page 
n/a 
Date of Superseding Amendment 1.0  12 April 2018 
 
Protocol 
Acceptance Page 
n/a 
Superseding Amendment 1.0/12 April 2018 
 
Synopsis 
For the exploratory objectives, a validated computer 
algorithm (Onyx Response Computational Assessment 
[ORCA]) will be used to assess response and disease 
progression. Time to event endpoints will include:  
• 
Duration of response, defined as the time from first 
evidence of PR or better to disease progression or 
death due to any cause; or will be censored at date of 
the last valid assessment 
• 
Duration of clinical benefit, defined as the time from 
first evidence of MR or better to disease progression 
or death due to any cause; or will be censored at date 
of the last valid assessment 
• 
Progression-free survival, defined as the time from 
first dose to the earlier of disease progression or death 
due to any cause; or will be censored at date of the 
last valid assessment 
• 
Overall survival, defined as the time from the first 
dose to the date of death (due to any cause); or will be 
censored at date of the last valid assessment 
n/a 
The right-censored rule for time to event endpoints is 
described in Section 12.5.1.2.   
Update to 
maintain 
consistency 
with section 12 
Statistical 
considerations 
Section 2.3 
Exploratory 
Objectives 
To estimate ORR, DOR, DCB, PFS and TTR using 
ORCA 
 
n/a 
s/a 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 109 of 151 
 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5 Subject 
Screening 
Evaluations obtained as part of routine medical care and 
performed prior to informed consent may be used in place 
of the study-specific evaluations, provided they meet the 
time windows described below  
Evaluations obtained as part of routine medical care and 
performed prior to informed consent may be used in place 
of the study-specific evaluations, provided they meet the 
time windows described in Section 9.2.1.   
Maintain 
consistency 
throughout the 
body of the 
protocol 
Section 12.4.2 Final 
Analysis 
Upon discontinuation of study treatment for reasons other 
than disease progression, subjects will be followed every 4 
weeks until disease progression or withdrawal of consent. 
After disease progression, each subject will be followed 
every 3 months (± 2 weeks) for OS for up to 3 years from 
the start of their study treatment, or until the subject has 
withdrawn from further participation, is lost to follow up, 
has died, or the sponsor makes a decision to close the 
study. 
Upon discontinuation of study treatment for reasons other 
than disease progression, subjects will be followed as 
described in Section 9.4.1 
 
After disease progression, each subject will be followed as 
described in Section 9.4.2. 
Maintain 
consistency 
throughout the 
body of the 
protocol 
Section 12.4.3 
Estimated Study 
Duration 
n/a 
Estimated study duration is about 48 months. 
 
Provide 
clarification 
Section 12.5.1.2 
Secondary Efficacy 
Analyses 
The duration of PFS will be right-censored for subjects 
who meet 1 of the following conditions:  1) starting a new 
anticancer therapy before documentation of disease 
progression or death; 2) death or disease progression 
immediately after more than 1 consecutively missed 
disease assessment visit or; 3) alive without 
documentation of disease progression before the data 
cutoff date.   
Median follow-up for PFS and OS will also be estimated 
according to the Kaplan-Meier estimate of potential 
follow-up also termed “reverse Kaplan-Meier” (Schemper 
1996). 
 
The duration of PFS will be right-censored for subjects 
who meet 1 of the conditions described in Table 12. 
 
If the date last known to be alive is after the data 
analysis cutoff date, the subject will be censored at the 
data analysis cutoff date. 
 
 
Duration of follow-up for PFS and OS will also be 
estimated according to the Kaplan-Meier estimate of 
potential follow-up also termed “reverse Kaplan-Meier” 
(Schemper 1996). 
 
Maintain 
consistency 
throughout the 
body of the 
protocol 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 110 of 151 
 
 
Confidential 
12 April 2018 
SUMMARY OF CHANGES Amendment 2 (09 November 2016) to Amendment 3 (23 
March 2018) 
 
This Summary of Changes outlines noteworthy changes from Amendment 2.0 to 
Amendment 3.0, and includes rationales for the changes.  Revisions to the main body of the 
protocol have also been made in the synopsis.  Deletions of text are presented in 
strikethrough; added text is presented in bold format. Minor and editorial changes are not 
listed in the following table.The main purposes for revising the 20140242 (CFZ005) protocol 
are to: 
1. Include the NCT number on the title page 
2. Update the name and contact number of the Study Medical Monitor 
3. Include new references throughout the document 
4. Add Exploratory Objectives 
5. Clarify the description of prior regimens 
6. Clarify the exclusion criteria for prior myocardial infarction 
7. Clarify the exclusion criteria for subjects with Hepatitis B 
8. Clarify the exclusion criteria regarding the treatment of active infection 
9. Clarify the guidelines for toxicity management (Tables 2, 3, and 6[removed]) 
10. Clarify the initiation of antiviral prophylaxis 
11. Provide a 2 day window for the administration of dexamethasone on days 22 and 
23 
12. Clarify the requirements for receiving radiation therapy and reporting 
Concomitant Medications. 
13. Include additional laboratory parameters  
14. Add ECOG to the screening assessment 
15. Clarify requirements for skeletal surveys 
16. Clarify acceptable imaging modalities for plasmacytomas 
17. Clarify and update the response criteria 
18. Clarify the criteria for discontinuation of study treatment 
19. Clarify the reporting period for adverse events 
20. Clarify the requirements for active and long term follow up 
21. Increase the window for obtaining the first PK specimen  
22. Include   Amgen templated language re withdrawal of consent 
23. Update Schedule of Assessments to be consistent with the above revisions 
24. Make minor editorial revisions 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 111 of 151 
 
Confidential 
12 April 2018 
Summary of Changes Amendment 2 to Amendment 3 
Section(s) 
Changed from 
Changed to 
Rationale 
Throughout the 
document 
n/a 
Additional references added:  Kumar S, Paiva B, 
Anderson KC, et al. International Myeloma Working 
Group consensus criteria for response and minimal 
residual disease assessment in multiple myeloma. 
Lancet Oncol 2016; 17:e328-46. 
Citations updated throughout the protocol: Kumar, 2016;  
Blade, 1998; Kyle, 2009 
 
Minor editorial revisions: e.g., spelling, grammar, bolding 
Update to 
include current 
references 
Cover Page 
n/a 
NCT Number   NCT03029234 
Regulatory 
requirement 
 
, MD  
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
  
, MD PhD 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
Change in 
Study Medical 
Monitor  
LIST OF 
ABBREVIATIONS 
AND 
DEFINITIONS OF 
TERMS 
n/a 
Added: 
aPTT activated partial thromboplastin time 
HBV Hepatitis B virus 
IFN 
Interferon alfa-2a 
IU 
International Units 
LLN Lower limit of normal 
ORCA Onyx Response Computational Assessment 
PEG-IFN 
Peginterferon alfa-2a   
 
Synopsis 
Efficacy variables 
Disease response will be assessed per investigator every 4 
weeks according to the International Myeloma Working 
Group – Uniform Response Criteria (IMWG-URC) 
(Durie, 2006; Rajkumar, 2011; MR will be assessed as per 
the modified European Group for Blood and Marrow 
Transplantation [EBMT] criteria, Bladé, 1998; Kyle, 
2009).  An IRC will assess best response after at least 6 
and after at least 12 cycles of Kd, from which ORR, CBR, 
Disease response will be assessed per investigator every 4 
weeks according to the International Myeloma Working 
Group – Uniform Response Criteria (IMWG-URC) 
(Durie, 2006; Rajkumar, 2011; Kumar, 2016); MR will be 
assessed as per Kumar, 2016.  An IRC will assess best 
response after at least 6 and after at least 12 cycles of Kd, 
from which ORR, CBR, DOR, DCB, TTR, and PFS will 
also be determined.   
To support 
exploratory 
endpoints  
PPD
PPD
PPD
PPD


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 112 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
DOR, DCB, TTR, and PFS will also be determined using 
investigator assessment of response.   
Section 1.3.2 
Clinical 
Background 
n/a 
 
As of 19 July 2017, Carfilzomib for Injection has been 
approved in 31 countries/regions worldwide. It is 
estimated that the number of patients exposed to 
carfilzomib from launch in July 2012 through 19 July 
2017 was 63 260 in the post marketing setting.   
Updated for 
clarity 
Section 1.4 Dose 
Rationale 
n/a 
The carfilzomib dosing schedule used in this study is 
used in the ongoing global phase 3 study, “A 
Randomized, Open-label, Phase 3 Study in Subjects 
with Relapsed and Refractory Multiple Myeloma 
Receiving Carfilzomib in Combination with 
Dexamethasone, Comparing Once-weekly versus 
Twice-weekly Carfilzomib Dosing” (Amgen 20140355). 
Updated for 
clarity 
Section 1.5 Study 
Rationale 
n/a 
To facilitate evaluation of response data, Multiple 
Myeloma disease response is assessed following the 
International Myeloma Working Group Uniform 
Response Criteria (IMWG-URC; Durie 2006, 
Rajkumar, 2011; Kumar 2016). The primary endpoint 
in this trial is ORR after each subject has had the 
opportunity to receive at least 6 cycles of therapy, with 
response as determined by review of subject data by an 
Independent Review Committee, following the IMWG-
URC.
To support new 
exploratory 
endpoints 
CCI
CCI


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 113 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 2.3 
Exploratory 
Objectives 
n/a 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are: 
• To evaluate ORR after at least 6 cycles of Kd using 
ORCA assessment of response 
• To evaluate ORR after at least 12 cycles of Kd using 
ORCA assessment of response 
• To estimate CBR after at least 6 and after at least 12 
cycles of Kd using ORCA 
• To estimate ORR, DOR, DCB, PFS and TTR using 
ORCA 
Include 
additional 
objectives to 
explore ORCA 
response 
criteria 
Section 3 Study 
Design 
n/a   
Subjects will receive treatment until disease progression, 
unacceptable toxicity, initiation of new anti-myeloma 
therapy, or discontinuation of study treatment for any 
other reason, whichever occurs first.   
Updated for 
clarity 
Section 4.1 
Inclusion Criteria 
2. c. 
In subjects without detectable serum or urine M 
protein, SFLC > 100 mg/L (involved light chain) and an 
abnormal κ/λ ratio 
2.  c. 
In subjects without measurable serum or urine 
M protein, SFLC > 100 mg/L (involved light chain) and 
an abnormal κ/λratio 
 
5. Subjects must have received ≥ 2 prior regimens.  
Induction therapy and stem cell transplant (± maintenance) 
will be considered as 1 regimen (as described in 9.1.2) 
Updated for 
clarity 
Section 4.2 
Exclusion Criteria 
12. Congestive heart failure ([CHF] New York Heart 
Association Class III to IV), symptomatic ischemia, 
conduction abnormalities, uncontrolled by conventional 
intervention or myocardial infarction within 6 months 
prior to Cycle 1 Day 1 
12. Congestive heart failure ([CHF] New York Heart 
Association Class III to IV), symptomatic ischemia, 
conduction abnormalities, uncontrolled by conventional 
intervention. Subjects cannot have experienced a 
myocardial infarction within 6 months prior to Cycle 1 
Day 1 
Updated for 
clarity 
Section 4.2 
Exclusion Criteria 
14. Acute active infection requiring systemic antibiotics, 
antivirals, or antifungals; within 2 weeks prior to Cycle 1 
Day 1 
 
14.  Acute active infection requiring systemic (either 
intravenous or oral)  antibiotics, antivirals, or 
antifungals; the treatment must be completed at least 2 
weeks prior to Cycle 1 Day 1 
 
Updated for 
clarity 
Section 4.2 
Exclusion Criteria 
n/a 
 
15. Known HIV seropositive, hepatitis C infection, and/or 
hepatitis B (except for patients with hepatitis B surface 
antigen or core antibody receiving and responding to 
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 114 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
antiviral therapy directed at hepatitis B: Note: patients 
who  are HepB surface antigen negative at screening, 
or are receiving IFN or PEG-IFN and have HBV DNA 
< 2000 IU at screening, or, are receiving a nucleos(t)ide 
analog and have HBV DNA below LLN at screening 
are eligible 
Section 8.1.3 
Dexamethasone 
Administration 
n/a 
Note: Days 22 and 23 dosing may be ± 2 days from the 
scheduled administration day.  Every effort should be 
made to maintain consecutive dosing days.  
  
 
 
Updated for 
clarity 
Table 2:  Guidelines 
for Hematologic 
Treatment Emergent 
Toxicities… 
 
 
 
 
 
 
 
 
Neutropenia 
When ANC 
first falls to  
≤ 0.5 × 
109/L 
If ANC < 0.5 
× 109/L 
Hold dose until 
ANC returns to 
≥ 0.5 × 109/L, 
then resume at 
same dose. 
For each 
subsequent 
drop to  
≤ 0.5 × 
109/L 
If ANC < 0.5 
× 109/L 
Hold dose until 
ANC returns to 
≥ 0.5 × 109/L, 
then resume at 1 
dose decrement. 
 
Neutropenia 
When ANC 
first falls to  
< 0.5 × 
109/L 
If ANC < 0.5 
× 109/L 
Hold dose until 
ANC returns to 
≥ 0.5 × 109/L, 
then resume at 
same dose.* 
For each 
subsequent 
drop to  
<0.5 × 109/L 
If ANC < 0.5 
× 109/L 
Hold dose until 
ANC returns to 
≥ 0.5 × 109/L, 
then resume at 1 
dose decrement. 
* If the first fall in platelet count or in ANC is observed 
before D8C1, then administer the protocol-specified 27 
mg/m2 on D8C1 
Updated for 
clarity   


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 115 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Table 3: Guidelines 
for Non-
hematologic 
Treatment Emergent 
Toxicities… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection  
Grade 3 or 4 
Hold 
carfilzomib 
until systemic 
treatment for 
infection is 
complete.  If 
ANC 
> 1.0 × 109/L, 
resume both 
drugs at same 
dose.  If 
ANC 
< 1.0 × 109/L, 
follow 
hematologic 
toxicities 
dose 
reduction 
guidelines  
 
Infection  
Grade 3 or 4 
Hold carfilzomib. 
Once infection is 
controlled and the 
subject is without 
infection-related 
symptoms, and if 
ANC > 0.5 × 109/L, 
resume at full dose. 
If ANC < 0.5 × 
109/L, follow 
hematologic 
toxicities dose 
reduction guidelines. 
Updated for 
clarity 
Table 3: Guidelines 
for Non-
hematologic 
Treatment Emergent 
Toxicities… 
 
 
 
b    If the Tumor Lysis Syndrome laboratory 
finding is observed before D8C1, administer the 
protocol-specified 27 mg/m2 when dosing is 
resumed. 
 
Tumor 
Lysis 
Syndrome  
3 or more of 
the following: 
… 
Hold carfilzomib 
until all 
abnormalities in 
serum chemistries 
have resolved; 
resume at same 
doseb 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 116 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 8.3 
Concomitant 
Medications 
n/a 
All concomitant medications must be recorded on the 
subject’s case report form (CRF) from informed consent to 
30 days following the last dose of study drug or initiation 
of new anti-myeloma therapy, whichever comes first.   
Updated for 
clarity 
Section 8.3.1 
Required and 
Optional 
Concomitant 
Medications 
n/a  
Valacyclovir 500 mg orally, daily (or equivalent antiviral) 
should continue for the duration of treatment. Antiviral 
prophylaxis is recommended to be initiated at least 24 
hours before the first dose of carfilzomib. 
Updated for 
clarity 
Section 8.3.2 
Excluded 
Concomitant 
Medications 
n/a   
Concurrent therapy with a marketed or investigational 
anticancer therapeutic (including steroids at a higher dose 
than this protocol specifies) or radiation to large marrow 
reserves for either a palliative or therapeutic intent is not 
allowed.  If a patient requires radiation therapy and 
wishes to remain on study, the radiation plan must be 
shared and written approval of the study medical 
monitor must be obtained prior to the initiation of 
radiation therapy. 
Updated for 
clarity 
Table 6: Dose 
Modifications 
During Carfilzomib 
Treatment 
Deleted 
n/a 
Table was not 
consistent with 
Tables  2 and 3:  
• Guidelines for 
Hematologic 
Treatment 
Emergent 
Toxicities  in 
Carfilzomib 
Patient 
• Guidelines for 
Non-
hematologic 
Treatment 
Emergent 
Toxicities  in 
Carfilzomib 
Patients 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 117 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 9.1.8.1 
Table 6: Laboratory 
Tests: Chemistry 
Panel 
n/a 
 
Bicarbonate or Total CO2 
Total Co2 
commonly 
measured in 
China  
Section 9.1.8.3  
Table 8: Laboratory 
Tests: Coagulation 
Panel 
n/a 
aPTT 
Activated partial thromboplastin time 
 
Abbreviations:  PT = Prothrombin time, aPTT = 
activated partial thromboplastin time, INR = 
international normalized ratio 
 
 
Section 9.1.10.1 
Plasmacytoma 
Evaluation 
n/a  
The baseline plasmacytoma evaluation may consist of 
palpation, ultrasound, computed tomography (CT) scan, 
magnetic resonance imaging (MRI), or positron emission 
tomography with diagnostic CT (PET/CT). Bone 
scintigraphy is not an acceptable method of 
plasmacytoma imaging. 
Updated for 
clarity 
Section 9.1.10.2 
Skeletal Survey 
n/a 
Skeletal survey by plain radiography will include lateral 
radiograph of the skull, anteroposterior and lateral views 
of the spine, and anteroposterior views of the pelvis, ribs, 
femora, and humeri. Skeletal survey may be done by X-
ray, CT, CT/PET, or MRI.  Bone scintigraphy is not an 
acceptable method of skeletal imaging.   The skeletal 
survey will be conducted at screening and will be repeated 
if worsening clinical symptoms suggest PD, or as 
clinically indicated. 
Updated for 
clarity   
Section 9.1.10.3 
Bone Marrow 
Aspirate and/or 
Biopsy 
n/a. . 
A bone marrow aspirate and/or biopsy, evaluated locally, 
is required to confirm a laboratory response of CR or 
sCR. . 
Updated for 
clarity 
Section 9.1.10.4 
Disease Response 
and Progression 
Assessments 
Minimal response will be assessed using the European 
Group for Blood and Marrow Transplant (EBMT) criteria 
(Appendix F).   
Minimal response will also be assessed (Kumar 2016; 
Appendix F.)   
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 118 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
9.1.10.4.1 
Laboratory 
Assessments of 
Disease - Screening 
n/a 
If multiple disease assessment measurements are 
available before initiation of therapy, the measurement 
closest to Cycle 1, Day 1 will be used as baseline 
(Kumar, 2016). 
Updated for 
clarity 
9.1.10.4.3 Response 
Assessments 
Two consecutive laboratory assessments of M protein 
level (serum and/or urine), made at least 24 hours apart 
and assessed at the central study lab, drawn at any time 
before the start of new (off protocol) myeloma therapy. 
 
 
 
 
 
No known evidence of progressive or new bone lesions on 
skeletal survey if radiographic studies are performed after 
baseline. 
 
 
SFLC assay and confirmatory SFLC (24 hours to 28 days 
later).  A normal κ/λ ratio is required to confirm a sCR.  
This test will be performed at the central laboratory 
 
Bone marrow aspirate and/or biopsy is required to confirm 
CR or sCR (Appendix E).   
 
Two consecutive laboratory assessments of M protein 
level (serum and/or urine) drawn at any time before the 
start of new (off protocol) myeloma therapy.  No 
minimum interval is required for SPEP, SIFE, SFLC, 
it can be done on the same day, however to confirm 
response or progressive disease, 2 discrete samples are 
required; testing cannot be based on the splitting of a 
single sample. 
 
No known evidence of progressive or new bone lesions on 
skeletal survey if radiographic studies are performed after 
baseline; however, radiology examination is not a 
scheduled assessment after baseline unless clinically 
indicated. 
SFLC assay and confirmatory SFLC.  A normal κ/λ ratio 
is required to confirm a sCR.  This test will be performed 
at the central laboratory 
 
 
Bone marrow aspirate and/or biopsy is required to confirm 
laboratory evidence of CR or sCR (Appendix E).   
Updated for 
clarity 
9.1.10.4.4 
Progressive Disease 
Progressive disease requires 2 consecutive laboratory 
assessments of M protein level made at least 24 hours 
apart before classification as relapse or disease 
progression and/or the institution of any new therapy.   
Progressive disease requires 2 consecutive laboratory 
assessments of M protein level before classification as 
relapse or disease progression and/or the institution of any 
new therapy.   
Updated for 
clarity 
Section 9.1.11 
Adverse events  
For all subjects, all AEs, regardless of causality, must be 
recorded in the designated CRF from the first dose of IP to 
30 days following the last dose of all study drugs. 
For all subjects, all AEs, regardless of causality, must be 
recorded in the designated CRF from the first dose of IP 
through 30 days following the last dose of all study drugs 
or the initiation of new anti-myeloma therapy 
To be 
consistent with 
Section 11 
Section  9.1.12 
Concomitant 
Medications 
n/a 
All concomitant medications must be recorded in the 
designated CRF from informed consent to 30 days 
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 119 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
following the last dose of all study drugs or initiation of 
new anti-myeloma therapy, whichever comes first.   
Section 9.1.14 
Survival 
Section Deleted:  
Upon study treatment discontinuation, subjects who have 
not progressed will be followed in Active Follow up every 
4 weeks ± 4 days to monitor for disease progression.  
Active Follow Up will end upon confirmed PD, 
withdrawal of consent for further participation, loss to 
follow up, death, or study closure.  After disease 
progression, subjects will be followed in Long Term 
Follow Up every 3 months (± 2 weeks) for survival for up 
to 3 years from start of Cycle 1 Day 1, or until the subject 
has withdrawn from further participation, is lost to follow 
up, has died, or the sponsor makes a decision to close the 
study.   
n/a 
Section 
incorporated 
into Section 9.4 
Follow-up 
Section 9.1.3 and 
Table 9 
Timing of Sample Collection 
• Immediately (within 1 minute) before the end of infusion 
Timing of Sample Collection 
• Immediately (within 2 minutes) before the end of 
infusion 
To 
accommodate 
clinical practice 
Section 9.2.1 
Screening 
Assessments 
• n/a 
 
 
 
 
 
• Obtain blood sample for coagulation tests (PT, PPT, and 
INR) 
 
• Perform bone marrow biopsy and/or aspirate, 
documenting percent plasma cells in the marrow.  
Performing FISH is preferred but optional.  Note:  Studies 
do not need to be repeated if previously done within 30 
days of informed consent. 
 
• Obtain skeletal survey.  Study does not need to be 
repeated if previously done within 30 days of informed 
consent. 
• Obtain medical history, including prior cancer 
surgery/radiotherapy, transplant, tobacco history (years of 
tobacco use; packs per day of cigarettes) and alcohol 
history (current number of alcoholic drinks per week), 
neuropathy history, and ECOG 
 
• Obtain blood sample for coagulation tests (PT, aPTT, or 
PTT, and INR) 
 
• Perform bone marrow biopsy and/or aspirate, 
documenting percent plasma cells in the marrow.  
Performing FISH is preferred but optional.  Note:  Bone 
marrow assessment does not need to be repeated if it is 
conducted within 30 days of informed consent  
 
 
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 120 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
 
 
• Obtain skeletal survey.  Note: skeletal assessment does 
not need to be repeated if done within 30 days of 
informed consent   
 
 
Section 9.2.2 Cycle 
1 Days -2 and -1 
n/a 
  
 
Antiviral prophylaxis is recommended to be initiated 
at least 24 hours prior to the first dose 
 
Updated for 
clarity 
Section 9.2.2 Cycle 
2 (and higher) Day 
1 
n/a 
Response assessments based upon the laboratory results 
are to be made once the disease assessment laboratory 
results become available, following guidelines in 
Appendix E.   
 
Section 9.2.16 End 
of Treatment 
Assessment… 
n/a 
• Obtain ECG as described in Section 9.1.6 
To be 
consistent with 
schedule of 
assessments 
Section 9.2.9 Cycle 
2 (and higher) 
Day 1 
n/a 
Response assessments based upon the laboratory results 
are to be made once the disease assessment laboratory 
results become available, following guidelines in 
Appendix E.   
To clarify that 
response is per 
protocol 
Section 9.4  
Long Term Follow-up Visits 
Follow-up Visits 
Updated for 
clarity 
Section 9.4.1 
n/a  
All subjects who discontinue study treatment for reasons 
other than PD will be followed in active follow-up every 4 
weeks (+or- 4 days; first visit should be 4 weeks after 
EOT visit) for disease progression until confirmed PD, 
withdrawal of consent for further participation, loss to 
follow-up, initiation of new, non-protocol anti-myeloma 
therapy, death, or study closure. During active follow-up, 
subjects will be evaluated every 4 weeks (+or- 4 days). 
Multiple myeloma disease assessment will be performed 
with laboratory evaluations as specified in Section 
9.1.10.4.2. Physical and laboratory assessments will be 
performed as clinically indicated. 
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 121 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 9.4.2 Long 
Term Follow-up 
n/a 
After disease progression or initiation of new non-
protocol anti-myeloma therapy, subjects will be 
followed every 3 months (± 2 weeks) for survival for up to 
3 years from start of study treatment, or until the subject 
has withdrawn consent for further participation, is lost to 
follow up, has died, or the sponsor makes the decision to 
close the study. 
Updated for 
clarity 
Section 10 Study 
Discontinuation 
Subjects who withdraw from treatment will be monitored 
for AEs as described in Section 11 and Appendix D 
(National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI-CTCAE], version 4.03).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator may discontinue study treatment for any 
of the following reasons: 
 
•Disease progression (PD must be verified with 1 set of 
confirmatory labs drawn at least 1 day following initial PD 
labs) 
 
Withdrawal of consent for a study means that the 
subject does not wish to receive further protocol-
required therapies or procedures, and the subject does 
not wish to or is unable to continue further study 
participation.  Subject data up to withdrawal of 
consent will be included in the analysis of the study, 
and where permitted, publically available data can be 
included after withdrawal of consent.  The investigator 
is to discuss with the subject appropriate procedures 
for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical 
records.  Subjects who withdraw from treatment will be 
monitored for AEs as described in Section 11 and 
Appendix D (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE], 
version 4.03).    
If a subject withdraws from the study, he/she may 
request destruction of any samples taken and not 
tested, and the investigator must notify Amgen 
accordingly. 
 
The investigator may discontinue study treatment for any 
of the following reasons: 
 
•Disease progression (PD must be verified with 1 set of 
confirmatory labs. 
 
To be 
consistent with 
Amgen 
templated 
language 
Section 11.3.1 
General 
n/a 
All AEs will be collected from the time the subject 
receives the first dose of carfilzomib through 30 days after 
Updated for 
clarity 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 122 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
receiving the last dose of carfilzomib, or until initiation 
of a new anti-cancer therapy after receiving the last 
dose of carfilzomib, whichever comes first. 
Section 11.3.2 
Disease Progression 
Discontinuation of treatment due to progression of disease 
should be recorded on the treatment discontinuation CRF 
as “Disease Progression.”  If the progression of disease 
meets any of the serious criteria, as outlined in Section 
11.4, it should also be recorded as a SAE in the AE CRF.  
All disease progression related deaths occurring from the 
time of signing of the ICF through 30 days after last dose 
of study drug(s) must be reported on the AE CRF as a 
SAE using the verbatim term “Disease Progression” rather 
than signs and/or symptoms that may have been the 
immediate cause of death. Additional details of the event 
(such as the contributory causes of death) should be 
reported on the Death CRF. 
Discontinuation of treatment due to progression of disease 
should be recorded on the treatment discontinuation CRF 
as “Disease Progression”.  Disease progression will be 
documented in an eCRF intended to capture PD 
information and will be analyzed as a study endpoint. 
Signs and symptoms related to disease progression 
(e.g., pathologic fracture in a subject with progressive 
multiple myeloma) should be reported in the 
appropriate eCRF as an AE or as an SAE (if the event 
in question meets the criteria for seriousness). 
Verbatim terms such as “disease progression,” 
“progressive disease,” etc. should not be reported as 
AEs or SAEs unless the investigator considers the 
progression to be atypical, accelerated, or caused by 
the study drug. Similarly deaths occurring as a result 
of disease progression should be reported on the eCRF 
intended to capture death information and should not 
be reported as SAEs.  
Additional details of the event (such as the contributory 
causes of death) should be reported on the Death CRF. 
Update to be 
consistent with 
ARROW 
protocol 
Section 11.5 Serious 
Adverse Event 
Reporting and 
Documentation 
Requirements 
n/a 
The investigator is responsible for ensuring that all SAEs 
observed by the investigator or observed by the subject 
that occur after signing the ICF through 30 days after the 
last dose of carfilzomib or initiation of new 
anti-myeloma therapy are recorded in the subjects’ 
medical record and are reported to the sponsor. 
New 
Exploratory 
endpoints 
Section 12.1.3 
Exploratory 
Endpoints 
n/a 
12.1.3 
Exploratory Endpoints: 
Efficacy endpoints related to response and disease 
progression will be determined based on a validated 
computer algorithm (Onyx Response Computational 
Assessment; [ORCA]) are: 
•ORR after at least 6 cycles of Kd and after at least 12 
cycles 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 123 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
•CBR after at least 6 cycles and after at least 12 cycles 
•Duration of response 
•Duration of clinical benefit 
•Progression-free survival 
•Time to response 
Section 12.4.4. 
Independent Review 
Committee 
Responses will be assessed using the IMWG-URC (Durie, 
2006; Rajkumar; 2011) (Appendix E) and minimal 
response as defined by EBMT criteria, Blade; 1998. 
Responses will be assessed using the IMWG-URC (Durie, 
2006; Kumar, 2016) (Appendix E) and minimal 
response will be evaluated following IMWG-URC 
(Kumar, 2016, Appendix F). 
 
Section 12.5.1.2 
Secondary Efficacy 
Analyses 
Clinical benefit rate, defined as the proportion of subjects 
with the best overall response (per the investigator) of MR 
or better, will be determined along with the 95% exact 
binomial CI.  Minimal response will be defined according 
to EBMT criteria 
Clinical benefit rate, defined as the proportion of subjects 
with the best overall response (per the investigator) of MR 
or better, will be determined along with the 95% exact 
binomial CI.  Minimal response will be defined according 
to IMWG criteria 
Update 
Section 12.5.1.3 
Exploratory 
Efficacy analysis 
n/a 
Efficacy endpoints related to response and disease 
progression determined by ORCA will be analyzed per 
the methods described in Section 12.5.1.1 and 12.5.1.2 
To support 
exploratory 
endpoints 
Section 12.6 Safety 
Analysis 
n/a 
Treatment-emergent adverse events are defined as AEs 
occurring from the first dose of study treatment through 30 
days after the last dose of study treatment or initiation of 
new anti-myeloma therapy, whichever comes first.   
Updated for 
clarity 
Section 12.7 
Pharmacokinetic 
Analyses 
n/a 
Pharmacokinetic data analysis set will include 
approximately 15 subjects who received carfilzomib. 
To account for 
simultaneous 
collection at 
multiple sites 
Appendix E  
International 
Uniform Response 
Criteria 
For Multiple 
Myeloma 
 
PR 
• 
≥ 50% reduction of serum M-protein 
and reduction in 24-hour urinary M-
protein by ≥ 90% or to < 200 mg per 
24 hours   
• 
If the serum and urine M-protein are 
not measurable, a decrease ≥ 50% in 
the difference between involved and 
uninvolved FLC levels is required in 
place of the M-protein criteria. 
 
Stable 
Disease 
Not meeting criteria for CR, VGPR, PR, 
MR or PD 
 
 
 
 
 
 
 
 
Patients with 
unmeasurable 
serum and urine 
M protein are 
not eligible for 
this trial  
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 124 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
• 
If the serum and urine M-protein are 
not measurable, and serum free light 
assay is also not measurable, ≥ 50% 
reduction in bone marrow PCs is 
required in place of M-protein, 
provided baseline percentage was ≥ 
30%. 
• 
In addition to the above criteria, if 
present at baseline, ≥ 50% reduction in 
the size of soft tissue plasmacytomas is 
also required.  
. 
 PD 
• 
Increase of 25% from lowest response 
value in any of the following: 
• 
Serum M-component (absolute 
increase must be ≥ 0.5 g/dL) and/or 
• 
Urine M-component (absolute 
increase must be ≥ 200 mg per 
24 hours) and/or 
• 
Only in patients without 
measurable serum and urine 
M-protein levels:  the difference 
between involved and uninvolved 
FLC levels (absolute increase must 
be >10 mg/dL) 
• 
Only in patients without 
measurable serum and urine M 
protein levels and without 
measurable disease by FLC levels, 
bone marrow PC percentage 
(absolute percentage must be ≥ 
10%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised for 
clarity (the FLC 
rules do not 
directly relate 
to the above 
rules for PD) 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 125 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
• 
Definite development of new bone 
lesions or soft tissue plasmacytomas or 
definite increase in size of existing 
bone lesions or soft tissue 
plasmacytomas  
• 
Development of hypercalcemia 
(corrected serum calcium > 11.5 mg/dL 
or 2.875 mmol/L) attributed solely to 
the plasma cell proliferative disorder* 
. 
 
 
 
 
 
Appendix E 
footnotes 
All response categories (CR, sCR, VGPR, PR) require 2 
consecutive laboratory assessments made at least 24 hours 
apart at any time before the institution of any new as well 
as no known evidence of progressive or new bone lesions 
if radiographic studies were performed.  Radiographic 
studies are not required to satisfy these response 
requirements.  Bone marrow assessments are not required 
to be confirmed by repeat testing. 
 
 
 
Response criteria for all categories and subcategories of 
response except CR and VGPR are applicable only to 
patients that have “measurable” disease defined by at least 
one of SPEP ≥ 1 g/dL or UPEP ≥ 200 mg per 24 hours; 
except for assessment of sCR, CR, or VGPR; patients with 
measurable disease restricted to SPEP will need to be 
followed only by SPEP.  Correspondingly, patients with 
measurable disease restricted to UPEP will need to be 
followed only by UPEP. 
 
Determination of PD while on study requires two 
consecutive assessments made at any time at least 24 
All response categories (CR, sCR, VGPR, PR) require 2 
consecutive laboratory assessments made at any time 
before the institution of any new therapy (no minimum 
interval is required, it can be done the same day, 
however, to confirm response or progressive disease 
two discrete samples are required), as well as no known 
evidence of progressive or new bone lesions if 
radiographic studies were performed.  Radiographic 
studies are not required to satisfy these response 
requirements.  Bone marrow assessments are not required 
to be confirmed by repeat testing. 
n/a 
 
Determination of PD while on study requires two 
consecutive assessments made at any time (no minimum 
interval is required, it can be done the same day, 
however, to confirm response or progressive disease 
two discrete samples are required)  before classification 
of PD and/or the institution of new therapy.  Serum M-
component increases of ≥ 1 g/dL from nadir are sufficient 
to define progression if nadir M-component is ≥ 5 g/dL.     
*Development of hypercalcemia attributed solely to the 
plasma cell proliferative disorder is considered PD 
Clarifying 
language added 
from Kumar, 
2016 
 
 
 
 
 
 
 
 
 
 
Clarifying 
language added 
from Kumar, 
2016 
 
 
 
 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 126 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
hours apart before classification of PD and/or the 
institution of new therapy.  Serum M-component increases 
of ≥ 1 g/dL from nadir are sufficient to define progression 
if nadir M-component is ≥ 5 g/dL.     
 
when confirmed with two consecutive assessments 
made at any time (Rajkumar, 2011). 
 
Clarification 
due to revision 
of IMWG-URC 
– protocol 
amendment 3 
continues to 
follow the 
Rajkumar 2011 
hypercalcemia 
definition. 
Rajkumar 2011 
specifies 
Hypercalcemia, 
corrected serum 
calcium >11.5 
mg/dL to fulfill 
criteria for PD.   
Kumar 2016 
does not define 
PD based on 
hypercalcemia 
(hypercalcemia 
to >11 mg/dL 
fulfils 
definition of 
‘Clinical 
Relapse’ per 
Kumar 2016) 
Appendix F 
Definition of 
Minimal Response 
DEFINITION OF MINIMAL RESPONSE PER EBMT 
CRITERIA 
Minimal Response 
Response 
Subcategory 
Response Criteria 
DEFINITION OF MINIMAL RESPONSE PER IMWG 
CRITERIA 
Minimal Response 
Response 
Subcategory 
Response Criteria 
To be 
consistent with  
IMWG-URC 
criteria 
 
Minimal 
response is not 
a component of 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 127 of 151 
 
Confidential 
12 April 2018 
Section(s) 
Changed from 
Changed to 
Rationale 
MR 
25% to 49% reduction in the level 
of serum M-protein or a 50% to 
89% reduction in 24-hour urinary 
M-protein, which still exceeds 200 
mg /24 hr, maintained for a 
minimum of 8 weeks. 
 
25% to 49% reduction in the size 
of soft-tissue plasmacytomas (by 
radiography or clinical 
examination) 
Abbreviations:  EBMT = European Group for Blood and 
Marrow Transplantation, hr = hour(s), MR = minimal 
response.  
Sources:  Bladé 1998; Kyle 2009. 
 
MR 
25% to 49% reduction in the level 
of serum M-protein and a 50% to 
89% reduction in 24-hour urinary 
M-protein, which still exceeds 200 
mg /24 hr  
 
If present at baseline, a >50% 
reduction in the size of soft 
tissue plasmacytomas is 
also required   
Abbreviations:  IMWG = International Myeloma 
Working Group.  hr = hour(s), MR = minimal response.  
Sources: Kumar, 2016 
 
the primary 
endpoint, ORR, 
but is a 
component of 
the secondary 
endpoints, CBR 
and DCB.  
Minimal 
response was 
not previously 
defined in 
IMWG URC. 
With the 
inclusion of 
MR in the 
Kumar 2016 
IMWG URC, 
this definition 
of MR is used 
in PA3.   This 
change does not 
impact trial 
conduct as 
subjects in 
minimal 
response are to 
continue 
therapy per 
protocol. 
Tables 13 and 14 
Schedule of 
Assessments 
n/a 
Footnotes updated to reflect the changes described above 
.. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 128 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
This Summary of Changes outlines noteworthy changes from the original protocol to 
Amendment 2.0, and includes rationales for the changes.  Minor and editorial changes are not 
listed in the following table. 
The main purposes for revising the 20140242 (CFZ005) protocol are to: 
1. Add a (-1) day to the collection window for chemistry on Day 1, 8 and 15. The chemistry 
panel for Days 2, 9 and 16 were made optional.  Collection of blood on day of dosing 
does not reflect normal practice.  Hence, the requirement of collecting blood on Day 2, 9 
and 16 could lead to protocol deviations and/or affect patient enrollment. 
2. Remove the requirement to perform FISH analysis, and made it optional.  This was done 
because not all the participating sites are able to perform FISH, so is has been confirmed 
that this requirement will lead to protocol deviations. 
3. Remove language that suggest x-ray for plasmacytoma imaging.  X-ray is not used for 
plasmacytoma imaging and hence, has been removed as a possible imaging technique. 
4. Change “Bone Marrow Aspirate and Biopsy” to “Bone Marrow Aspirate and/or Biopsy”.  
Not all the participating sites can do both bone marrow aspirate and biopsy.  Hence the 
wording was update to “and/or” to avoid protocol deviations. 
5. Update the primary objective to clarify that the overall response rate (ORR) will be 
evaluated after “at least” 6 cycles of carfilzomib in combination with dexamethasone 
(Kd), and a second ORR evaluation will be evaluated after “at least” 12 cycles. 
6. Update the End Of Study definitions. Some of the changes include: 
a.  Changed primary completion to change it from when all subjects “complete”, to 
“have had the opportunity to complete” 
b. End of Trial was updated to End of Study and the definition was clarified. 
7. Clarify in the subject design that subjects “must have received at least two prior 
regiments”. 
8. Clarify in the study design that subjects will receive treatment until disease progression, 
unacceptable toxicity, or discontinuation of study treatment for any other reason, 
“whichever occurs first”. 
9. Clarify that subjects of child-bearing potential (FCBP) must have a negative serum 
pregnancy test within 7 days prior to first dose of carfilzomib, instead of within 21 days 
prior to enrollment. 
10. Clarify that intravenous hydration will be given immediately prior and following 
carfilzomib administration during Cycle 1. If uric acid is elevated at Cycle 2, Day 1, then 
the recommended IV hydration should be repeated for all of Cycle 2, and, at the 
investigator’s discretion, in conjunction with subsequent cycles. 
11. The excluded concomitant medication was updated to clarify that no alternative 
anticancer therapy are allowed prior to confirmed progressive disease. 
12. Added information regarding Posterior Reversible Encephalopathy Syndrome, 
Thrombotic Microangiopathy, and Venous Thrombosis to the Safety Guidance for 
Investigators section 
13. Serious Adverse Events are now being collected at the time of signing of the ICF, while 
the Adverse Events are still being collected at time of first dose. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 129 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
14. Update the background information 
15. Study Medical Monitor information and details regarding sponsor was updated 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 130 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
SUMMARY OF CHANGES Amendment 1 (10 May 2016) to Amendment 2 (09 November 2016) 
 
Significant changes are described in the table below. The revisions done in protocol main body also applies to protocol synopsis. 
Deletions of text are presented in strikethrough format. Added text is presented in bold format. 
 
 
 
Section(s) 
Changed from 
Changed to 
Rationale 
Global 
10 May 2016 
09 November 2016 
Administrative 
Global 
To evaluate ORR after 6 cycles of Kd 
To evaluate ORR after 12 cycles of 
Kd 
To evaluate ORR after at least 6 cycles of Kd 
To evaluate ORR after at least 12 cycles of Kd 
Clarification 
Global 
Bone marrow aspirate and biopsy 
Bone marrow aspirate and/or biopsy 
Clarification 
Cover page 
Sponsor:  
Onyx Therapeutics, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
Study Medical Monitors: 
 
, MD 
Room 1501-1506, No 233 Platinum 
Tower 
Taicing Road 
Shanghai 200020 China 
 
 
 
, MD, PhD  
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
Sponsor:  
Onyx Therapeutics, Inc., 
an Amgen subsidiary. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
 
Study Medical Monitors: 
 
, MD 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
  
Administrative 
updates 
Cover page 
N/A 
Add: 
Date of Protocol Amendment 2.0   
09 November 2016 
Administrative 
update 
PPD
PPD
PPD
PPD
PPD
PPD


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 131 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Cover page, 
Confidentiality 
Statement 
This material is the property of 
Amgen, Inc.  The material is highly 
confidential and is to be used only in 
connection with matters authorized by 
a senior representative of Amgen, 
Inc., and no part of it is to be 
disclosed to a third party without the 
express prior written permission of 
Amgen, Inc. 
This material is the property of Onyx Therapeutics, Inc., a wholly 
owned subsidiary of Onyx Pharmaceuticals, Inc., an Amgen Inc. 
subsidiary.  The material is highly confidential and is to be used only in 
connection with matters authorized by a senior representative of Onyx 
Therapeutics, Inc., and no part of it is to be disclosed to a third party 
without the express prior written permission of Amgen, Inc. 
Administrative 
update 
Cover page, 
Compliance 
Statement 
This study will be conducted in 
accordance with Protocol 20140242 
(CFZ005), the International 
Conference on Harmonisation (ICH), 
Good Clinical Practice (GCP) 
guidelines, and the applicable country 
and regional regulatory requirements. 
This study will be conducted in accordance with Protocol 20140242 
(CFZ005), the relevant Onyx Therapeutics, Inc., an Amgen Inc. 
subsidiary, policies and procedures, the International Conference on 
Harmonisation (ICH), Good Clinical Practice (GCP) guidelines, and the 
applicable country and regional (local) regulatory requirements. 
Administrative 
update 
Protocol 
Acceptance Page 
Issue/Date: 20140242 
(CFZ005)/Protocol 
Amendment 1.0/10 May 2016 
Issue/Date: 20140242 (CFZ005)/Protocol 
Amendment 2.0/09 November 2016  
Administrative 
update 
Synopsis, Name of 
sponsor/ company: 
Amgen, Inc. 
Onyx Therapeutics, Inc. (Subsidiary of Amgen, Inc.) 
Administrative 
update 
Synopsis, Study 
Design, Paragraph 
1 
N/A 
Add: 
Subjects must have received at least two prior regimens and are 
required to have previous treatment with an alkylating agent or 
anthracycline, bortezomib, and an IMiD.   
Clarification 
Synopsis, Study 
Design, 
Paragraph 3, 4, 
and 5 
Study treatments will be administered 
until disease progression, 
unacceptable toxicity, or 
discontinuation of study treatment for 
any other reason.   Dose reductions of 
carfilzomib and dexamethasone will 
be permitted per protocol guidelines. 
 
The enrollment period is anticipated 
to be approximately 16 months.   
 
Study treatments will be administered until disease progression, 
unacceptable toxicity, or discontinuation of study treatment for any other 
reason, whichever occurs first.   Dose reductions of carfilzomib and 
dexamethasone will be permitted per protocol guidelines. 
 
The enrollment period is anticipated to be approximately 16 months.   
 
Upon discontinuation of study treatment for reasons other than disease 
progression, subjects will be followed every 4 weeks until disease 
progression, or withdrawal of consent.   
Wording changed 
to secure 
clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 132 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Upon discontinuation of study 
treatment for reasons other than 
disease progression, subjects will be 
followed every month until disease 
progression, withdrawal of consent, or 
initiation of new, non-protocol 
antimyeloma therapy, whichever 
occurs first.   
Synopsis, 
Treatment 
regimen(s): 
N/A 
Add: 
Carfilzomib and dexamethasone treatments will be administered in 
28-day cycles until disease progression, unacceptable toxicity, or 
discontinuation from study treatment for any other reason, whichever 
occurs first. 
Clarification 
Synopsis, 
Inclusion Criteria 
4. Refractory to the most recently 
received therapy.  Refractory 
disease defined as ≤ 25% 
response to, or progressing during 
therapy or within 60 days after 
completion of therapy 
14 Refractory to the most recently received therapy.  Refractory 
disease defined as ≤ 25% response to, or progressing during therapy 
or within 60 days after last therapy 
Clarification 
Synopsis, 
Exclusion Criteria 
15. 
Written informed consent in 
accordance with federal, local, 
and institutional guidelines 
16. 
Female subjects of child-
bearing potential (FCBP) must 
have a negative serum 
pregnancy test within 21 days 
prior to enrollment and agree to 
use an effective method of 
contraception during and for 30 
days following last dose of 
carfilzomib. 
17. 
Male subjects must use an 
effective barrier method of 
contraception during the study 
and for 3 months following the 
last dose of carfilzomib if 
sexually active with a FCBP. 
15. 
Written informed consent in accordance with national, local, 
and institutional guidelines 
 
16. 
Female subjects of child-bearing potential (FCBP) must have a 
negative serum pregnancy test within 7 days prior to first dose of 
carfilzomib and agree to use an effective method of contraception 
during and for 30 days following last dose of carfilzomib. 
17. 
Male subjects must use an effective barrier method of 
contraception during the study and for 90 days following the last 
dose of carfilzomib if sexually active with a FCBP. 
Correction of 
wording 
 
Requirement 
changed to reflect 
003A1 protocol 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 133 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Synopsis, 
Exclusion Criteria 
N/A 
Add: 
9. Participation in an investigational therapeutic study within 3 weeks 
or within 5 drug half-lives (T½) prior to Cycle 1 Day 1, whichever 
time is greater 
Clarification 
Synopsis, 
Exclusion Criteria 
N/A 
Delete: 
19. Subjects in whom the required program of PO and IV fluid 
hydration is contraindicated, e.g., due to pre-existing pulmonary, 
cardiac, or renal impairment 
Clarification 
Synopsis, Criteria 
for evaluation, 
Efficacy variables 
An IRC will assess best response after 
6 and after 12 cycles of Kd, from 
which ORR, CBR, DOR, DCB, TTR, 
and PFS will also be determined using 
investigator assessment of response.  
Subjects will be followed every month 
for disease progression 
An IRC will assess best response after at least 6 and after at least 
12 cycles of Kd, from which ORR, CBR, DOR, DCB, TTR, and PFS 
will also be determined using investigator assessment of response.  
Subjects will be followed every 4 weeks for disease progression 
Clarification 
Synopsis, 
Statistical methods 
and analyses, 
Paragraph 7 
N/A 
Delete: 
OS analysis will be performed at the end of study. 
Clarification 
List of 
Abbreviations and 
Definitions of 
Terms 
N/A 
Add: 
PD 
progressive disease 
PRES 
posterior reversible 
encephalopathy syndrome 
TTP/HUS 
thrombotic 
thrombocytopenic purpura 
/ haemolytic uraemic 
syndrome 
 
Addition of 
lacking 
abbreviation 
1.1 Multiple 
Myeloma 
Multiple myeloma, a clonal neoplastic 
proliferation of plasma cells, is the 
second most common hematologic 
malignancy and is responsible for 
approximately 72,000 annual deaths 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is 
the second most common hematologic malignancy and is responsible for 
approximately 72,000 annual deaths worldwide (Ferlay 2010).  There 
are an estimated 4,000 multiple myeloma deaths per year in China 
(Ferlay 2008), 11,000 deaths per year in the United States (US) and 
Clarification and 
updated data 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 134 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
worldwide (Ferlay 2010).  There are 
an estimated 4,000 multiple myeloma 
deaths per year in China (Ferlay 
2008), 11,000 deaths per year in the 
United States (US) and more than 
19,000 deaths per year in Europe 
(American Cancer Society 2005; 
Boyle 2005).  Multiple myeloma is 
characterized by anemia, bone 
destruction, monoclonal gammopathy, 
renal failure, hypercalcemia, and 
increased susceptibility to infections.  
The disease is systemic and 
chemotherapy is indicated for 
management of symptomatic 
myeloma.  Current treatment options 
in China commonly include 
combination chemotherapy with 
regimens using melphalan, 
bortezomib, and thalidomide (an 
immunomodulatory drug [IMiD]) 
with and without corticosteroids such 
as dexamethasone or prednisone and 
other agents.  Eligible subjects 65 to 
70 years old or younger frequently 
undergo consolidation therapy with 
myeloablative chemotherapy or 
radiation followed by autologous stem 
cell transplantation.  Although 
improvements in progression-free 
survival (PFS) and overall survival 
(OS) have occurred in the past 5 
years, even with the best available 
approved agents, essentially all 
patients eventually relapse.  Median 
survival from diagnosis was reported 
at 42 months (Jawed 2007). 
more than 19,000 deaths per year in Europe (American Cancer Society 
2005; Boyle 2005).  Multiple myeloma is characterized by anemia, bone 
destruction, monoclonal gammopathy, renal failure, hypercalcemia, and 
increased susceptibility to infections.  Current treatment options in 
China commonly include combination chemotherapy with regimens 
using melphalan, bortezomib, and thalidomide (an immunomodulatory 
drug [IMiD]) with and without corticosteroids such as dexamethasone or 
prednisone.  Eligible subjects 65 to 70 years old or younger frequently 
undergo induction therapy with myeloablative chemotherapy or 
radiation followed by autologous stem cell transplantation.  Although 
improvements in progression-free survival (PFS) and overall survival 
(OS) have occurred in the past 5 years, even with the best available 
approved agents, essentially all patients eventually relapse.  Median 
survival from the time of diagnosis is approximately 6 years 
(Kumar et al, 2014). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 135 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
1.2 Proteasome 
Background 
The proteasome is a multicatalytic 
proteinase complex that is responsible 
for degradation of a wide variety of 
protein substrates within normal and 
transformed cells.  Intracellular 
proteins targeted for degradation by 
the proteasome are first ubiquitinated 
via the ubiquitin conjugation system.  
Ubiquitinated proteins are cleaved 
within the proteasome by 1 or more of 
3 separate N-terminal threonine 
protease activities:  a chymotrypsin-
like activity, a trypsin-like activity, 
and a caspase-like activity. 
The proteasome is a multicatalytic proteinase complex that is 
responsible for degradation of a wide variety of protein substrates within 
both normal and malignant transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the 
ubiquitin conjugation system.  Ubiquitinated proteins are cleaved within 
the proteasome by 1 or more of 3 separate N-terminal threonine protease 
activities:  a chymotrypsin-like, a trypsin-like, and a caspase-like 
activity. 
Clarification 
1.3.1 Preclinical 
Background, 
Paragraph 1 
Carfilzomib (formerly known as PR-
171) is a tetrapeptide epoxyketone-
based inhibitor of the chymotrypsin-
like activity of the 20S proteasome.  
Carfilzomib, which is structurally and 
mechanistically different from the 
dipeptide boronic acid proteasome 
inhibitor bortezomib, showed less off-
target activity when measured against 
a broad panel of proteases including 
metallo-, aspartyl-, and serine 
proteases compared to bortezomib; the 
latter showed off-target inhibitory 
activity in the nanomolar range 
against several serine proteases 
(Arastu-Kapur 2009). 
Carfilzomib (formerly known as PR-171) is a tetrapeptide epoxyketone-
based inhibitor of the chymotrypsin-like activity of the 20S proteasome.  
Carfilzomib, is structurally and mechanistically different from the 
dipeptide boronic acid proteasome inhibitor bortezomib.  Compared to 
bortezomib, carfilzomib showed less off-target activity when measured 
against a broad panel of proteases including metallo-, aspartyl-, and 
serine proteases.  Bortezomib showed off-target inhibitory activity in the 
nanomolar range against several serine proteases (Arastu-Kapur 2009). 
Clarification 
1.3.1 Preclinical 
Background, 
Paragraph 3 
This finding was in contrast to 
preclinical testing with the boronate 
class of inhibitors that prohibited 
uninterrupted daily dosing due to 
substantial morbidity and mortality.  
Carfilzomib has also been 
administered to rats and monkeys for 
This finding was in contrast to preclinical testing with the boronate class 
of proteasome inhibitors that prohibited daily dosing due to substantial 
morbidity and mortality.  Carfilzomib has also been administered to rats 
and monkeys for 6 and 9 months, respectively (once daily dosing for 2 
consecutive days for 3 weeks on a 28-day cycle).  In this setting, 
carfilzomib was well tolerated at doses resulting in more than 80% 
proteasome inhibition, with no behavioral or histological evidence of 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 136 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
6 and 9 months, respectively (once 
daily dosing for 2 consecutive days 
for 3 weeks on a 28-day cycle).  
Carfilzomib was well tolerated at 
doses resulting in more than 80% 
proteasome inhibition, with no 
behavioral or histological evidence of 
peripheral neuropathy and no 
neutropenia (Onyx data on file and 
Carfilzomib Investigator’s Brochure 
[Carfilzomib IB]). 
peripheral neuropathy and no neutropenia (Onyx data on file and 
Carfilzomib Investigator’s Brochure [Carfilzomib IB]). 
3 Study Design, 
Paragraph 4 
N/A 
Add: 
Subjects will receive treatment until disease progression, unacceptable 
toxicity, or discontinuation of study treatment for any other reason, 
whichever occurs first.   
Clarification 
3.3 End of Study 
Primary Completion:  The time when 
all subjects complete the IRC 
assessment of ORR after 6 cycles of 
Kd, or have withdrawn from study 
treatment.  
 
End of Trial:  The time when the last 
subject completes 3 years of 
monitoring after initiation of study 
treatment, withdraws consent, or dies. 
Primary Completion:  The time when all subjects have had the 
opportunity to complete at least 6 cycles of Kd, or have withdrawn 
from study treatment.  
 
End of Study:  Three years after last subject initiates treatment or 
when all subjects have withdrawn consent or died, whichever occurs 
first. 
Clarification 
 
 
 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 137 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
4.1 Inclusion 
Criteria 
4. 
Refractory to the most recently 
received therapy.  Refractory 
disease defined as ≤ 25% 
response to, or progressing 
during therapy or within 60 
days after completion of 
therapy 
15. 
Written informed consent in 
accordance with federal, local, 
and institutional guidelines 
16. 
Female subjects of child-
bearing potential (FCBP) must 
have a negative serum 
pregnancy test within 21 days 
prior to enrollment and agree to 
use an effective method of 
contraception during and for 30 
days following last dose of drug 
(more frequent pregnancy tests 
may be conducted if required 
per local regulations). 
17. 
Male subjects must use an 
effective barrier method of 
contraception during the study 
and for 3 months following the 
last dose of carfilzomib if 
sexually active with a FCBP.  
Male subjects must not donate 
sperm during treatment and for 
an additional 90 days thereafter.  
Male subjects with pregnant 
partners must practice sexual 
abstinence or use a condom 
during vaginal sex. 
4. 
Refractory to the most recently received therapy.  Refractory 
disease defined as ≤ 25% response to, or progressing during 
therapy or within 60 days after last therapy 
15. 
Written informed consent in accordance with national, local, and 
institutional guidelines 
16. 
Female subjects of child-bearing potential (FCBP) must have a 
negative serum pregnancy test within 7 days prior to  first dose of 
carfilzomib and agree to use an effective method of contraception 
during and for 30 days following last dose of carfilzomib (more 
frequent pregnancy tests may be conducted if required per local 
regulations). 
17. 
Male subjects must use an effective barrier method of 
contraception during the study and for 90 days following the last 
dose of carfilzomib if sexually active with a FCBP.  Male subjects 
must not donate sperm during treatment and for an additional 
90 days after last dose of carfilzomib.  Male subjects with 
pregnant partners must practice sexual abstinence or use a condom 
during vaginal sex. 
Clarification 
 
 
Correction of 
wording 
 
 
Clarification of 
requirement 
 
 
 
Clarification, 
changed to secure 
consistency 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 138 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
4.2 Exclusion 
CriteriaCriteria 
N/A 
Delete: 
19. 
Subjects in whom the required program of PO or IV fluid 
hydration is contraindicated, e.g., due to pre-existing pulmonary, 
cardiac, or renal impairment 
Clarification 
7.3 Study Drug 
Accountability 
N/A 
Delete: 
The records will document shipment dates, method of shipment, batch 
numbers, product presentation, quantity of vials contained in the 
shipment, and dispensation to individual subjects using the subject 
identification number. 
Clarification, not 
required to 
document 
8.1.1 Oral and 
Intravenous 
Hydration 
Intravenous hydration will be given 
immediately prior to carfilzomib  
administration during Cycle 1 and at 
the investigator’s discretion in Cycle 2 
and higher.  This will consist of 250 to 
500 mL IV normal saline or other 
appropriate IV fluid.  The goal of the 
hydration program is to maintain 
robust urine output (e.g., ≥ 2 L/day).  
Subjects should be monitored 
periodically during this period for 
evidence of fluid overload (refer to 
Company Core Safety Information 
[the CCSI]).  For subjects thought to 
be at particularly high risk for the 
development of tumor lysis syndrome 
(TLS), based on high tumor burden, 
PO hydration up to 48 hours before 
starting carfilzomib should be given. 
Intravenous hydration will be given immediately prior to and following 
carfilzomib  administration during Cycle 1, and at the investigator’s 
discretion in Cycle 2 and higher.  If uric acid is elevated at Cycle 2, 
Day 1, then the recommended IV hydration should be repeated for 
all of Cycle 2, and, at the investigator’s discretion, in conjunction 
with subsequent cycles.  This will consist of 250 to 500 mL IV normal 
saline or other appropriate IV fluid.  The goal of the hydration program 
is to maintain robust urine output (e.g., ≥ 2 L/day).  Subjects should be 
monitored periodically during this period for evidence of fluid overload.  
In subjects considered to be at risk for tumor lysis syndrome (TLS) at 
completion of Cycle 1, hydration should be continued into Cycle 2, if 
clinically indicated.  Subjects in whom this program of oral and IV 
fluid hydration is contraindicated, e.g., due to pre-existing 
pulmonary, cardiac, or renal impairment, will not be eligible to 
participate in the clinical trial.   
Clarification, 
changed to align 
with the 003A1 
study 
Table 3:   
Guidelines for 
Non-hematologic 
Treatment 
Emergent 
Toxicities in 
Carfilzomib 
Patients 
N/A 
Add: 
Serum creatinine clearance < 15 mL/min (or CrCl decreases to ≤ 50% 
of baseline), or need for dialysis 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 139 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
8.3.2 Excluded 
Concomitant 
Medication 
Additionally, no alternative anticancer 
therapy including Chinese herbal 
medicine with curative intent (other 
than that administered in the study), or 
other investigational agents are 
allowed prior to treatment 
discontinuation. 
Additionally, alternative anticancer therapy including Chinese herbal 
medicine with curative intent (other than that administered in the study), 
or other investigational agents are not allowed prior to confirmed 
progressive disease (PD). 
Clarification 
8.4.4 
Thrombocytopenia 
and Neutropenia 
N/A 
Delete: 
Refer to the CCSI for detailed information. 
Clarification 
8.4.6 
Gastrointestinal 
Events 
N/A 
Delete: 
Refer to the CCSI for detailed information. 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 140 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
8.4.6 
Gastrointestinal 
Events, Table 6 
Dose 
Modifications 
During 
Carfilzomib 
Treatment 
N/A 
Add: 
 
 
Added dose 
modification 
schedule to reflect 
current carfilzomib 
SmPC 
8.4.9 Posterior 
Reversible 
Encephalopathy 
Syndrome 
 
 
 
 
 
 
 
N/A 
Add: 
8.4.9 Posterior reversible encephalopathy syndrome 
Cases of posterior reversible encephalopathy syndrome (PRES) 
have been reported in patients receiving carilzomib.   Posterior 
reversible encephalopathy syndrome  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, and the 
diagnosis is confirmed by neuro-radiological imaging.  Carfilzomib 
should be discontinued if PRES is suspected. 
 
Added info on AE 
to reflect current 
CFZ SmPC 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 141 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
8.4.10 Thrombotic 
Microangiopathy 
 
 
 
 
 
 
8.4.11 Venous 
Thrombosis 
8..4.10 Thrombotic microangiopathy 
Cases of thrombotic microangiopathy, including thrombotic 
thrombocytopenic purpura and haemolytic uraemic syndrome 
(TTP/HUS) have been reported in patients who received 
carfilzomib.  Some of these events have been fatal.  Monitor for 
signs and symptoms of TTP/HUS.  If the diagnosis is suspected, 
treatment should be interrupted. If diagnosis of TTP/HUS is 
excluded, carfilzomib can be restarted. 
 
8.4.11 Venous thrombosis 
Cases of venous thromboembolic events, including deep vein 
thrombosis and pulmonary embolism with fatal outcomes, have 
been reported in patients who received carfilzomib.  Patients with 
known risk factors for thromboembolism, including prior 
thrombosis, should be closely monitored.  Action should be taken to 
try to minimise all modifiable risk factors (e.g., smoking, 
hypertension, and hyperlipidaemia).  Caution should be used in the 
concomitant administration of other agents that may increase the 
risk of thrombosis (e.g., erythropoietic agents or hormone 
replacement therapy).  Patients and physicians are advised to be 
observant for the signs and symptoms of thromboembolism.  
Patients should be instructed to seek medical care if they develop 
symptoms such as shortness of breath, chest pain, haemoptysis, arm 
or leg swelling or pain.  Thromboprophylaxis should be considered 
based on an individual benefit/risk assessment.   
 
9.1.9 Pregnancy 
Evaluation and 
Contraception 
Considerations 
For FCBPs, a serum pregnancy test 
that is confirmed negative is required 
for eligibility.  This protocol defines a 
FCBP as a sexually mature woman 
who:  1) has not undergone a 
hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy, or 2) has 
not been naturally postmenopausal for 
at least 24 consecutive months (i.e., 
has had menses at any time in the 
preceding 12 consecutive months).  
For FCBPs, a serum pregnancy test that is confirmed negative is 
required for eligibility.  This protocol defines a FCBP as a sexually 
mature woman who:  1) has not undergone a hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy, or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive months). 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 142 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
9.1.10.1 
Plasmacytoma 
Evaluations 
N/A 
Delete: 
The baseline plasmacytoma evaluation may consist of palpation, 
ultrasound, x-ray, computed tomography (CT) scan, magnetic resonance 
imaging (MRI), or positron emission tomography with diagnostic CT 
(PET/CT). 
X-ray not an 
appropriate 
method to evaluate 
plasmacytoma 
9.1.10.3 Bone 
Marrow Aspirate 
and/or Biopsy 
9.1.10.3 Bone Marrow Aspirate and 
Biopsy 
 
All subjects will have a baseline bone 
marrow aspirate and biopsy done and 
evaluated locally for percent plasma 
cell involvement and by multiple 
myeloma-specific interphase 
fluorescent in situ hybridization 
(FISH) testing.  Percent plasma cells 
and percentage positivity for 
chromosome 1 abnormalities, t (4;14), 
t(6;14), t (11;14), t(14; 20), del(13) 
and del(17p) will be reported. 
 
A bone marrow aspirate and biopsy, 
evaluated locally, is required to 
confirm a response of CR or sCR. 
9.1.10.3 Bone Marrow Aspirate and/or Biopsy 
 
All subjects will have a baseline bone marrow aspirate and/or biopsy 
done and evaluated locally for percent plasma cell involvement.  
Multiple myeloma-specific interphase Fluorescent In Situ Hybridization 
(FISH) testing is optional.   
 
A bone marrow aspirate and/or biopsy, evaluated locally, is required to 
confirm a response of CR or sCR. 
FISH made 
optional since not 
all sites can 
perform it 
9.1.10.4 Disease 
Response and 
Progression 
Assessments 
N/A 
Add: 
Subjects will be evaluated by the investigator for disease response 
according to the IMWG-URC assessment parameters as outlined in 
Appendix E on Day 1 of Cycles 2 and higher through to EOT and 
during Active Follow-up (Durie, 2006; Rajkumar, 2011). 
Clarification 
9.1.10.4.2 
Laboratory 
Assessments of 
Disease – During 
Treatment Period 
and Active 
Follow-Up 
• 
Urine M-protein:  Subjects with 
urine positive for M-protein 
levels measured by UPEP 
(> 200mg/24 hr at baseline) – 
must have 24 hour urine for 
UPEP and UIFE done on day 1 of 
each cycle (± 3 days) from 
Cycle 2 and beyond, at EOT, and 
• 
Urine M-protein:  All subjects must have 24 hour urine for UPEP 
and UIFE done on day 1 of each cycle (± 3 days) from Cycle 2 and 
beyond, at EOT, and during active follow-up.  UPEP and UIFE will 
be performed at the central laboratory. 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 143 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
during active follow-up.  UPEP 
and UIFE will be performed at 
the central laboratory. 
9.1.10.4.3 
Response 
Assessments 
N/A 
Delete: 
9.1.10.4.3 Response Assessments for sCR, CR, VGPR, and PR 
In addition to the above-described assessments of multiple myeloma 
disease marker levels in serum and urine, the following response 
assessments are required to confirm all response categories (PR, VGPR, 
CR, sCR, MR, PD): 
• 
Two consecutive laboratory assessments of M-protein level (serum 
and/or urine), made at least 24 hours apart and assessed at the 
central study lab, drawn at any time before the start of new (off 
protocol) myeloma therapy or before the start of the next cycle of 
study treatment. 
Clarification 
9.2.1 Screening 
Assessments, 
Bullet 14 
• 
Perform bone marrow biopsy and 
aspirate, documenting percent 
plasma cells in the marrow and 
findings of multiple myeloma 
FISH study.  Note:  Studies do 
not need to be repeated if 
previously done within 30 days of 
informed consent. 
• 
Perform bone marrow biopsy and/or aspirate, documenting percent 
plasma cells in the marrow.  Performing FISH is preferred but 
optional.  Note:  Studies do not need to be repeated if previously 
done within 30 days of informed consent. 
FISH made 
optional since not 
all sites can 
perform it 
9.2.3 Cycle 1 
Day 1, Bullet 5, 6, 
and 8 
• 
Obtain blood sample for 
chemistry and review results prior 
to Cycle 1 Day 1 dose  
• 
Obtain blood sample for 
hematology panel and review 
results prior to Cycle 1 Day 1 
dose 
• 
In subjects participating in the PK 
sub-study, obtain serial blood 
samples.  See Section 9.3 and 
Appendix B for additional details. 
• 
Obtain blood sample for chemistry up to 1 day prior to Cycle 1 
Day 1 and review results prior to carfilzomib dose  
• 
Obtain blood sample for hematology panel up to 1 day prior to 
Cycle 1 Day 1 and review results prior to carfilzomib dose 
• 
In subjects participating in the PK sub-study, obtain serial blood 
samples.  See Section 9.3 and Appendix B for additional details. 
• 
Administer IV hydration predose 
Window added 
since not all sites 
can get lab results 
on the same day 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 144 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
9.2.4 Cycle 1 
Day 2, Bullet 2 
and 7 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Obtain optional blood sample for serum chemistry 
 
 
• 
Administer IV hydration postdose 
Blood samples on 
day 2 removed due 
to logistic reasons 
9.2.5 Cycle 1 
Day 8, Bullet 2, 3, 
and 8 
N/A 
Add: 
• 
Obtain blood sample for serum chemistry (review results up to 
1 day prior to carfilzomib dosing) 
• 
Obtain blood sample for hematology panel (review results up to 
1 day prior to carfilzomib dosing) 
 
• 
Administer IV hydration postdose 
Window added 
since not all sites 
can get lab results 
on the same day 
9.2.6 Cycle 1 
Day 9, Bullet 2 
and 7 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Obtain optional blood sample for serum chemistry 
 
 
• 
Administer IV hydration postdose 
Blood sample 
optional due to 
logistic reasons 
9.2.7 Cycle 1 
Day 15, Bullet 2, 
3, and 8 
N/A 
Add: 
• 
Obtain blood sample for serum chemistry (review results up to 
1 day prior to carfilzomib dosing) 
• 
Obtain blood sample for hematology panel (review results up to 
1 day prior to carfilzomib dosing) 
 
• 
Administer IV hydration postdose 
Window added 
since not all sites 
can get lab results 
on the same day 
9.2.8 Cycle 1 
Day 16, Bullet 2 
and 7 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Obtain optional blood sample for serum chemistry 
 
 
• 
Administer IV hydration postdose 
Blood sample 
optional due to 
logistic reasons 
9.2.10 Cycle 2 
(and higher) 
Day 1, Bullet 3, 5 
and 6 
N/A 
Add: 
• 
Measure blood pressure, heart rate, respiratory rate, and temperature 
within 1 hour prior to carfilzomib dosing 
• 
Urine or serum pregnancy test must be confirmed negative prior to 
start of each cycle of therapy for FCBP 
Window added 
since not all sites 
can get lab results 
on the same day 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 145 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
• 
Obtain blood sample for chemistry panel (review results up to 
1 day prior to carfilzomib dosing)* 
• 
Obtain blood sample for hematology panel (review results up to 
1 day prior to carfilzomib dosing) 
9.2.10 Cycle 2 
(and higher) 
Day 1, Bullet 7 
• 
Obtain disease response 
assessment as outlined in Section 
9.1.10.4.2 (± 2-day window, 
response labs must be drawn prior 
to administration of Kd) 
• 
Obtain disease response assessment as outlined in Section 9.1.10.4.2 
(± 3-day window, response labs must be drawn prior to 
administration of Kd) 
Clarification 
9.2.11 Cycle 2 
(and higher) 
Day 2, Bullet 2 
and Footnote 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Obtain optional blood sample for serum chemistry* 
 
 
*If uric acid was elevated at Cycle 2 (and higher) Day 1, then the 
recommended IV hydration should be repeated for all of Cycle 2, 
and, at the investigator’s discretion, in conjunction with subsequent 
cycles. 
Blood sample 
optional due to 
logistic reasons 
9.2.12 Cycle 2 
(and higher) 
Day 8, Bullet 1, 2, 
3 and Footnote 
N/A 
Add: 
• 
Measure blood pressure, heart rate, respiratory rate, and temperature 
within 1 hour prior to carfilzomib dosing 
• 
Obtain blood sample for serum chemistry (review results up to 
1 day prior to carfilzomib dosing)* 
• 
Obtain blood sample for hematology panel (review results up to 
1 day prior to carfilzomib dosing) 
 
* If uric acid was elevated at Cycle 2 (and higher) Day 1, then the 
recommended IV hydration should be repeated for all of Cycle 2, 
and, at the investigator’s discretion, in conjunction with subsequent 
cycles. 
Window added 
since not all sites 
can get lab results 
on the same day 
9.2.13 Cycle 2 
(and higher) 
Day 9, Bullet 1, 2, 
and Footnote 
• 
Measure blood pressure, heart 
rate, respiratory rate, and 
temperature within 1 hour prior to 
dosing 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Measure blood pressure, heart rate, respiratory rate, and temperature 
within 1 hour prior to carfilzomib dosing 
• 
Obtain optional blood sample for serum chemistry* 
 
 
*If uric acid was elevated at Cycle 2 (and higher) Day 1, then the 
recommended IV hydration should be repeated for all of Cycle 2, 
and, at the investigator’s discretion, in conjunction with subsequent 
cycles. 
Blood sample 
optional due to 
logistic reasons 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 146 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
9.2.14 Cycle 2 
(and higher) 
Day 15, Bullet 2, 
3, and Footnote 
N/A 
Add: 
• 
Obtain blood sample for serum chemistry (review results up to 
1 day prior to carfilzomib dosing)* 
• 
Obtain blood sample for hematology panel (review results up to 
1 day prior to carfilzomib dosing) 
 
 
*If uric acid was elevated at Cycle 2 (and higher) Day 1, then the 
recommended IV hydration should be repeated for all of Cycle 2, 
and, at the investigator’s discretion, in conjunction with subsequent 
cycles 
Window added 
since not all sites 
can get lab results 
on the same day 
9.2.15 Cycle 2 
(and higher) 
Day 16, Bullet 2 
and Footnote 
• 
Obtain blood sample for serum 
chemistry (review results prior to 
carfilzomib dosing) 
• 
Obtain optional blood sample for serum chemistry* 
 
 
*If uric acid was elevated at Cycle 2 (and higher) Day 1, then the 
recommended IV hydration should be repeated for all of Cycle 2, 
and, at the investigator’s discretion, in conjunction with subsequent 
cycles. 
Blood sample 
optional due to 
logistic reasons 
9.2.17  End of 
Treatment 
Assessment 
(within 30 days of 
Treatment 
discontinuation) 
N/A 
Delete: 
Adverse event, pregnancy, withdrawal by subject, physician decision, 
and progressive disease. 
Clarification 
11.3.2 Disease 
Progression 
All disease progression-related deaths 
occurring from the time of the first 
dose of carfilzomib through 30 days 
after last dose of study drug(s) must 
be reported on the AE CRF as a SAE 
using the verbatim term “Disease 
Progression” rather than signs and/or 
symptoms that may have been the 
immediate cause of death 
All disease progression-related deaths occurring from the time of 
signing of the ICF through 30 days after last dose of study drug(s) must 
be reported on the AE CRF as a SAE using the verbatim term “Disease 
Progression” rather than signs and/or symptoms that may have been the 
immediate cause of death. 
Adjusted to reflect 
Amgen standards 
11.5 Serious 
Adverse Event 
The investigator is responsible for 
ensuring that all SAEs observed by 
The investigator is responsible for ensuring that all SAEs observed by 
the investigator or observed by the subject that occur after signing the 
Adjusted to reflect 
Amgen standards 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 147 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Reporting and 
Documentation 
Requirements 
the investigator or observed by the 
subject that occur after the first dose 
of carfilzomib through 30 days after 
the last dose of carfilzomib are 
recorded in the subjects’ medical 
record and are reported to the sponsor. 
ICF through 30 days after the last dose of carfilzomib are recorded in 
the subjects’ medical record and are reported to the sponsor. 
12.2 
Determination of 
Sample Size, 
Paragraph 4 
N/A 
Delete: 
Clarification 
12.3 Safety 
Oversight 
N/A 
Delete: 
12.3 Safety Oversight 
A sponsor Drug Safety review team will conduct periodic analysis of 
study safety data using standard programmed outputs from the clinical 
and drug safety databases.  Study data will be reviewed regularly, but no 
less often than quarterly, until study closure.  These safety reviews may 
occur more frequently, or be called ad-hoc as needed.  Any potential 
safety signals or concerns identified will be escalated by the study 
medical monitor or designee and sponsor Drug Safety lead to the 
appropriate sponsor safety governance teams prior to outcome 
discussions with study investigators.  
 
Deleted as this is 
not part of the 
Safety Monitoring 
Plan 
12.4.2 Final 
Analysis 
12.5.2 Primary Completion 
Final analysis will be performed when 
all of the enrolled subjects have 
received 12 cycles of Kd or have 
discontinued the treatment with Kd. 
12.4.2 Final Analysis 
Final analysis will be performed when all of the enrolled subjects have 
received at least 12 cycles of Kd or have discontinued the treatment 
with Kd.   
 
Study treatments will be administered until disease progression, 
unacceptable toxicity, or discontinuation of study treatment for any 
other reason, whichever occurs first.  Dose reductions of carfilzomib 
and dexamethasone will be permitted per protocol guidelines. 
 
Upon discontinuation of study treatment for reasons other than 
disease progression, subjects will be followed every 4 weeks until 
disease progression, or withdrawal of consent. 
 
After disease progression, each subject will be followed every 3 
months (± 2 weeks) for OS for up to 3 years from the start of their 
Clarification 
CCI


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 148 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
study treatment, or until the subject has withdrawn from further 
participation, is lost to follow-up, has died, or the sponsor makes a 
decision to close the study. 
12.5.3 End of 
Study 
N/A 
Delete: 
12.5.3 End of Study 
The end of study for each subject is defined as 3 years after Cycle 1 
Day 1, the date the subject withdraws full consent from the study, is 
determined to be lost to follow-up, or dies. 
 
As the subjects will be followed every 3 months for survival for up to 
3 years from Cycle 1 Day 1,an OS analysis will be performed at the end 
of study. 
Clarification 
12.4.3 Estimated 
Study Duration 
Patients will be followed until 
withdrawal of consent, death, loss to 
follow-up, or 3 years after Cycle 1 
Day 1. 
Patients will be followed until withdrawal of consent, death, loss to 
follow-up, or the sponsor makes a decision to close the study, 
whichever occurs first. 
Clarification 
12.4.4 
Independent 
Review 
Committee 
N/A 
Delete: 
The outcomes determined by the IRC will serve as the primary data 
source for the primary final analysis for ORR6-IRC.   
Clarification 
References 
N/A 
Delete: 
Jawed I, Lee CM, Tward JD, et al. Survival outcomes for multiple 
myeloma over three decades: A Surveillance, Epidemiology, and End 
Results (SEER) analysis. J Clin Oncol. 2007;25 (No. 18S June 20 
Supplement): Abstract 8019. 
This reference was 
deleted from the 
body of the 
protocol 
References 
N/A 
Add: 
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement 
in survival in multiple myeloma: changes in early mortality and 
outcomes in older patient. Leukemia. 2014;28:1122-1128. 
Updated reference 
added 
Appendix A.  
Schedule of 
Assessments, 
Table 14 
N/A 
Add: 
 
Day 
-21 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
15 
Day 
16 
Chemistry Panelf 
x 
x 
(x) 
x 
(x) 
x 
(x) 
Adverse Eventso 
x 
x 
x 
x 
x 
 
 
Correction to 
previous version 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 149 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Pharmacokinetic 
Assessmentsp 
x 
 
 
 
 
 
 
 
Appendix A:  
Schedule of 
Assessments, 
Footnoes to Table 
14 
e.   For FCBP, obtain serum 
pregnancy test within 7 days of first 
dose of study drug.  Urine or serum 
pregnancy test must be confirmed 
negative locally on Day 1 of each 
cycle prior to dosing. 
f.   Obtain chemistry panel (Table 7) 
prior to each administration of 
carfilzomib on Days 2, 8, 9, 15, and 
16.  Results of local laboratory studies 
must be reviewed and deemed 
acceptable prior to administration of 
carfilzomib. 
g.  Obtain hematology panel (Table 8) 
prior to administration of carfilzomib 
on Days 8 and 15.  Results must be 
reviewed and deemed acceptable prior 
to administration of carfilzomib. 
 
l.  Bone marrow biopsy and aspirate 
documenting percent marrow 
involvement  and multiple myeloma 
FISH will be performed at screening.   
The screening studies do not need to 
be repeated if previously done within 
30 days of consent. 
o.  Record all AEs from time of first 
administration of carfilzomib through 
30 days post-last dose of study drug or 
initiation of a new anti-cancer therapy. 
e.  For FCBP, obtain serum pregnancy test within 7 days of first dose of 
carfilzomib.  Urine or serum pregnancy test must be confirmed negative 
locally on Day 1 of each cycle prior to dosing. 
f.  Obtain chemistry panel (Table 7) up to 1 day prior to administration 
of carfilzomib on Days 1, 8, and 15.  A chemistry panel on Days 2, 9 
and 16 is optional.  Results of local laboratory studies must be reviewed 
and deemed acceptable prior to administration of carfilzomib. 
g.  Obtain hematology panel (Table 8) up to 1 day prior to 
administration of carfilzomib on Days 1, 8, and 15.  Results must be 
reviewed and deemed acceptable prior to administration of carfilzomib. 
 
 
 
l.  Bone marrow biopsy and/or aspirate documenting percent marrow 
involvement.  FISH is optional at screening.   The screening studies do 
not need to be repeated if previously done within 30 days of consent. 
 
o.  Record all AEs from time of first administration of carfilzomib 
through 30 days post-last dose of study drug or initiation of a new anti-
cancer therapy.  Note:  All Serious Adverse Events (SAEs) should be 
collected after signing of the informed consent form (ICF).   
p.  Pharmacokinetic (PK) analyses will be characterized in a subset 
of approximately 15 subjects at selected sites.  Subjects who do not 
provide all required PK assessments at Cycle 1 Day 1 and Cycle 2 
Day 1 will be replaced.  See Section 9.1.13, Section 9.3, or Appendix 
B for more details. 
Reflects changes 
made to body of 
protocol 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 150 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
Appendix A:  
Schedule of 
Assessments, 
Table 15 
N/A 
Add: 
Assessments 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
15 
Day 
16 
Chemistry Panel 
x 
(x) 
x 
(x) 
x 
(x) 
IV Hydration 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Pharmacokinetic 
Assessmentsn 
x 
 
 
 
 
 
Correction to 
previous version 
Appendix A:  
Schedule of 
Assessments, 
Table 15 
Footnotes 
d.   Obtain chemistry panel (Table 7) 
prior to each administration of 
carfilzomib on Days 1, 2, 8, 9, 15, 16, 
and EOT.  Results of laboratory 
studies must be reviewed and deemed 
acceptable prior to administration of 
carfilzomib. 
d.  Obtain chemistry panel (Table 7) up to 1 day prior to administration 
of carfilzomib on Days 1, 8, 15,  and EOT.  Results of laboratory studies 
must be reviewed and deemed acceptable prior to administration of 
carfilzomib.  A chemistry panel on Days 2, 9, and 16 is optional. 
Reflects changes 
made to body of 
protocol 
Appendix A:  
Schedule of 
Assessments, 
Table 15 
Footnotes 
N/A 
Add: 
e.  Obtain hematology panel (Table 8) up to 1 day prior to 
administration of carfilzomib on Days 1, 8, 15, and End of Treatment.  
Results must be reviewed and deemed acceptable prior to administration 
of carfilzomib. 
k.   Record all AEs from first administration of carfilzomib through 30 
days post-last dose of carfilzomib or initiation of a new anti-cancer 
therapy.  Note:  All Serious Adverse Events (SAEs) should be 
collected after signing of the informed consent form (ICF).   
 
n.  Pharmacokinetic (PK) analyses will be characterized in a subset 
of approximately 15 subjects at selected sites.  Subjects who do not 
provide all required PK assessments at Cycle 1 Day 1 and Cycle 2 
Day 1 will be replaced.  See Section 9.1.13, Section 9.3, or Appendix 
B for more details. 
Reflects changes 
made to body of 
protocol 
Appendix B:  
Pharmacokinetic 
Sampling 
Schedule 
 
Predose 
5 min 
Postdose 
 
 
Predose5 
5 min Post Start 
of Infusion 
 
Clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140242 (CFZ005) 
Carfilzomib for Injection 
Page 151 of 151 
 
 
 
 
Confidential 
12 April 2018 
 
 
Appendix B:  
Pharmacokinetic 
Sampling 
Schedule, 
Footnote 
N/A 
 
Add: 
* All timepoints are relative to the start and end of carfilzomib   
 
15 Within 15 minutes of starting the infusion   
Clarification 

SAP_001.pdf: 
Product:  Carfilzomib 
Statistical Analysis Plan:  20140242 
Date:  31 October 2018 
Page 1 
 
STATISTICAL ANALYSIS PLAN 
An Open-label, Single-arm, Phase 3 Study of Carfilzomib in Combination With 
Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma in 
China 
Protocol Number: 
20140242 
Version: 
Version 3.0 
Date: 
31 October 2018 
Authors: 
 
PPD
 
NCT Number: NCT03029234 
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
7DEOHRI&RQWHQWV
7DEOHRI$EEUHYLDWLRQV 
 
,QWURGXFWLRQ 
 
2EMHFWLYHV 
 
3ULPDU\2EMHFWLYH 
 
6HFRQGDU\2EMHFWLYHV 
 
([SORUDWRU\2EMHFWLYHV 
 
6WXG\2YHUYLHZ 
 
6WXG\'HVLJQ 
 
6DPSOH6L]H 
 
6WXG\(QGSRLQWVDQG&RYDULDWHV 
 
6WXG\(QGSRLQWV 
 
3ULPDU\(IILFDF\(QGSRLQW 
 
6HFRQGDU\(IILFDF\(QGSRLQWV 
 
([SORUDWRU\(IILFDF\(QGSRLQWV 
 
3ODQQHG&RYDULDWHV 
 
+\SRWKHVHVDQGRU(VWLPDWLRQV 
 
'HILQLWLRQV 
 
$QDO\VLV6XEVHWV 
 
6DIHW\$QDO\VLV6HW 
 
3HU3URWRFRO6HW 
 
3KDUPDFRNLQHWLF&RQFHQWUDWLRQ$QDO\VHV6HW 
 
6XEJURXS$QDO\VHV 
 
,QWHULP$QDO\VLVDQG(DUO\6WRSSLQJ*XLGHOLQHV 
 
'DWD6FUHHQLQJDQG$FFHSWDQFH 
 
*HQHUDO3ULQFLSOHV 
 
'DWD+DQGOLQJDQG(OHFWURQLF7UDQVIHURI'DWD 
 
+DQGOLQJRI0LVVLQJDQG,QFRPSOHWH'DWD 
 
'HWHFWLRQRI%LDV 
 
2XWOLHUV 
 
'LVWULEXWLRQDO&KDUDFWHULVWLFV
 
9DOLGDWLRQRI6WDWLVWLFDO$QDO\VHV
 
6WDWLVWLFDO0HWKRGVRI$QDO\VLV 
 
*HQHUDO3ULQFLSOHV 
 
6XEMHFW$FFRXQWDELOLW\ 
 
,PSRUWDQW3URWRFRO'HYLDWLRQV 
 
'HPRJUDSKLFDQG%DVHOLQH&KDUDFWHULVWLFV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
 
(IILFDF\$QDO\VHV 
 
$QDO\VHVRI3ULPDU\(IILFDF\(QGSRLQWV 
 
$QDO\VHVRI6HFRQGDU\(IILFDF\(QGSRLQWV 
 
$QDO\VHVRI([SORUDWRU\(IILFDF\(QGSRLQWV 
 
6DIHW\$QDO\VHV 
 
$GYHUVH(YHQWV 
 
/DERUDWRU\7HVW5HVXOWV 
 
9LWDO6LJQV 
 
(OHFWURFDUGLRJUDP(&* 
 
([SRVXUHWR,QYHVWLJDWLRQDO3URGXFW 
 
3ULRU0HGLFDWLRQ&RQFRPLWDQW0HGLFDWLRQDQG$QWL
FDQFHU7KHUDS\ 
 
3KDUPDFRNLQHWLF$QDO\VLV 
 
&KDQJHV)URP3URWRFROVSHFLILHG$QDO\VHV 
 
/LWHUDWXUH&LWDWLRQV5HIHUHQFHV 
 
3ULRULWL]DWLRQRI$QDO\VHV 
 
'DWD1RW&RYHUHGE\7KLV3ODQ 
 
$SSHQGLFHV 
/LVWRI7DEOHV
7DEOH&,VIRU9DULRXV2EVHUYHG255V:LWK6WXG\6L]HRI
6XEMHFWV 
7DEOH3ODQQHG&DUILO]RPLE'RVHSHU:HHN 
7DEOH(QGSRLQW6XPPDU\7DEOH 
7DEOH'DWHRI3URJUHVVLRQRU&HQVRULQJIRU3URJUHVVLRQIUHH6XUYLYDO 
/LVWRI)LJXUHV
)LJXUH6WXG\'HVLJQDQG7UHDWPHQW6FKHPD 
/LVWRI$SSHQGLFHV
$SSHQGL[$+DQGOLQJRI'DWHV,QFRPSOHWH'DWHVDQG0LVVLQJ'DWHVIRU
$GYHUVH(YHQWVDQG&RQFRPLWDQW0HGLFDWLRQV 



3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
7DEOHRI$EEUHYLDWLRQV
$EEUHYLDWLRQ
'HILQLWLRQ
$/7
DODQLQHDPLQRWUDQVIHUDVH
$1&
DEVROXWHQHXWURSKLOFRXQW
$67
DVSDUWDWHDPLQRWUDQVIHUDVH
$8&LQI
DUHDXQGHUWKHFXUYHH[WUDSRODWHGWRLQILQLW\
$8&ODVW
DUHDXQGHUWKHFXUYHIURPWLPHWRWKHODVWFRQFHQWUDWLRQPHDVXUHG
$8&ODVW
DUHDXQGHUWKHSODVPDFRQFHQWUDWLRQFXUYHXSWRWKHODVWPHDVXUDEOH
FRQFHQWUDWLRQ
%6$
ERG\VXUIDFHDUHD
&%5
FOLQLFDOEHQHILWUDWH
&)=
FDUILO]RPLE>EUDQGQDPH.\SUROLVFDUILO]RPLEIRU,QMHFWLRQ
&,
FRQILGHQFHLQWHUYDO
&/
WRWDOSODVPDFOHDUDQFH
&PD[
PD[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQ
&5
FRPSOHWHUHVSRQVH
&5)
FDVHUHSRUWIRUP
&U&O
FUHDWLQLQHFOHDUDQFH
'25
GXUDWLRQRIUHVSRQVH
'&%
GXUDWLRQRIFOLQLFDOEHQHILW
(&*
(OHFWURFDUGLRJUDP
(&2*
(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS
('&
(OHFWURQLF'DWD&DSWXUH
(27
(QGRI7UHDWPHQW
),6+
IOXRUHVFHQWLQVLWXK\EULGL]DWLRQ
+$
DOWHUQDWLYHK\SRWKHVLV
+
QXOOK\SRWKHVLV
,&)
LQIRUPHGFRQVHQWIRUP
,0L'
LPPXQRPRGXODWRU\GUXJWKDOLGRPLGHOHQDOLGRPLGHRUSRPDOLGRPLGH
,0:*
,QWHUQDWLRQDO0\HORPD:RUNLQJ*URXS
,0:*85&
,QWHUQDWLRQDO0\HORPD:RUNLQJ*URXS8QLIRUP5HVSRQVH&ULWHULD
,3
LQYHVWLJDWLRQDOSURGXFW
,5&
,QGHSHQGHQW5HYLHZ&RPPLWWHH
.G
FDUILO]RPLELQFRPELQDWLRQZLWKGH[DPHWKDVRQH
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
05
PLQLPDOUHVSRQVH
057
PHDQUHVLGHQFHWLPH


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
$EEUHYLDWLRQ
'HILQLWLRQ
1&,&7&$(
1DWLRQDO&DQFHU,QVWLWXWH&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV
255
RYHUDOOUHVSRQVHUDWH
26
RYHUDOOVXUYLYDO
3)6
SURJUHVVLRQIUHHVXUYLYDO
3.
SKDUPDFRNLQHWLFV
35
SDUWLDOUHVSRQVH
6$(
VHULRXVDGYHUVHHYHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
V&5
VWULQJHQWFRPSOHWHUHVSRQVH
6)/&
VHUXPIUHHOLJKWFKDLQ
6,)(
VHUXPLPPXQRIL[DWLRQHOHFWURSKRUHVLV
63(3
VHUXPSURWHLQHOHFWURSKRUHVLV
7ò
WHUPLQDOHOLPLQDWLRQKDOIOLIHRUKDOIOLIH
7PD[
WLPHWRPD[LPXPSODVPDFRQFHQWUDWLRQ
775
WLPHWRUHVSRQVH
8,)(
XULQHLPPXQRIL[DWLRQHOHFWURSKRUHVLV
8/1
XSSHUOLPLWRIWKHQRUPDO
83(3
XULQHSURWHLQHOHFWURSKRUHVLV
9DUHD
YROXPHRIGLVWULEXWLRQ
9VV
YROXPHRIGLVWULEXWLRQDWVWHDG\VWDWH
9*35
YHU\JRRGSDUWLDOUHVSRQVH
:%&
ZKLWHEORRGFHOO


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

,QWURGXFWLRQ
7KHSXUSRVHRIWKLV6WDWLVWLFDO$QDO\VLV3ODQ6$3LVWRSURYLGHGHWDLOVRIWKHVWDWLVWLFDO
DQDO\VHVWKDWKDYHEHHQRXWOLQHGZLWKLQWKHSURWRFRODPHQGPHQWVXSHUVHGLQJ
DPHQGPHQWIRUVWXG\FDUILO]RPLEGDWHG$SULO7KHVFRSHRIWKLV
SODQLQFOXGHVWKHSULPDU\DQDO\VLVILQDODQDO\VLVDQGORQJWHUPIROORZXSDQDO\VLVWKDW
DUHSODQQHGDQGZLOOEHH[HFXWHGE\WKH%LRVWDWLVWLFVGHSDUWPHQWXQOHVVRWKHUZLVH
VSHFLILHG6WDQGDUGSKDUPDFRNLQHWLF3.WDEOHVILJXUHVDQGOLVWLQJVZLOOEH
SURYLGHGE\WKH&OLQLFDO3KDUPDFRORJ\0RGHOLQJDQG6LPXODWLRQJURXS

2EMHFWLYHV

3ULPDU\2EMHFWLYH
7KHSULPDU\REMHFWLYHRIWKLVVWXG\LVWRHYDOXDWHWKHRYHUDOOUHVSRQVHUDWH255DIWHUDW
OHDVWF\FOHVRIFDUILO]RPLELQFRPELQDWLRQZLWKGH[DPHWKDVRQH.GLQVXEMHFWVZLWK
PXOWLSOHP\HORPDZKRKDYHSUHYLRXVO\UHFHLYHGDQDON\ODWLQJRUDQWKUDF\FOLQH
ERUWH]RPLEDQGDQ,0L'KDYHUHODSVHGDIWHURUPRUHOLQHVRIWKHUDS\DQGDUH
UHIUDFWRU\WRWKHPRVWUHFHQWO\UHFHLYHGWKHUDS\
255LVGHILQHGDVWKHSURSRUWLRQRIVXEMHFWVZLWKDEHVWRYHUDOOUHVSRQVHRIV&5&5
9*35RU35DPRQJDOOHQUROOHGVXEMHFWVZLWKDWOHDVWRQHGRVHRIFDUILO]RPLE255ZLOO
EHGHWHUPLQHGXVLQJEHVWRYHUDOOUHVSRQVHDVDVVHVVHGE\WKH,QGHSHQGHQW5HYLHZ
&RPPLWWHH,5&SHU,0:*85&FULWHULD3URWRFRO$SSHQGL[(255ZLOOEHDQDO\]HG
ZKHQDOOWKHHQUROOHGVXEMHFWVKDYHKDGWKHRSSRUWXQLW\WREHWUHDWHGZLWKDWOHDVW
F\FOHVRI.GDQGDOOWKHUHVSRQVHDVVHVVPHQWVE\WKHGDWDFXWRIIGDWHZLOOEHXVHG

6HFRQGDU\2EMHFWLYHV
7KHVHFRQGDU\REMHFWLYHVRIWKLVVWXG\DUH
x
7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.GXVLQJLQYHVWLJDWRUDVVHVVPHQWRI
UHVSRQVH
x
7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.G
x
7RHVWLPDWH&OLQLFDO%HQHILW5DWH&%5GHILQHGDVWKHSURSRUWLRQRIVXEMHFWVZLWK
DEHVWRYHUDOOUHVSRQVHRI05RUEHWWHUDIWHUDWOHDVWF\FOHVDQGDIWHUDWOHDVW
F\FOHV
x
7RHVWLPDWH'XUDWLRQRI5HVSRQVH'25
x
7RHVWLPDWH'XUDWLRQRI&OLQLFDO%HQHILW'&%
x
7RHVWLPDWH3URJUHVVLRQ)UHH6XUYLYDO3)6
x
7RHVWLPDWH2YHUDOO6XUYLYDO26
x
7RHVWLPDWHWLPHWRUHVSRQVH775
x
7RFKDUDFWHUL]HSKDUPDFRNLQHWLFV3.LQDVXEVHWRIVXEMHFWV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

([SORUDWRU\2EMHFWLYHV
$YDOLGDWHGFRPSXWHUDOJRULWKP2Q\[5HVSRQVH&RPSXWDWLRQDO$VVHVVPHQW
>25&$@FDQEHXVHGWRGHWHUPLQHUHVSRQVHDQGGLVHDVHSURJUHVVLRQ
7KHH[SORUDWRU\REMHFWLYHVRIWKLVVWXG\DUH
x
7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRI
UHVSRQVH
x
7RHYDOXDWH255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRI
UHVSRQVH
x
7RHVWLPDWH&%5DIWHUDWOHDVWDQGDIWHUDWOHDVWF\FOHVRI.GXVLQJ
25&$
x
7RHVWLPDWH'25'&%3)6DQG775XVLQJ25&$

6WXG\2YHUYLHZ

6WXG\'HVLJQ
7KLV3KDVHVWXG\ZLOOEHFRQGXFWHGDVDPXOWLFHQWHURSHQODEHOVLQJOHDUPVWXG\DW
DSSUR[LPDWHO\FHQWHUVLQ&KLQD7KHVWXG\LVGHVLJQHGWRHYDOXDWHWKHHIILFDF\DQG
VDIHW\RIFDUILO]RPLELQFRPELQDWLRQZLWKORZGRVHGH[DPHWKDVRQHLQVXEMHFWVZLWK
PXOWLSOHP\HORPDZKRKDYHSUHYLRXVO\UHFHLYHGDQDON\ODWLQJDJHQWRUDQWKUDF\FOLQH
ERUWH]RPLEDQGDQ,0L'UHODSVHGIROORZLQJRUPRUHWKHUDSLHVDQGDUHUHIUDFWRU\WR
WKHPRVWUHFHQWO\UHFHLYHGWKHUDS\
7UHDWPHQWF\FOHVDUHHYHU\GD\V,Q&\FOHVXEMHFWVZLOOUHFHLYHFDUILO]RPLE
PJPLQIXVLRQRQ'D\VDQG,IZHOOWROHUDWHGWKHGRVHZLOOHVFDODWHWRPJP
WREHJLYHQ&\FOH'D\DQGRQZDUG
'H[DPHWKDVRQHPJZLOOEHJLYHQWRVXEMHFWVRQ'D\VDQGRQ
DVFKHGXOHRIHYHU\GD\V2QGD\VZKHQFDUILO]RPLELVDGPLQLVWHUHGWKH
GH[DPHWKDVRQHLVWREHJLYHQPLQXWHVWRKRXUVSULRUWRFDUILO]RPLE
6XEMHFWVZLOOUHFHLYHWUHDWPHQWXQWLOGLVHDVHSURJUHVVLRQXQDFFHSWDEOHWR[LFLW\RU
GLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWIRUDQ\RWKHUUHDVRQZKLFKHYHURFFXUVILUVW
'RVHUHGXFWLRQRIFDUILO]RPLEDQGGH[DPHWKDVRQHZLOOEHSHUPLWWHGSHUSURWRFRO
JXLGHOLQHVVHHSURWRFROVHFWLRQ
3KDUPDFRNLQHWLFDQDO\VHVZLOOEHFKDUDFWHUL]HGLQDVXEVHWRIDSSUR[LPDWHO\VXEMHFWV
DWVHOHFWHGVLWHV6XEMHFWVZKRGRQRWSURYLGHDOOUHTXLUHG3.DVVHVVPHQWVDW&\FOH
'D\DQG&\FOH'D\ZLOOEHUHSODFHG
7KHGHVLJQVFKHPDIRUWKLVRSHQODEHOVLQJOHDUPVWXG\LVSUHVHQWHGLQ)LJXUH


Product:  Carfilzomib 
Statistical Analysis Plan:  20140242 
Date:  31 October 2018 
Page 8 
 
Figure 1.  Study Design and Treatment Schema 
 
Abbreviations:  CBR = clinical benefit rate; DOR = duration of response; DCB = duration of clinical benefit; 
ECOG = Eastern Cooperative Oncology Group Performance Status; IMiD = immunomodulatory drug; 
N = number; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetic(s); TTR = Time to Response 
3.2 
Sample Size 
This study will enroll approximately 120 subjects with relapsed and refractory multiple 
myeloma.
CCI
CCI
CCI


Product: Carfilzomib 
Statistical Analysis Plan: 20140242 
Date: 31 October 2018 
Page9 
4. 
4.1 
Study Endpoints and Covariates 
Study Endpoints 
4.1.1 
Primary Efficacy Endpoint 
The primary endpoint of this study is: 
•
ORR after at least 6 cycles of Kd based on best response assessment by IRC. 
The ORR is defined as the proportion of subjects with a best overall response of 
sCR, CR, VGPR, or PR per IMWG-URC criteria (Protocol Appendix E). ORR will 
be analyzed when all the enrolled subjects have had the opportunity to be treated 
with at least 6 cycles of Kd and all the response assessments by the primary 
analysis data cut-off date will be used. 
4.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints of this study are: 
•
ORR after at least 6 cycles of Kd based on response assessed by the 
investigator
•
ORR after at least 12 cycles of Kd based on response assessed by both 
investigator and IRC, respectively. ORR will be analyzed when all the enrolled 
subjects have had the opportunity to be treated with at least 12 cycles of Kd and 
all the response assessments by the final analysis data cut-off date will be used.
•
CBR after at least 6 cycles and after at least 12 cycles, based on response 
assessed by both investigator and IRC, respectively. Clinical benefit rate is 
defined as the proportion of subjects with the best overall response of MR or 
better per IMWG-URC criteria  (Protocol Appendix E and F). 
AMGEN 


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
x
'XUDWLRQRIUHVSRQVHGHILQHGDVWKHWLPHIURPILUVWHYLGHQFHRI35RUEHWWHUWR
GLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVHEDVHGRQUHVSRQVHDVVHVVHGE\
ERWKLQYHVWLJDWRUDQG,5&UHVSHFWLYHO\
x
'XUDWLRQRIFOLQLFDOEHQHILWGHILQHGDVWKHWLPHIURPILUVWHYLGHQFHRI05RUEHWWHU
WRGLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVHEDVHGRQUHVSRQVHDVVHVVHG
E\ERWKLQYHVWLJDWRUDQG,5&UHVSHFWLYHO\
x
3URJUHVVLRQIUHHVXUYLYDOGHILQHGDVWKHWLPHIURPILUVWGRVHRIDQ\VWXG\
WUHDWPHQWWRWKHHDUOLHURIGLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVHEDVHG
RQUHVSRQVHDVVHVVHGE\ERWKLQYHVWLJDWRUDQG,5&UHVSHFWLYHO\
x
2YHUDOOVXUYLYDOGHILQHGDVWKHWLPHIURPILUVWGRVHRIDQ\VWXG\WUHDWPHQWWRWKH
GDWHRIGHDWKGXHWRDQ\FDXVH
x
7LPHWRUHVSRQVHGHILQHGDVWKHWLPHIURPILUVWGRVHRIDQ\VWXG\WUHDWPHQWWR
WKHILUVWFRQILUPHGUHVSRQVH35RUEHWWHUEDVHGRQUHVSRQVHDVVHVVHGE\ERWK
LQYHVWLJDWRUDQG,5&UHVSHFWLYHO\
x
3KDUPDFRNLQHWLFVRIFDUILO]RPLE

([SORUDWRU\(IILFDF\(QGSRLQWV
7KHH[SORUDWRU\HQGSRLQWVRIWKLVVWXG\DUH
x
255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRIUHVSRQVH
x
255DIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$DVVHVVPHQWRIUHVSRQVH
x
&%5DIWHUDWOHDVWDQGDIWHUDWOHDVWF\FOHVRI.GXVLQJ25&$
x
'25'&%3)6DQG775XVLQJ25&$

3ODQQHG&RYDULDWHV
1RW$SSOLFDEOH

+\SRWKHVHVDQGRU(VWLPDWLRQV
7KHQXOO+DQGWKHDOWHUQDWLYH+$K\SRWKHVHVDUHDVIROORZV
+255.G
+$255.G!
7KLVVWXG\ZLOOHQUROODSSUR[LPDWHO\VXEMHFWVZLWKUHODSVHGDQGUHIUDFWRU\PXOWLSOH
P\HORPD7KHQXOOK\SRWKHVLVZLOOEHUHMHFWHGDQGWKHVWXG\ZLOOEHFRQVLGHUHG
VXFFHVVIXOZLWKWKHORZHUERXQGRIWKHVLGHGH[DFWELQRPLDO&,DERXWWKHRYHUDOO
UHVSRQVHUDWHHQGSRLQWH[FHHGLQJ


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

'HILQLWLRQV
x
6WXG\WUHDWPHQW
&DUILO]RPLEPJP,9RQ'D\DQGRI&\FOHHVFDODWLQJLIWROHUDWHGWR
PJPRQ'D\DQGRI&\FOHDQGRQZDUG7UHDWPHQWF\FOHVDUH
GD\V
'H[DPHWKDVRQHPJRQ'D\DQGRQDVFKHGXOHRIHYHU\
GD\V
x
6WXG\EDVHOLQH
6WXG\EDVHOLQHLVGHILQHGDVWKHYDOXHWDNHQRQ'D\&\FOHEHIRUHVWDUWRIWKHILUVW
GRVHRIDQ\VWXG\WUHDWPHQW,IVXFKYDOXHLVQRWDYDLODEOHLWPD\EHUHSODFHGE\WKH
ODWHVWDYDLODEOHUHVXOWWDNHQEHIRUHVWDUWRIWKHILUVWGRVHRIDQ\VWXG\WUHDWPHQW
GXULQJWKHVWXG\
x
6WXG\'D\
'D\LVGHILQHGDVWKHGD\RIWUHDWPHQWVWDUWZKLFKLVHTXDOWRWKHGD\RIWKHILUVW
GRVHRIDQ\VWXG\WUHDWPHQW
x
6WXG\'D\
6WXG\GD\UHSUHVHQWVWKHHODSVHGQXPEHURIGD\VIURP6WXG\'D\LQFOXVLYH
6WXG\GD\Q 'DWHRIDVVHVVPHQW±'DWHRI6WXG\'D\
8QOHVVRWKHUZLVHVSHFLILHGWKHWLPLQJRIDOOVWXG\UHODWHGYLVLWVDVVHVVPHQWVDQG
LQWHUYHQWLRQVZLOOEHFDOFXODWHGUHODWLYHWR6WXG\'D\6WXG\'D\ZLOOEHWKHGD\
EHIRUH6WXG\'D\DQGLQJHQHUDOQHJDWLYHGD\VZLOOEHPHDVXUHGEDFNZDUGV
VWDUWLQJIURP6WXG\'D\
x
7UHDWPHQWSHULRG
6XEMHFWVZLOOUHFHLYHWUHDWPHQWXQWLOGLVHDVHSURJUHVVLRQXQDFFHSWDEOHWR[LFLW\RU
GLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWIRUDQ\RWKHUUHDVRQ
x
(QGRI7UHDWPHQW(27
3DWLHQWVPD\ZLWKGUDZIURPVWXG\WUHDWPHQWDWDQ\WLPH5HDVRQVIRU
GLVFRQWLQXDWLRQLQFOXGHGHFLVLRQE\VSRQVRUFRPSOHWHGORVWWRIROORZXSGHDWK
QRQFRPSOLDQFHDGYHUVHHYHQWSUHJQDQF\ZLWKGUDZDOE\VXEMHFWDQGSURJUHVVLYH
GLVHDVH7KH(QGRI7UHDWPHQWDVVHVVPHQWVPXVWEHFRPSOHWHGZLWKLQGD\VRI
WUHDWPHQWGLVFRQWLQXDWLRQDQGSULRUWRLQLWLDWLRQRIDQ\QHZDQWLP\HORPDWKHUDS\
x
$FWLYH)ROORZXS
$OOVXEMHFWVZKRGLVFRQWLQXHVWXG\WUHDWPHQWIRUUHDVRQVRWKHUWKDQ3'ZLOOEH
IROORZHGLQDFWLYHIROORZXSHYHU\ZHHNVGD\VILUVWYLVLWVKRXOGEHZHHNV
DIWHU(27YLVLWIRUGLVHDVHSURJUHVVLRQXQWLOFRQILUPHG3'ZLWKGUDZDORIFRQVHQW
ORVVWRIROORZXSLQLWLDWLRQRIQHZQRQSURWRFRODQWLP\HORPDWKHUDS\GHDWKRU


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
VWXG\FORVXUH3K\VLFDODQGODERUDWRU\DVVHVVPHQWVZLOOEHSHUIRUPHGDV
FOLQLFDOO\LQGLFDWHG
x
/RQJ7HUP)ROORZXS
$IWHUGLVHDVHSURJUHVVLRQRULQLWLDWLRQRIQHZQRQSURWRFRODQWLP\HORPD
WKHUDS\VXEMHFWVZLOOEHIROORZHGHYHU\PRQWKVZHHNVIRUVXUYLYDOIRUXSWR
\HDUVIURPLQLWLDWLRQRIVWXG\WUHDWPHQWRUXQWLOWKHVXEMHFWKDVZLWKGUDZQFRQVHQWLV
ORVWWRIROORZXSKDVGLHGRUWKHVSRQVRUPDNHVWKHGHFLVLRQWRFORVHWKHVWXG\
x
(QGRI6WXG\
7KHWLPHZKHQWKHODVWVXEMHFWFRPSOHWHV\HDUVRIPRQLWRULQJDIWHULQLWLDWLRQRI
VWXG\WUHDWPHQWRUZKHQDOOVXEMHFWVKDYHZLWKGUDZQFRQVHQWRUGLHG
ZKLFKHYHURFFXUVILUVW
x
3ULPDU\$QDO\VLV
3ULPDU\DQDO\VLVZLOOEHSHUIRUPHGZKHQDOORIWKHHQUROOHGVXEMHFWVKDYHUHFHLYHGDW
OHDVWF\FOHVRI.GRUKDYHGLVFRQWLQXHGWUHDWPHQWZLWK.G$OOGDWDE\WKHSULPDU\
DQDO\VLVGDWDFXWRIIGDWHZLOOEHXVHG
x
)LQDO$QDO\VLV
)LQDODQDO\VLVZLOOEHSHUIRUPHGZKHQDOORIWKHHQUROOHGVXEMHFWVKDYHKDGWKH
RSSRUWXQLW\WREHWUHDWHGZLWKDWOHDVWF\FOHVRI.GRUKDYHGLVFRQWLQXHGWUHDWPHQW
ZLWK.G$OOGDWDE\WKHILQDODQDO\VLVGDWDFXWRIIGDWHZLOOEHXVHG
x
/RQJ7HUP)ROORZXS$QDO\VLV
/RQJWHUPIROORZXSDQDO\VLVZLOOEHSHUIRUPHGZKHQDOORIWKHHQUROOHG
VXEMHFWVKDYHEHHQIROORZHGXSIRU26IRUXSWR\HDUVIURPWKHVWDUWRIWKHLU
VWXG\WUHDWPHQWRUZLWKGUDZIURPIXUWKHUSDUWLFLSDWLRQLVORVWWRIROORZXSKDV
GLHGRUWKHVSRQVRUPDNHVDGHFLVLRQWRFORVHWKHVWXG\$OOH[SRVXUHDQG
VDIHW\GDWDE\ORQJWHUPIROORZXSGDWDFXWRIIGDWHZLOOEHXVHG
x
%HVW2YHUDOO5HVSRQVH
%HVWRYHUDOOUHVSRQVHLVWKHEHVWFRQILUPHGUHVSRQVHE\WKHGDWDFXWRII7KH
UHVSRQVHDVVHVVPHQWVGRQHDIWHULQLWLDWLRQRIQHZDQWLFDQFHUWKHUDS\ZLOOEH
H[FOXGHGIURPWKHHYDOXDWLRQRIEHVWRYHUDOOUHVSRQVH
$FRQILUPHGUHVSRQVHRIPLQLPDOUHVSRQVH05RUEHWWHUUHTXLUHVDWOHDVWWZR
FRQVHFXWLYHDVVHVVPHQWVZLWKWKHVDPHUHVSRQVHRUEHWWHU3URJUHVVLYHGLVHDVH
3'UHTXLUHVWZRFRQVHFXWLYH3'DVVHVVPHQWVEDVHGRQWKHVDPHDQDO\WHH[FHSW
ZKHQ3'LVGXHWRDQ\RIWKHIROORZLQJFULWHULD
x
'HILQLWHGHYHORSPHQWRIQHZERQHOHVLRQVRUGHILQLWHLQFUHDVHLQWKHVL]HRI
H[LVWLQJERQHOHVLRQV
x
'HILQLWHLQFUHDVHRUQHZDSSHDUDQFHRIVRIWWLVVXHSODVPDF\WRPDV
x
'HILQLWHLQFUHDVHRISODVPDFHOOVLQERQHPDUURZ
%HVWRYHUDOOUHVSRQVHZLOOEHGHFLGHGLQWKHIROORZLQJRUGHURIFRQILUPHGUHVSRQVHV
VWULQJHQWFRPSOHWHUHVSRQVHV&5FRPSOHWHUHVSRQVH&5YHU\JRRGSDUWLDO


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
UHVSRQVH9*35SDUWLDOUHVSRQVH35056'3'VWDUWLQJIURPWKHEHVWWRWKH
ZRUVW
x
7UHDWPHQWHPHUJHQWDGYHUVHHYHQW7($(
7($(VDUHGHILQHGDVWKRVHZKLFKVWDUWEHWZHHQWKHILUVWGRVHRIDQ\VWXG\
WUHDWPHQWDQGGD\VDIWHUWKHHQGRIVWXG\WUHDWPHQWRULQLWLDWLRQRIQHZDQWL
P\HORPDWKHUDS\ZKLFKHYHUFRPHVILUVW,QFDVHWKHVWDUWWLPHRUWKHH[DFWVWDUW
GDWHRIWKH$(LVQRWDYDLODEOHDQGLWLVWKXVXQFOHDUZKHWKHUDQ$(VWDUWHGDIWHUVWDUW
RIDQ\VWXG\WUHDWPHQWRUEHIRUHGD\VDIWHUWKHHQGRIWUHDWPHQWWKH$(ZLOOEH
LQFOXGHGLQWKHDQDO\VLVDV7($(
x
7LPHPRQWKVIURPLQLWLDOPXOWLSOHP\HORPDGLDJQRVLVWRVWXG\GD\
'HILQHGDVVWXG\GD\±LQLWLDOGLDJQRVLVGDWH
x
7LPHPRQWKVIURPODVWUHODSVHWRVWXG\GD\
'HILQHGDVVWXG\GD\±ODVWUHODSVHGDWH
x
&DOFXODWHG,66VWDJHDWEDVHOLQHVWDJH,VWDJH,,VWDJH,,,
,IȕPLFURJOREXOLQOHYHOPJ/DQGDOEXPLQOHYHOJG/WKHVXEMHFWLVDW,66
VWDJH,,IȕPLFURJOREXOLQOHYHO!PJ/WKHVXEMHFWLVDW,66VWDJH,,,,IWKH
VXEMHFWLVQHLWKHUDWVWDJH,RUVWDJH,,,WKHQWKHVXEMHFWLVDW,66VWDJH,,
x
5LVNJURXSE\),6+KLJKULVNJURXSVWDQGDUGULVNJURXS
+LJKULVNJURXSFRQVLVWVRIVXEMHFWVZKRKDYHWKHJHQHWLFVXEW\SHVWW
RUGHOSVWDQGDUGULVNJURXSFRQVLVWVRIVXEMHFWVZKRGRQRWKDYHDQ\RIWKH
DERYHJHQHWLFVXEW\SHV
x
5HIUDFWRU\WRSULRUPXOWLSOHP\HORPDWKHUDS\
6XEMHFWLVUHIUDFWRU\WRDGUXJUHFHLYHGLQSULRUUHJLPHQVLIWKHGDWDFROOHFWHGRQSULRU
PXOWLSOHP\HORPDWKHUDS\&5)LQGLFDWHVWKDWDQ\RIWKHIROORZLQJFULWHULDLVPHW

%HVW5HVSRQVHWRDQ\UHJLPHQFRQWDLQLQJWKHGUXJLVVWDEOHGLVHDVHRU
SURJUHVVLYHGLVHDVH

5HDVRQWKHGUXJZDVVWRSSHGLVSURJUHVVLRQLQDQ\UHJLPHQ

'DWHRIUHODSVHSURJUHVVLRQLVDIWHUVWDUWGDWHDQGZLWKLQGD\VDIWHUVWRS
GDWHRIWKHGUXJLQDQ\UHJLPHQ
x
&XPXODWLYH'RVHRI6WXG\7UHDWPHQW
&DUILO]RPLE
&XPXODWLYHGRVHZLOOEHFDOFXODWHGLQPJDQGPJP7KHFXPXODWLYHGRVHLQPJZLOO
EHFDOFXODWHGDVWKHVXPPDWLRQRIWRWDOTXDQWLW\DGPLQLVWHUHGPJRYHULQIXVLRQV
7KHFXPXODWLYHGRVHLQPJPZLOOEHFDOFXODWHGDVWKHIROORZLQJRYHULQIXVLRQV
෍ܶ݋ݐ݈ܽ ݍݑܽ݊ݐ݅ݐݕ ܽ݀݉݅݊݅ݏݐ݁ݎ݁݀ (݉݃)
ܤܵܣ (݉ଶ)



3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
%6$LVWREHGHWHUPLQHGE\DVWDQGDUGIRUPXODVXFKDVWKH0RVWHOOHU)RUPXOD
0RVWHOOHUERG\VXUIDFHDUHD%6$Pð >+HLJKWFPî:HLJKWNJ@
ò7KHRQHFROOHFWHGRQF\FOHGD\ZLOOEHXVHGLQWKHFDOFXODWLRQWLOOZKHQ
%6$FKDQJHVIURPF\FOHGD\(YHU\WLPH%6$FKDQJHVIURP
FXUUHQW%6$XVHGLQWKHFDOFXODWLRQWKHQHZ%6$ZLOOEHXVHGIRUVXEVHTXHQW
LQIXVLRQV,I%6$LV!WKHQZLOOEHXVHGLQWKHFDOFXODWLRQ
'H[DPHWKDVRQH
7KHFXPXODWLYHGRVHLQPJZLOOEHFDOFXODWHGDVWKHVXPPDWLRQRIWRWDOTXDQWLW\
DGPLQLVWHUHGPJRYHUWKHVWXG\
x
5HODWLYH'RVH,QWHQVLW\5',
5',UHIOHFWVZKHWKHUWKHGRVHLQWHQVLW\RIDWKHUDS\ZDVLPSOHPHQWHGDVSODQQHG,W
ZLOOEHFDOFXODWHGDVWKHUDWLRRIDFWXDOGRVHLQWHQVLW\UHODWLYHWRSODQQHGGRVH
LQWHQVLW\
Relative Dose Intensity (%) = 100 × Actual Dose Intensity
Planned Dose Intensity
&DUILO]RPLE$FWXDOGRVHLQWHQVLW\LVGHILQHGDVWKHDFWXDODPRXQWRIGUXJLQPJP
GHOLYHUHGWRDVXEMHFWSHUZHHNRIWUHDWPHQW
Actual Dose Intensity (mg/݉ଶ/week) = Cumulative Dose of Carfilzomib (mg/ ݉ଶ)
Number of Weeks of Actual Treatment 
&XPXODWLYHGRVHRIFDUILO]RPLELQPJPLVGHILQHGEHIRUH1XPEHURIZHHNVRI
DFWXDOWUHDWPHQWZLOOEHFDOFXODWHGDV/DVW'RVH'DWHRI&DUILO]RPLE±)LUVW'RVH
'DWHRI&DUILO]RPLELZKHUHL LIWKHODVWLQIXVLRQLVJLYHQRQGD\RUZLWKLQ
WKHODVWF\FOHL LIWKHODVWLQIXVLRQLVJLYHQRQGD\RUL LIWKHODVWLQIXVLRQLV
JLYHQRQGD\L LIWKHODVWLQIXVLRQLVJLYHQRQGD\
3ODQQHGGRVHLQWHQVLW\LVGHILQHGDVWKHSODQQHGDPRXQWRIFDUILO]RPLELQPJP
GHOLYHUHGWRDVXEMHFWSHUZHHNRIWUHDWPHQW
Planed Dose Intensity (mg/݉ଶ/week)
= Planned cumulative Dose of Carfilzomib (mg/ ݉ଶ)
Number of protocol specified treatment weeks 
,WZLOOEHFDOFXODWHGDVWKHSODQQHGFXPXODWLYHGRVHRIFDUILO]RPLELQPJPGLYLGHG
E\WKHSODQQHGQXPEHURIZHHNVIRUWKHWUHDWPHQWSHUSURWRFROEDVHGRQWKH
FRUUHVSRQGLQJF\FOHDQGGD\RIWKHODVWFDUILO]RPLELQIXVLRQ3HUSURWRFRORQHF\FOH
LVGD\VZHHNVVRWKHSODQQHGQXPEHURIWUHDWPHQWZHHNVZLOOEHFDOFXODWHG
DV[FMZKHUHFLVWKHF\FOHLQZKLFKWKHODVWFDUILO]RPLELQIXVLRQLVJLYHQDQG
M LIWKHODVWFDUILO]RPLELQIXVLRQLVJLYHQRQGD\RUZLWKLQWKHODVWF\FOHM LI
WKHODVWLQIXVLRQLVJLYHQRQGD\RUM LIWKHODVWLQIXVLRQLVJLYHQRQGD\RU
7KHSODQQHGFXPXODWLYHGRVHRIFDUILO]RPLELVWKHVXPPDWLRQRISODQQHG
FDUILO]RPLEGRVHSHUZHHNDVVSHFLILHGLQ7DEOHDFURVVWKHSODQQHGWUHDWPHQW
ZHHNV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
7DEOH3ODQQHG&DUILO]RPLE'RVHSHU:HHN
&\FOH
:HHN
3URWRFRO6SHFLILHG'RVHIRU7UHDWPHQW:HHN
PJP

VW

RUODWHU
VW

$OOF\FOHV
QGUG

$OOF\FOHV
WK

'H[DPHWKDVRQH$FWXDOGRVHLQWHQVLW\LVWKHDFWXDODPRXQWRIGUXJLQPJGHOLYHUHG
WRDVXEMHFWSHUZHHNRIWUHDWPHQW
Actual Dose Intensity (mg/week) = Cumulative Dose of Dexamethasone (mg)
Number of Weeks of Actual Treatment 
&XPXODWLYHGRVHRIGH[DPHWKDVRQHLQPJLVGHILQHGEHIRUH1XPEHURIZHHNVRI
DFWXDOWUHDWPHQWZLOOEHFDOFXODWHGDV/DVW'RVH'DWHRI'H[DPHWKDVRQH±)LUVW
'RVH'DWHRI'H[DPHWKDVRQHLZKHUHL LIWKHODVWGH[DPHWKDVRQHGRVHLV
JLYHQRQGD\DQGL LIWKHODVWGH[DPHWKDVRQHGRVHLVJLYHQRQGD\
DQGRU
3ODQQHGGRVHLQWHQVLW\PJZHHNLVGHILQHGDVWKHSODQQHGDPRXQWRI
GH[DPHWKDVRQHLQPJGHOLYHUHGWRDVXEMHFWSHUZHHNRIWUHDWPHQW,WZLOOEH
PJZHHNIRUGH[DPHWKDVRQH

$QDO\VLV6XEVHWV

6DIHW\$QDO\VLV6HW
7KHVDIHW\DQDO\VLVVHWLVGHILQHGDVDOOHQUROOHGVXEMHFWVZKRUHFHLYHGDWOHDVWRQHGRVH
RIFDUILO]RPLE7KLVGHILQLWLRQLVLQOLQHZLWKWKHLQWHQWWRWUHDW,77SULQFLSOHLQ
VLQJOHDUPRSHQODEHOVWXGLHV$OOVDIHW\DQDO\VHVDQGHIILFDF\DQDO\VHVZLOOEH
EDVHGRQWKHVDIHW\DQDO\VLVVHW

3HU3URWRFRO6HW
7KHSHUSURWRFROVHWLVGHILQHGDVDOOHQUROOHGVXEMHFWVZKRUHFHLYHGDWOHDVWRQHGRVHRI
FDUILO]RPLEDQGGLGQ¶WKDYHDQ\LPSRUWDQWSURWRFROGHYLDWLRQV,3'WKDWPLJKWLPSDFWWKH
HIILFDF\HYDOXDWLRQRIWKHVXEMHFW


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
6XEMHFWVZLWK,3'VLQWKHIROORZLQJOLVWRI,3'FRGHVZLOOEHH[FOXGHGIURPWKHSHU
SURWRFROVHW
x
,3',QFOXVLRQFULWHULDRIPXOWLSOHP\HORPD
x
,3'6XEMHFWVPXVWKDYHPHDVXUDEOHGLVHDVH
x
,3'6XEMHFWVPXVWKDYHEHHQUHVSRQVLYHLHDFKLHYHGD05RUEHWWHUWRDW
OHDVWSULRUWUHDWPHQWUHJLPHQV
x
,3'5HIUDFWRU\WRWKHPRVWUHFHQWO\UHFHLYHGWKHUDS\
x
,3'6XEMHFWVPXVWKDYH! SULRUUHJLPHQV
x
,3'6XEMHFWVPXVWKDYHUHFHLYHGSULRUWUHDWPHQWZLWKERUWH]RPLEDQGDQ,0L'
x
,3'*OXFRFRUWLFRLGWKHUDS\SUHGQLVRQH!PJGD\RUHTXLYDOHQWZLWKLQ
ZHHNVSULRUWR&\FOH'D\
x
,3'&KHPRWKHUDS\ZLWKDSSURYHGRULQYHVWLJDWLYHDQWLFDQFHUWKHUDSHXWLFV
LQFOXGLQJVWHURLGWKHUDS\ZLWKLQWKHZHHNVSULRUWR&\FOH'D\
x
,3'5DGLDWLRQWKHUDS\RULPPXQRWKHUDS\LQWKHZHHNVSULRUWR&\FOH'D\
ORFDOL]HGUDGLDWLRQWKHUDS\ZLWKLQZHHNSULRUWR&\FOH'D\
x
,3'1RQKHPDWRORJLFPDOLJQDQF\ZLWKLQWKHSDVW\HDUV
x
,3'6XEMHFWUHTXLUHGWKHXVHRIH[FOXGHGFRQFRPLWDQWPHGLFDWLRQRUSURFHGXUH
ZKLOHRQVWXG\DQGZDVQRWZLWKGUDZQIURPVWXG\WUHDWPHQW
x
,3'6XEMHFWHQGHGWUHDWPHQWZLWKRXWFRQILUPDWLRQRI3'IRUUHDVRQRWKHUWKDQ
SURJUHVVLYHGLVHDVHRULQWROHUDELOLW\WRWUHDWPHQWDQGQRIXUWKHUGLVHDVHDVVHVVPHQWV
ZHUHFDUULHGRXW
x
,3'$Q\EDVHOLQHGLVHDVHDVVHVVPHQWVQRWGRQHLQVXFKDZD\WKDWSDWLHQWLV
QRWPHDVXUDEOHDVGHILQHGSHUSURWRFRO
$VHQVLWLYLW\DQDO\VLVEDVHGRQWKLVSHUSURWRFROVHWZLOOEHSHUIRUPHGIRUWKHSULPDU\
HQGSRLQWDQGVHFRQGDU\HIILFDF\HQGSRLQWVEDVHGRQ,5&DVVHVVPHQWDVZHOODV26
VHH7DEOH

3KDUPDFRNLQHWLF&RQFHQWUDWLRQ$QDO\VHV6HW
7KHSKDUPDFRNLQHWLF3.FRQFHQWUDWLRQDQDO\VLVVHWZLOOFRQWDLQDOOVXEMHFWVZKR
UHFHLYHGFDUILO]RPLEJLYHQDVDPLQXWHV,9LQIXVLRQDQGKDYHDGHTXDWH
FDUILO]RPLESODVPDFRQFHQWUDWLRQYHUVXVWLPHGDWDIRUWKHHVWLPDWLRQRI3.SDUDPHWHUV
E\DQRQFRPSDUWPHQWDODQDO\VLV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

6XEJURXS$QDO\VHV
6XEJURXSDQDO\VHVZLOOEHSHUIRUPHGWRH[DPLQHWKHFRQVLVWHQF\RIWKHWUHDWPHQWHIIHFW
IRUWKHSULPDU\HQGSRLQWDQGNH\VHFRQGDU\HIILFDF\HQGSRLQWV255DIWHUDWOHDVW
F\FOHVRI.GSHU,5&3)6SHU,5&DQG26ZKLFKZLOOEHEDVHGRQWKHIROORZLQJ
IDFWRUV
x
6H[PDOHYVIHPDOH
x
$JHDVFDWHJRULFDOYDULDEOH\HDUV
x
%DVHOLQH(&2*SHUIRUPDQFHVWDWXV
x
%DVHOLQHFUHDWLQLQHFOHDUDQFHP/PLQ
x
%DVHOLQHFRUUHFWHGFDOFLXP !PJG/
x
,66VWDJHDWEDVHOLQHVWDJH,VWDJH,,VWDJH,,,
x
,66VWDJHDWGLDJQRVLVVWDJH,VWDJH,,VWDJH,,,8QNQRZQ
x
ȕPLFURJOREXOLQOHYHODQGPJ/
x
1XPEHURISULRUUHJLPHQV
x
3ULRUWUDQVSODQW\HVQR
x
%RUWH]RPLE%7=RU,[D]RPLEUHIUDFWRU\WRDQ\SULRUOLQHUHJLPHQ\HVQR
x
,0L'UHIUDFWRU\WRDQ\SULRUOLQHUHJLPHQ\HVQR
x
%RWK3URWHDVRPHLQKLELWRU>%RUWH]RPLE%7=RU,[D]RPLE@DQG,0L'UHIUDFWRU\WR
DQ\SULRUOLQHUHJLPHQ\HVQR
7KHVHVXEJURXSVZLOOEHUHH[DPLQHGDQGDSSURSULDWHO\UHFDWHJRUL]HGEHIRUHGDWDEDVH
VQDSVKRWRUORFNIRUSULPDU\DQDO\VLV6XEJURXSDQDO\VLVFRQWDLQLQJDVXEJURXSRIOHVV
WKDQRIWKHZKROHSRSXODWLRQZLOOQRWEHFRQGXFWHGRUZLOOEHUHFDWHJRUL]HGLILWLV
SURSHU

,QWHULP$QDO\VLVDQG(DUO\6WRSSLQJ*XLGHOLQHV
1RW$SSOLFDEOH

'DWD6FUHHQLQJDQG$FFHSWDQFH

*HQHUDO3ULQFLSOHV
7KHREMHFWLYHRIWKHGDWDVFUHHQLQJLVWRDVVHVVWKHTXDQWLW\TXDOLW\DQGVWDWLVWLFDO
FKDUDFWHULVWLFVRIWKHGDWDUHODWLYHWRWKHUHTXLUHPHQWVRIWKHSODQQHGDQDO\VHV

'DWD+DQGOLQJDQG(OHFWURQLF7UDQVIHURI'DWD
7KH$PJHQ*OREDO6WXG\2SHUDWLRQV'DWD0DQDJHPHQW*62'0GHSDUWPHQWZLOO
SURYLGHDOOGDWDWREHXVHGLQWKHSODQQHGDQDO\VHV7KLVVWXG\ZLOOXVHWKH5$9(
GDWDEDVH


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
$Q$QDO\VLV'DWDVHWIRU3.&RQFHQWUDWLRQV$'3&ZLOOEHSURYLGHGWRWKHDSSURSULDWH
&306UHSUHVHQWDWLYHIURP*OREDO%LRVWDWLVWLFDO6FLHQFH

+DQGOLQJRI0LVVLQJDQG,QFRPSOHWH'DWD
,QJHQHUDOPLVVLQJGDWDZLOOQRWEHLPSXWHGXQOHVVRWKHUZLVHVSHFLILHG)RUWKHSULPDU\
HQGSRLQW255SDWLHQWVZLWKRXWSRVWEDVHOLQHUHVSRQVHGDWDZLOOEHFRQVLGHUHGDV
QRQUHVSRQGHUV7KHHQGSRLQWVSHFLILFUXOHVRQPLVVLQJGDWDDUHGHVFULEHGLQ
6HFWLRQ'DWDZLOOEHDQDO\]HGDVUHWULHYHGIURPWKHGDWDEDVHSURYLGHGE\&'0
H[FHSWIRUDQDO\VHVUHTXLULQJLPSXWDWLRQV7KHLPSXWHGGDWDZLOOEHZULWWHQWRWKH
GHULYHGGDWDVHWVEXWQRWWRWKHUDZGDWD7KHLPSXWDWLRQDOJRULWKPZLOOEHGHVFULEHGLQ
WKH'DWD'HILQLWLRQ7DEOH''7
7KHKDQGOLQJRILQFRPSOHWHDQGSDUWLDOGDWHVIRUDGYHUVHHYHQWVDQGFRQFRPLWDQW
PHGLFDWLRQVDUHGHVFULEHGLQ$SSHQGL[$
,IWKHVWDUWGD\RIQHZDQWLFDQFHUWKHUDS\LVPLVVLQJDQGPRQWKDQG\HDUDUHQRWVDPH
DVODVWGRVLQJGDWHRIVWXG\WUHDWPHQWLWZLOOEHDVVXPHGWREHWKHILUVWGD\RIWKHPRQWK
,IWKHVWDUWGD\RIQHZDQWLFDQFHUWKHUDS\LVPLVVLQJDQGPRQWKDQG\HDUDUH
VDPHDVODVWGRVLQJGDWHRIVWXG\WUHDWPHQWDQGWKHVXEMHFWGRHVQRWKDYH
SURWRFROGHYLDWLRQRIXVLQJH[FOXGHGSURFHGXUHZKLOHRQVWXG\WKHVWDUWGDWHZLOO
EHDVVXPHGDVODVWGRVHGDWHRIVWXG\WUHDWPHQWSOXVGD\,QRWKHUVLWXDWLRQGR
QRWLPSXWHLW
,IWKHGD\RILQLWLDOGLDJQRVLVLVPLVVLQJDQGPRQWKDQG\HDUDUHSUHVHQWLPSXWHIRU
WKHGD\)RURWKHUFDVHVGRQRWLPSXWH
,IRQO\WKHGD\RIDGHDWKGDWHLVPLVVLQJWKHGHDWKZLOOEHDVVXPHGWREHRQWKHILUVW
GD\RIWKHPRQWKLIWKHODVWNQRZQDOLYHGDWHLVHDUOLHU,IWKHODVWNQRZQDOLYHGDWHLV
ODWHUWKDQWKHILUVWGD\RIWKHPRQWKWKHQWKHGHDWKGDWHZLOOEHDVVXPHGWREHWKHODVW
NQRZQDOLYHGDWHSOXVGD\
3.FRQFHQWUDWLRQVWKDWDUHEHORZWKHTXDQWLILFDWLRQOLPLWVZLOOEHVHWWR]HURZKHQ
HQJDJLQJQRQFRPSDUWPHQWDOPRGHOWRFRPSXWH3.SDUDPHWHUV

'HWHFWLRQRI%LDV
7KHVRXUFHVRISRVVLEOHELDVZLOOEHVXPPDUL]HGDQGEHFRQVLGHUHGZKLOHLQWHUSUHWLQJ
VWXG\UHVXOWV6RXUFHVRIELDVWREHFRQVLGHUHGPD\LQFOXGHSURWRFROYLRODWLRQVRU
LQIRUPDWLYHFHQVRULQJ


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

2XWOLHUV
$Q\VXVSHFWHGRXWOLHUVZLOOEHLQYHVWLJDWHGE\WKHVWXG\WHDPDQGZLOOEHLQFOXGHGLQWKH
GDWDEDVHXQOHVVGHWHUPLQHGWREHDQHUURURUWKHUHLVVXSSRUWLQJHYLGHQFHRU
H[SODQDWLRQWRMXVWLI\WKHH[FOXVLRQ$Q\RXWOLHUVH[FOXGHGIURPWKHDQDO\VLVZLOOEH
GLVFXVVHGLQWKH&OLQLFDO6WXG\5HSRUW&65LQFOXGLQJWKHUHDVRQVIRUH[FOXVLRQDQG
WKHLPSDFWRIWKHLUH[FOXVLRQRQWKHVWXG\
3.FRQFHQWUDWLRQGDWDZLOOEHHYDOXDWHGIRURXWOLHUVE\YLVXDOLQVSHFWLRQDQGGHFLVLRQVWR
UHDVVD\LQGLYLGXDOVDPSOHVZLOOEHPDGHLQDFFRUGDQFHZLWKVWDQGDUGSKDUPDFRNLQHWLF
HYDOXDWLRQSUDFWLFH

'LVWULEXWLRQDO&KDUDFWHULVWLFV
1RW$SSOLFDEOH

9DOLGDWLRQRI6WDWLVWLFDO$QDO\VHV
3URJUDPVZLOOEHGHYHORSHGDQGPDLQWDLQHGDQGRXWSXWZLOOEHYHULILHGLQDFFRUGDQFH
ZLWKFXUUHQWULVNEDVHGTXDOLW\FRQWUROSURFHGXUHV
7DEOHVILJXUHVDQGOLVWLQJVZLOOEHSURGXFHGZLWKYDOLGDWHGVWDQGDUGPDFURSURJUDPV
ZKHUHVWDQGDUGPDFURVFDQSURGXFHWKHVSHFLILHGRXWSXWV
7KHSURGXFWLRQHQYLURQPHQWIRUVWDWLVWLFDODQDO\VHVFRQVLVWVRI$PJHQVXSSRUWHG
YHUVLRQVRIVWDWLVWLFDODQDO\VLVVRIWZDUHIRUH[DPSOHWKH6$66\VWHPYHUVLRQRU
ODWHUIRUDQDO\VLVH[FHSW3.3'

6WDWLVWLFDO0HWKRGVRI$QDO\VLV

*HQHUDO3ULQFLSOHV
)RUFDWHJRULFDOYDULDEOHVWKHIUHTXHQF\DQGSHUFHQWDJHLQHDFKFDWHJRU\ZLOOEH
SUHVHQWHG3RLQWHVWLPDWHVIRUFDWHJRULFDOHIILFDF\HQGSRLQWVZLOOEHDFFRPSDQLHGE\
VLGHGH[DFWELQRPLDOFRQILGHQFHLQWHUYDO
)RUFRQWLQXRXVYDULDEOHVWKHQXPEHURIVXEMHFWVZLWKQRQPLVVLQJGDWD1PHDQ
VWDQGDUGGHYLDWLRQ6'PHGLDQWK SHUFHQWLOHWK SHUFHQWLOHPLQLPXPDQGPD[LPXP
ZLOOEHSUHVHQWHG
)RUWLPHWRHYHQWHQGSRLQWVWKHGLVWULEXWLRQDQGSHUFHQWLOHVZLOOEHHVWLPDWHGE\
.DSODQ0HLHU.0PHWKRGDQGWKHLUFRQILGHQFHLQWHUYDOV&,ZLOOEHSURYLGHG
XWLOL]LQJWKH%URRNPH\HUDQG&URZOH\PHWKRGZLWKORJORJWUDQVIRUPDWLRQ


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

6XEMHFW$FFRXQWDELOLW\
7KHQXPEHUDQGSHUFHQWRIVXEMHFWVZKRZHUHHQUROOHGUHFHLYHGFDUILO]RPLEDVZHOODV
GH[DPHWKDVRQHZHUHVWLOORQWUHDWPHQWGLVFRQWLQXHGFDUILO]RPLEDORQJZLWKWKHUHDVRQV
DQGGLVFRQWLQXHGVWXG\DORQJZLWKWKHUHDVRQVZLOOEHVXPPDUL]HG
7KHQXPEHUDQGSHUFHQWRIHQUROOHGVXEMHFWVZLOOEHWDEXODWHGE\VWXG\VLWH.H\VWXG\
GDWHVIRUWKHILUVWVXEMHFWHQUROOHGODVWVXEMHFWHQUROOHGDQGGDWDFXWRIIGDWHIRUDQDO\VLV
ZLOOEHSUHVHQWHG

,PSRUWDQW3URWRFRO'HYLDWLRQV
,PSRUWDQW3URWRFRO'HYLDWLRQV,3'VFDWHJRULHVDUHGHILQHGE\WKHVWXG\WHDPEHIRUH
WKHILUVWVXEMHFW¶VILUVWYLVLWDQGXSGDWHGGXULQJWKH,3'UHYLHZVWKURXJKRXWWKHVWXG\SULRU
WRGDWDEDVHORFN7KHVHGHILQLWLRQVRI,3'FDWHJRULHVVXEFDWHJRU\FRGHVDQG
GHVFULSWLRQVZLOOEHXVHGGXULQJWKHFRXUVHRIWKHVWXG\(OLJLELOLW\GHYLDWLRQVDUHGHILQHG
LQWKHSURWRFRO
7KHQXPEHUDQGSHUFHQWRIVXEMHFWVZLWKWKHLPSRUWDQWSURWRFROGHYLDWLRQVZLOOEH
VXPPDUL]HGE\WKH,3'FDWHJRU\DQGVXEFDWHJRU\DQGDOVREHOLVWHG

'HPRJUDSKLFDQG%DVHOLQH&KDUDFWHULVWLFV
7KHIROORZLQJGHPRJUDSKLFDQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGXVLQJ
GHVFULSWLYHVWDWLVWLFVIRUWKHVDIHW\DQDO\VLVVHW
x
$JH\HDUV
x
$JHJURXS\HDUV
x
VH[)HPDOH0DOH
x
(&2*
x
KHLJKW
x
ZHLJKW
x
ERG\VXUIDFHDUHDP
x
7LPHPRQWKVIURPLQLWLDOPXOWLSOHP\HORPDGLDJQRVLVWRVWXG\'D\
x
7LPHPRQWKVIURPODVWUHODSVHWRVWXG\'D\
x
%DVHOLQHODERUDWRULHVLQFOXGLQJKHPRJORELQIRUPDOHJ/! J/IRU
IHPDOHJ/! J/$1&OHYHOA/! A/SODWHOHW
FRXQWOHYHOA/! A/FUHDWLQLQHFOHDUDQFH
P/PLQ
x
%DVHOLQH/9()
x
,66VWDJHDWEDVHOLQHVWDJH,VWDJH,,VWDJH,,,
x
,66VWDJHDWGLDJQRVLVVWDJH,VWDJH,,VWDJH,,,
x
1XPEHURISULRUUHJLPHQV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
x
ȕPLFURJOREXOLQOHYHODWEDVHOLQHPJ/
x
'HWHUPLQDWLRQRIPHDVXUDEOHGLVHDVH63(383(3ERWK63(3DQG83(3
V)/&
x
0SURWHLQKHDY\DQGOLJKWFKDLQVXEW\SH
x
6HUXPIUHHOLJKWFKDLQ.DSSD/DPEGDUDWLR
x
3UHVHQFHRISODVPDF\WRPD\HVQR
x
3UHVHQFHRIERQHOHVLRQV\HVQR
x
&RUUHFWHGFDOFLXPDWEDVHOLQH !PJG/
x
5HIUDFWRU\WR3,>HLWKHUERUWH]RPLE%7=RU,[D]RPLE@LQDQ\SULRUOLQHUHJLPHQ
\HVQR
x
5HIUDFWRU\WR,0L'LQDQ\SULRUOLQHUHJLPHQ\HVQR
x
5HIUDFWRU\WRERWK3,>%RUWH]RPLE%7=RU,[D]RPLE@DQG,0L'LQDQ\SULRUOLQH
UHJLPHQ\HVQR
x
3ULRUWUDQVSODQW\HVQR
x
3ULRUVXUJHU\\HVQR
x
3ULRUUDGLRWKHUDS\\HVQR

(IILFDF\$QDO\VHV
$WDEOHVXPPDUL]LQJWKHHIILFDF\HQGSRLQWVDQGSODQQHGDQDO\VLVPHWKRGVLVSURYLGHG
EHORZ7DEOHIRUWKHSULPDU\DQGNH\VHFRQGDU\HQGSRLQWV([SORUDWRU\HQGSRLQWVZLOO
DOVREHDQDO\]HGSHUPHWKRGVLQ7DEOH
7DEOH(QGSRLQW6XPPDU\7DEOH
(QGSRLQW
3ULPDU\6XPPDU\DQG$QDO\VLV0HWKRG
3ULPDU\(QGSRLQW

255DIWHUDWOHDVWF\FOHV
RI.GEDVHGRQ,5&
UHVSRQVHDVVHVVPHQW
x
(VWLPDWHDORQJZLWKWKHFRUUHVSRQGLQJH[DFWELQRPLDO
&,LQWKHVDIHW\DQDO\VLVVHW
x
7KHQXOOK\SRWKHVLVZLOOEHUHMHFWHGDQGWKHVWXG\ZLOOEH
FRQVLGHUHGVXFFHVVIXOZLWKWKHORZHUERXQGDU\RIWKH
VLGHGH[DFWELQRPLDO&,H[FHHGLQJ
,5&UHVSRQVHDVVHVVPHQWGDWDZLOOEHXVHG
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHW
6HFRQGDU\(IILFDF\
(QGSRLQWV

255DIWHUDWOHDVWF\FOHV
RI.GEDVHGRQ
,QYHVWLJDWRU¶VUHVSRQVH
DVVHVVPHQW
x
(VWLPDWHDORQJZLWKWKHFRUUHVSRQGLQJH[DFWELQRPLDO
&,LQWKHVDIHW\DQDO\VLVVHW
x
,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEHXVHG
3DJHRI


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
7DEOH(QGSRLQW6XPPDU\7DEOH
(QGSRLQW
3ULPDU\6XPPDU\DQG$QDO\VLV0HWKRG
6HFRQGDU\(IILFDF\
(QGSRLQWVFRQWLQXHG

255DIWHUDWOHDVW
F\FOHVRI.GEDVHGRQ
,5&DQGLQYHVWLJDWRU¶V
UHVSRQVHDVVHVVPHQW
x
(VWLPDWHDORQJZLWKWKHFRUUHVSRQGLQJH[DFWELQRPLDO
&,LQWKHVDIHW\DQDO\VLVVHW
x
,5&DQG,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEH
XVHGUHVSHFWLYHO\
x
7KLVDQDO\VLVZLOOEHRQO\SHUIRUPHGDWILQDODQDO\VLV
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHWIRU,5&DVVHVVPHQW
&%5DIWHUDWOHDVWDQGDW
OHDVWF\FOHVRI.GEDVHG
RQ,5&DQGLQYHVWLJDWRU¶V
UHVSRQVHDVVHVVPHQW
x
(VWLPDWHDORQJZLWKWKHFRUUHVSRQGLQJH[DFWELQRPLDO
&,LQWKHVDIHW\DQDO\VLVVHW
x
,5&DQG,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEH
XVHGUHVSHFWLYHO\
x
&%5DIWHUF\FOHVZLOORQO\EHSHUIRUPHGDWILQDODQDO\VLV
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHWIRU,5&DVVHVVPHQW
'25EDVHGRQ,5&DQG
LQYHVWLJDWRU¶VUHVSRQVH
DVVHVVPHQW
x
$VWLPHWRHYHQWHQGSRLQWPHGLDQDQGRWKHUSHUFHQWLOH
HVWLPDWHXVLQJ.0FXUYHDQG&,XVLQJ%URRNPH\HU
DQG&URZOH\PHWKRG
x
6XEMHFWVZKRDFKLHYHG35RUEHWWHUDUHLQFOXGHGDFFRUGLQJ
WR,0:*85&FULWHULD
x
,5&DQG,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEH
XVHGUHVSHFWLYHO\
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHWIRU,5&DVVHVVPHQW
'&%EDVHGRQ,5&DQG
LQYHVWLJDWRU¶VUHVSRQVH
DVVHVVPHQW
x
$VWLPHWRHYHQWHQGSRLQWPHGLDQDQGRWKHUSHUFHQWLOH
HVWLPDWHXVLQJ.0FXUYHDQG&,XVLQJ%URRNPH\HU
DQG&URZOH\PHWKRG
x
6XEMHFWVZKRDFKLHYHG05RUEHWWHUDUHLQFOXGHGSHU
,0:*85&FULWHULD
x
,5&DQG,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEH
XVHGUHVSHFWLYHO\
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHWIRU,5&DVVHVVPHQW
3)6EDVHGRQ,5&DQG
LQYHVWLJDWRU¶VUHVSRQVH
DVVHVVPHQW
x
$VWLPHWRHYHQWHQGSRLQWPHGLDQDQGRWKHUSHUFHQWLOH
HVWLPDWHXVLQJ.0FXUYHDQG&,XVLQJ%URRNPH\HU
DQG&URZOH\PHWKRGLQWKHVDIHW\DQDO\VLVVHW
x
,5&DQG,QYHVWLJDWRU¶VUHVSRQVHDVVHVVPHQWGDWDZLOOEH
XVHGUHVSHFWLYHO\
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHWIRU,5&DVVHVVPHQW
26
x
$VWLPHWRHYHQWHQGSRLQWPHGLDQDQGRWKHUSHUFHQWLOH
HVWLPDWLRQXVLQJ.0FXUYHDQG&,XVLQJ%URRNPH\HU
DQG&URZOH\PHWKRGLQWKHVDIHW\DQDO\VLVVHW
x
7KHVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGXVLQJWKHSHU
SURWRFROVHW
3DJHRI


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

$QDO\VHVRI3ULPDU\(IILFDF\(QGSRLQWV
2YHUDOOUHVSRQVHUDWHGHILQHGDVWKHSURSRUWLRQRIVXEMHFWVZLWKWKHEHVWRYHUDOO
UHVSRQVHRI35RUEHWWHUZLOOEHHVWLPDWHGDORQJZLWKFRUUHVSRQGLQJH[DFWELQRPLDO
&,255ZLOOEHDQDO\]HGZKHQDOOWKHHQUROOHGVXEMHFWVKDYHKDGWKHRSSRUWXQLW\WREH
WUHDWHGZLWKDWOHDVWF\FOHVRI.GDQGDOOWKHUHVSRQVHDVVHVVPHQWVE\WKHGDWDFXWRII
GDWHZLOOEHXVHG5HVSRQVHVZLOOEHDVVHVVHGE\WKH,5&DFFRUGLQJWRWKH,0:*85&
FULWHULD3URWRFRO$SSHQGL[(7KHSULPDU\DQDO\VLVZLOOEHEDVHGRQWKHVDIHW\DQDO\VLV
VHW6XPPDU\RIUHVSRQVHVVWDWXVE\HDFKUHVSRQVHFDWHJRU\ZLOOEHDOVRSURYLGHG

$QDO\VHVRI6HFRQGDU\(IILFDF\(QGSRLQWV
2YHUDOO5HVSRQVH5DWH
2YHUDOOUHVSRQVHUDWHDIWHUDWOHDVWF\FOHVRI.GEDVHGRQWKHLQYHVWLJDWRU¶V
DVVHVVPHQWRIEHVWUHVSRQVHDFFRUGLQJWR,0:*85&FULWHULDZLOOEHHVWLPDWHGDORQJ
ZLWKFRUUHVSRQGLQJH[DFWELQRPLDO&,7KHSULPDU\DQDO\VLVZLOOEHEDVHGRQWKH
VDIHW\DQDO\VLVVHW6XPPDU\RIRWKHUEHVWUHVSRQVHVVWDWXVE\HDFKUHVSRQVHFDWHJRU\
ZLOOEHDOVRSURYLGHG
2YHUDOOUHVSRQVHUDWHDIWHUDWOHDVWF\FOHVRI.GEDVHGRQERWK,5&DQG
LQYHVWLJDWRUDVVHVVPHQWRIEHVWRYHUDOOUHVSRQVHZLOOEHHVWLPDWHGDORQJZLWKWKH
FRUUHVSRQGLQJH[DFWELQRPLDO&,6XPPDU\RIRWKHUEHVWUHVSRQVHVVWDWXVE\HDFK
UHVSRQVHFDWHJRU\ZLOOEHDOVRSURYLGHG7KHGLVFRUGDQFHEHWZHHQUHVXOWVIURP,5&DQG
WKHLQYHVWLJDWRUVZLOOEHVXPPDUL]HG7KLVDQDO\VLVZLOORQO\EHDQDO\]HGDWILQDODQDO\VLV
ZKHQDOOWKHHQUROOHGVXEMHFWVKDYHKDGWKHRSSRUWXQLW\WREHWUHDWHGZLWKDWOHDVW
F\FOHVRI.GDQGDOOWKHUHVSRQVHDVVHVVPHQWVE\WKHILQDODQDO\VLVGDWDFXWRIIGDWH
ZLOOEHXVHG
7KHGLVFRUGDQFHEHWZHHQ255UHVXOWVIURP,5&LQYHVWLJDWRUVDQG25&$ZLOOEH
VXPPDUL]HG
&OLQLFDO%HQHILW5DWH&%5
&OLQLFDOEHQHILWUDWHGHILQHGDVWKHSURSRUWLRQRIVXEMHFWVZLWKWKHEHVWRYHUDOOUHVSRQVH
RI05RUEHWWHUZLOOEHHVWLPDWHGDORQJZLWKWKHH[DFWELQRPLDO&,0LQLPDO
UHVSRQVHZLOOEHGHILQHGDFFRUGLQJWR,0:*85&FULWHULD3URWRFRO$SSHQGL[)
&OLQLFDOEHQHILWUDWHZLOOEHFDOFXODWHGDIWHUDWOHDVWDQGDWOHDVWF\FOHVRI.GDQG
GHWHUPLQHGE\ERWKLQYHVWLJDWRUDQG,5&UHVSRQVHDVVHVVPHQWVUHVSHFWLYHO\


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
'XUDWLRQRI5HVSRQVH'25
'XUDWLRQRIUHVSRQVH'25LVGHILQHGDVWKHWLPHIURPILUVWHYLGHQFHRI35RUEHWWHUWR
GLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVH'XUDWLRQRIUHVSRQVHZLOOEHGHWHUPLQHG
EDVHGRQERWKLQYHVWLJDWRUDQG,5&UHVSRQVHDVVHVVPHQWVUHVSHFWLYHO\'XUDWLRQRI
UHVSRQVHZLOOEHULJKWFHQVRUHGEDVHGRQWKHFHQVRULQJFRQYHQWLRQVGHILQHGLQ7DEOH
IRU3)67KHDQDO\VLVRI'25ZLOOEHFDUULHGRXWIRUWKHVXEMHFWVLQWKHVDIHW\DQDO\VLV
VHWZKRDFKLHYH35RUEHWWHUDFFRUGLQJWR,0:*85&FULWHULD
'XUDWLRQRI&OLQLFDO%HQHILW'&%
'XUDWLRQRIFOLQLFDOEHQHILW'&%LVGHILQHGDVWKHWLPHIURPILUVWHYLGHQFHRI05RU
EHWWHUWRGLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVH'XUDWLRQRIFOLQLFDOEHQHILWZLOO
EHULJKWFHQVRUHGEDVHGRQWKHFHQVRULQJFRQYHQWLRQVGHILQHGLQ7DEOHIRU3)67KH
DQDO\VLVRI'&%ZLOOEHFDUULHGRXWIRUWKHVXEMHFWVLQWKHVDIHW\DQDO\VLVVHWZKRDFKLHYH
05RUEHWWHUDFFRUGLQJWR,0:*85&FULWHULD
3URJUHVVLRQIUHH6XUYLYDO3)6
3URJUHVVLRQIUHHVXUYLYDO3)6LVGHILQHGDVWKHWLPHIURPILUVWGRVHRIDQ\VWXG\
WUHDWPHQWWRWKHHDUOLHURIGLVHDVHSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVH3URJUHVVLRQ
IUHHVXUYLYDOZLOOEHGHWHUPLQHGEDVHGRQERWKLQYHVWLJDWRUDQG,5&UHVSRQVH
DVVHVVPHQWV)RUSXUSRVHRIFDOFXODWLQJ3)6WKHVWDUWGDWHIRU3'LVWKHGDWHDWZKLFK
SURJUHVVLRQLVILUVWREVHUYHG7KHGXUDWLRQRI3)6ZLOOEHULJKWFHQVRUHGIRUVXEMHFWV
ZKRPHHWRQHRIWKHIROORZLQJFRQGLWLRQVGHVFULEHGLQ7DEOH
7DEOH'DWHRI3URJUHVVLRQRU&HQVRULQJIRU3URJUHVVLRQIUHH6XUYLYDO
6LWXDWLRQ
'DWHRI3URJUHVVLRQRU&HQVRULQJ
2XWFRPH
1REDVHOLQHGLVHDVHDVVHVVPHQWV
'DWHRIILUVWGRVH
&HQVRUHG
1HZDQWLFDQFHUWKHUDS\VWDUWHG
EHIRUHGRFXPHQWDWLRQRI3'RUGHDWK
'DWHRIODVWGLVHDVHDVVHVVPHQWSULRU
WRVWDUWRIQHZDQWLFDQFHUWKHUDS\
&HQVRUHG
'HDWKRU3'LPPHGLDWHO\DIWHUPRUH
WKDQFRQVHFXWLYHO\PLVVHGGLVHDVH
DVVHVVPHQWYLVLW
'DWHRIODVWGLVHDVHDVVHVVPHQWYLVLW
ZLWKRXWGRFXPHQWDWLRQRI3'WKDWLV
EHIRUHWKHILUVWPLVVHGYLVLW
&HQVRUHG
$OLYHDQGZLWKRXW3'GRFXPHQWDWLRQ
'DWHRIODVWGLVHDVHDVVHVVPHQW
&HQVRUHG
'HDWKRU3'EHWZHHQSODQQHG
GLVHDVHDVVHVVPHQWV
'DWHRIGHDWKRUILUVWGLVHDVH
DVVHVVPHQWVKRZLQJ3'ZKLFKHYHU
RFFXUVILUVW
3URJUHVVHG
'HDWKEHIRUHILUVWGLVHDVH
DVVHVVPHQW
'DWHRIGHDWK
3URJUHVVHG


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
2YHUDOO6XUYLYDO26
2YHUDOOVXUYLYDO26LVGHILQHGDVWKHWLPHIURPWKHILUVWGRVHRIDQ\VWXG\WUHDWPHQWWR
WKHGDWHRIGHDWKGXHWRDQ\FDXVH6XEMHFWVZKRDUHDOLYHRUORVWWRIROORZXSDVRIWKH
GDWDDQDO\VLVFXWRIIGDWHZLOOEHULJKWFHQVRUHGDWWKHVXEMHFW¶VGDWHRIODVWFRQWDFWODVW
NQRZQWREHDOLYH
$QDO\VHVIRUDOOWLPHWRHYHQWVHFRQGDU\HQGSRLQWV'25'&%3)626ZLOOEH
SHUIRUPHGXVLQJWKH.DSODQ0HLHUPHWKRGDQGFDOFXODWHGXVLQJERWK,5&DQG
LQYHVWLJDWRUUHVSRQVHDVVHVVPHQWVUHVSHFWLYHO\H[FHSW260HGLDQVDQGRWKHU
TXDUWLOHVIRUHDFKHQGSRLQWZLOOEHFDOFXODWHGZLWKWKHFRUUHVSRQGLQJWZRVLGHG&,
0HGLDQIROORZXSIRU3)6DQG26ZLOODOVREHHVWLPDWHGDFFRUGLQJWRWKH.DSODQ0HLHU
HVWLPDWHRISRWHQWLDOIROORZXSDOVRWHUPHG³UHYHUVH.DSODQ0HLHU´6FKHPSHU
7LPHWR5HVSRQVH775
7LPHWRUHVSRQVH775LVWKHWLPHIURPWKHILUVWGRVHRIDQ\VWXG\WUHDWPHQWWRWKHILUVW
FRQILUPHGUHVSRQVH35RUEHWWHUDQGZLOOEHGHWHUPLQHGEDVHGRQERWKLQYHVWLJDWRU
DQG,5&UHVSRQVHDVVHVVPHQWV7KHGHVFULSWLYHVWDWLVWLFVLQFOXGLQJPHDQVWDQGDUG
GHYLDWLRQPHGLDQPLQLPXPDQGPD[LPXPZLOOEHFDOFXODWHG7KHDQDO\VLVRI775ZLOO
EHFDUULHGRXWIRUVXEMHFWVLQWKHVDIHW\DQDO\VLVVHWZKRDFKLHYHDWOHDVWD35RUEHWWHU
DFFRUGLQJWR,0:*85&FULWHULD

$QDO\VHVRI([SORUDWRU\(IILFDF\(QGSRLQWV
255DIWHUDWOHDVWF\FOHVDQGDIWHUDWOHDVWF\FOHVRI.G&%5DIWHUDWOHDVW
DQGDIWHUDWOHDVWF\FOHVRI.G'25'&%3)6DQG775GHWHUPLQHGE\25&$
ZLOOEHDQDO\]HGSHUWKHPHWKRGVGHVFULEHGLQ6HFWLRQDQG6HFWLRQ

6DIHW\$QDO\VHV
$OOVDIHW\DQDO\VHVZLOOEHEDVHGRQWKHVDIHW\DQDO\VLVVHW

$GYHUVH(YHQWV
7KH0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$YHUVLRQRUODWHUZLOOEH
XVHGWRFRGHDOODGYHUVHHYHQWV$(WRDV\VWHPRUJDQFODVVDQGDSUHIHUUHGWHUP$(V
RILQWHUHVW(2,FDWHJRULHVZLOOEHEDVHGRQVHDUFKVWUDWHJLHVGHILQHGE\WKH(2,
VWHHULQJFRPPLWWHH
$VXEMHFWUHSRUWLQJWKHVDPH$(PRUHWKDQRQFHZLOOEHFRXQWHGRQO\RQFHZKHQ
FDOFXODWLQJZLWKLQDJLYHQV\VWHPRUJDQFODVVDQGZLWKLQDJLYHQV\VWHPRUJDQ
FODVVDQGSUHIHUUHGWHUPFRPELQDWLRQ)RUVXFKFDVHVWKHPD[LPXP1&,&7&$(


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
WR[LFLW\JUDGHDQGVWURQJHVWFDXVDOUHODWLRQVKLSWRLQYHVWLJDWLRQDOSURGXFWIRUWKHHYHQW
ZLOOEHXVHGLQWKHLQFLGHQFHFDOFXODWLRQV
7KHVXEMHFWLQFLGHQFHRI$(VZLOOEHVXPPDUL]HGIRUDOO7($(VJUDGH7($(V
VHULRXV$(V$(VOHDGLQJWRPRGLILFDWLRQLHGLVFRQWLQXDWLRQUHGXFWLRQRULQWHUUXSWLRQ
RIFDUILO]RPLEGH[DPHWKDVRQHIDWDO$(VWUHDWPHQWUHODWHG$(VWUHDWPHQWUHODWHG6$(V
WUHDWPHQWUHODWHGJUDGH7($(VE\SUHIHUUHGWHUP7KRVH$(VZLOODOVREH
VXPPDUL]HGE\V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPLQGHVFHQGLQJRUGHU,Q
DGGLWLRQDVXPPDU\RI7($(VZLOOEHWDEXODWHGE\V\VWHPRUJDQFODVVSUHIHUUHG
WHUPDQGZRUVWJUDGHEDVHGRQ1&,&7&$(9HUVLRQRUODWHUYHUVLRQ
$(VRILQWHUHVW(2,VHULRXV(2,JUDGH(2,WUHDWPHQWUHODWHG(2,(2,OHDGLQJWR
PRGLILFDWLRQRIFDUILO]RPLEZLOOEHWDEXODWHGE\VHDUFKVWUDWHJ\DQGSUHIHUUHGWHUPLQ
GHVFHQGLQJRUGHURIIUHTXHQF\6XEMHFWLQFLGHQFHRI(2,VZLOODOVREHWDEXODWHGE\
ZRUVWJUDGHEDVHGRQ1&,&7&$(YHUVLRQRUODWHUYHUVLRQLQGHVFHQGLQJRUGHU
RIIUHTXHQF\
6XPPDULHVRIWUHDWPHQWHPHUJHQW$(VVHULRXV$(VDQG(2,VRFFXUULQJLQDWOHDVW
RIWKHVXEMHFWVZLOOEHSURYLGHGE\V\VWHPRUJDQFODVVRUVHDUFKVWUDWHJ\IRU(2,
DQGSUHIHUUHGWHUPLQGHVFHQGLQJRUGHURIIUHTXHQF\
$OOGHDWKVGXULQJWUHDWPHQWSHULRGGD\VRIWKHODVWGRVHRIVWXG\WUHDWPHQWRUXQWLO
QHZDQWLP\HORPDWKHUDS\ZKLFKHYHUFRPHVILUVWDQGGHDWKVEH\RQGWUHDWPHQW
SHULRGZLOOEHVXPPDUL]HGDORQJZLWKWKHUHDVRQDQGDOVREHOLVWHGUHJDUGOHVVRI
ZKHWKHUGXHWR$(RUQRW
$OO$(VZLOOEHLQFOXGHGLQLQGLYLGXDOVXEMHFWOLVWLQJV

/DERUDWRU\7HVW5HVXOWV
/DERUDWRU\SDUDPHWHUVLQFOXGLQJKHPDWRORJ\DQGFKHPLVWU\SDUDPHWHUVZLOOEH
VXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFVPHDQVWDQGDUGGHYLDWLRQPHGLDQUDQJHIRU
HDFKVFKHGXOHGDVVHVVPHQWWLPHSRLQW&KDQJHVDQGSHUFHQWFKDQJHVIURPVWXG\
EDVHOLQHZLOOEHGHVFULSWLYHO\VXPPDUL]HGDWHDFKVFKHGXOHGYLVLW
/DERUDWRU\WHVWUHVXOWVZLOOEHDVVLJQHGWR[LFLW\JUDGHVXVLQJWKH1&,&RPPRQ7R[LFLW\
&ULWHULDIRU$GYHUVH(YHQWV&7&$(7KHVXEMHFWLQFLGHQFHRI*UDGHDQG
ODERUDWRU\WR[LFLWLHVZLOOEHSURYLGHG6KLIWVLQODERUDWRU\WR[LFLW\JUDGHVWRRXWVLGHWKH
QRUPDOUDQJHZLOOEHHYDOXDWHGIRUVHOHFWHGODERUDWRU\SDUDPHWHUV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
6XEMHFWVZLWKRXWDEDVHOLQHDQGRUSRVWEDVHOLQHYDOXHZLOOEHH[FOXGHG6XEMHFWVZLWK
PLVVLQJGDWDIRUDVFKHGXOHGDVVHVVPHQWWLPHSRLQWZLOOEHH[FOXGHG/DERUDWRU\
YDOXHVIURPXQVFKHGXOHGDVVHVVPHQWVZLOOEHH[FOXGHG/DERUDWRU\UHVXOWVIURP
VDPSOHVWDNHQDIWHUQHZDQWLP\HORPDWKHUDS\RU!GD\VDIWHUWKHODVW
DGPLQLVWUDWLRQRIVWXG\WUHDWPHQWZLOOEHH[FOXGHGIURPDOOODERUDWRU\VXPPDULHV

9LWDO6LJQV
9LWDOVLJQUHVXOWVLQFOXGLQJEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUH
ZLOOEHVXPPDUL]HGGHVFULSWLYHO\IRUHDFKVFKHGXOHGSURWRFROWLPHSRLQW&KDQJHVDQG
WKHSHUFHQWFKDQJHVIURPVWXG\EDVHOLQHZLOOEHGHVFULSWLYHO\VXPPDUL]HGDWHDFK
VFKHGXOHGYLVLWPLQLPXPPD[LPXPDQGODVWREVHUYHGYDOXHV
6XEMHFWVZLWKRXWDEDVHOLQHDQGRUSRVWEDVHOLQHYDOXHZLOOEHH[FOXGHG6XEMHFWVZLWK
PLVVLQJGDWDIRUDVFKHGXOHGDVVHVVPHQWWLPHSRLQWZLOOEHH[FOXGHG9LWDOVLJQYDOXHV
IURPXQVFKHGXOHGDVVHVVPHQWVZLOOEHH[FOXGHG9LWDOVLJQUHVXOWVREWDLQHGDIWHU
QHZDQWLP\HORPDWKHUDS\RU!GD\VDIWHUWKHODVWDGPLQLVWUDWLRQRIVWXG\WUHDWPHQW
ZLOOEHH[FOXGHG

(OHFWURFDUGLRJUDP(&*
7KHWZHOYHOHDG(&*PHDVXUHPHQWVIURPWKLVFOLQLFDOVWXG\ZHUHUHTXLUHGLQDOOVXEMHFWV
DWVFUHHQLQJDQGDWWKHHQGRIWUHDWPHQWRQO\%HFDXVHWKHVHHYDOXDWLRQVPD\QRW
QHFHVVDULO\EHSHUIRUPHGXQGHUWKHULJRURXVFRQGLWLRQVH[SHFWHGWROHDGWRPHDQLQJIXO
HYDOXDWLRQRI47FGDWDWKHDQDO\VLVRI(&*VZLOORQO\LQYROYHGHVFULSWLYHVWDWLVWLFV

([SRVXUHWR,QYHVWLJDWLRQDO3URGXFW
'HVFULSWLYHVWDWLVWLFVZLOOEHSURGXFHGWRGHVFULEHWKHH[SRVXUHWRLQYHVWLJDWLRQDO
SURGXFWIRUVXEMHFWVLQWKH6DIHW\$QDO\VLV6HW7KHQXPEHURIF\FOHVRI
SURWRFROVSHFLILHGWKHUDS\DGPLQLVWHUHGZLOOEHVXPPDUL]HGZLWKDQDGGLWLRQDO
EUHDNGRZQRIWKHQXPEHURIF\FOHVVWDUWHG,QDGGLWLRQWKHGXUDWLRQRIWKHUDS\
WKHFXPXODWLYHGRVHDQGWKHDYHUDJHGRVHSHUDGPLQLVWUDWLRQDQGUHODWLYHGRVH
LQWHQVLW\ZLOOEHVXPPDUL]HGIRUHDFKGUXJ7KHQXPEHUDQGSHUFHQWRIVXEMHFWV
ZLWKGRVHPRGLILFDWLRQVHJGRVHUHGXFWLRQVGRVHLQWHUUXSWLRQVDQGUHDVRQIRU
PRGLILFDWLRQZLOOEHVXPPDUL]HG

3ULRU0HGLFDWLRQ&RQFRPLWDQW0HGLFDWLRQDQG$QWLFDQFHU7KHUDS\
3ULRUPHGLFDWLRQVDUHGHILQHGDVPHGLFDWLRQWDNHQRUDGPLQLVWHUHGSULRUWRILUVWGRVHRI
VWXG\WUHDWPHQWDGPLQLVWUDWLRQ3ULRUPHGLFDWLRQVFDQEHGLVFRQWLQXHGEHIRUHWKHILUVW
GRVHRIVWXG\WUHDWPHQWRUFDQEHFRQWLQXLQJLQWRWKHWUHDWPHQWSHULRG


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
&RQFRPLWDQWPHGLFDWLRQVDUHDQ\PHGLFDWLRQVUHFHLYHGE\WKHVXEMHFWFRQFRPLWDQWO\WR
DQ\VWXG\WUHDWPHQWIURPILUVWVWXG\WUHDWPHQWDGPLQLVWUDWLRQWKURXJKGD\VDIWHUWKH
ODVWVWXG\WUHDWPHQWDGPLQLVWUDWLRQRULQLWLDWLRQRIQHZDQWLP\HORPDWKHUDS\
ZKLFKHYHUFRPHVILUVW
$JLYHQPHGLFDWLRQFDQEHFODVVLILHGERWKDVDSULRUPHGLFDWLRQDQGDVDFRQFRPLWDQW
PHGLFDWLRQ
7KHQXPEHUDQGSURSRUWLRQRIVXEMHFWVUHFHLYLQJSULRUDQGFRQFRPLWDQWPHGLFDWLRQVZLOO
EHVXPPDUL]HGE\SUHIHUUHGWHUPRUFDWHJRU\DVFRGHGE\WKH:RUOG+HDOWK
2UJDQL]DWLRQ'UXJ:+2'58*GLFWLRQDU\
6XEMHFWVZKRUHFHLYHGDQWLFDQFHUWKHUDS\GXULQJORQJWHUPIROORZXSZLOOEH
VXPPDUL]HG

3KDUPDFRNLQHWLF$QDO\VLV
3KDUPDFRNLQHWLFFRQFHQWUDWLRQDQDO\VLVVHWZLOOLQFOXGHVXEMHFWVZKRUHFHLYHG
FDUILO]RPLEDQGKDGDGHTXDWHFDUILO]RPLESODVPDFRQFHQWUDWLRQYHUVXVWLPHGDWDIRUWKH
HVWLPDWLRQRI3.SDUDPHWHUVE\DQRQFRPSDUWPHQWDODQDO\VLV
,QGLYLGXDODQGPHDQSODVPDFRQFHQWUDWLRQYHUVXVWLPHGDWDZLOOEHWDEXODWHGDQGSORWWHG
IRUWKHVXEMHFWVSDUWLFLSDWLQJLQWKH3.SRUWLRQRIWKHVWXG\7KHIROORZLQJ3.SDUDPHWHUV
ZLOOEHGHWHUPLQHGZKHQSRVVLEOHIRUFDUILO]RPLE
x
0D[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQ&PD[
x
7LPHRIPD[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQWPD[
x
$UHDXQGHUWKHSODVPDFRQFHQWUDWLRQWLPHFXUYHIURPWLPH]HURWRWLPHRIODVW
TXDQWLILDEOHFRQFHQWUDWLRQDQGWRLQILQLW\$8&ODVWDQG$8&LQIUHVSHFWLYHO\
x
7HUPLQDOHOLPLQDWLRQKDOIOLIHW
x
6\VWHPLFSODVPDFOHDUDQFH&/
x
9ROXPHRIGLVWULEXWLRQ9DUHD
x
9ROXPHRIGLVWULEXWLRQDWVWHDG\VWDWH9VV
x
0HDQUHVLGHQFHWLPH057
$OO3.SDUDPHWHUVZLOOEHFRPSXWHGXVLQJDFWXDOGRVHVDGPLQLVWHUHGDQGDFWXDOHODSVHG
WLPHFDOFXODWHGUHODWLYHWRWKHVWDUWRIGRVHDGPLQLVWUDWLRQ
6WDQGDUGSKDUPDFRNLQHWLF3.WDEOHVILJXUHVDQGOLVWLQJVZLOOEHSURYLGHGE\
&OLQLFDO3KDUPDFRORJ\0RGHOLQJ	6LPXODWLRQ

&KDQJHV)URP3URWRFROVSHFLILHG$QDO\VHV
1RW$SSOLFDEOH


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

/LWHUDWXUH&LWDWLRQV5HIHUHQFHV
%URRNPH\HU5DQG&URZOH\-$&RQILGHQFH,QWHUYDOIRUWKH0HGLDQ6XUYLYDO
7LPH%LRPHWULFV
*UHLSS350LJXHO-6'XULH%*&URZOH\--%DUORJLH%%ODGp-	
/DKXHUWD--,QWHUQDWLRQDOVWDJLQJV\VWHPIRUPXOWLSOHP\HORPD-RXUQDORI
FOLQLFDORQFRORJ\
.XPDU63DLYD%$QGHUVRQ.&'XULH%/DQGJUHQ20RUHDX3	
'LPRSRXORV0,QWHUQDWLRQDO0\HORPD:RUNLQJ*URXSFRQVHQVXVFULWHULDIRU
UHVSRQVHDQGPLQLPDOUHVLGXDOGLVHDVHDVVHVVPHQWLQPXOWLSOHP\HORPD7KH/DQFHW
2QFRORJ\HH
5DMNXPDU69+DURXVVHDX-/'XULH%$QGHUVRQ.&'LPRSRXORV0.\OH
5	-DJDQQDWK6&RQVHQVXVUHFRPPHQGDWLRQVIRUWKHXQLIRUPUHSRUWLQJRI
FOLQLFDOWULDOVUHSRUWRIWKH,QWHUQDWLRQDO0\HORPD:RUNVKRS&RQVHQVXV3DQHO%ORRG
EORRG
6FKHPSHU06WDUH-([SODLQHGYDULDWLRQLQVXUYLYDODQDO\VLV6WDW0HG
±


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

3ULRULWL]DWLRQRI$QDO\VHV
1RW$SSOLFDEOH

'DWD1RW&RYHUHGE\7KLV3ODQ
1RW$SSOLFDEOH


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH

$SSHQGLFHV


3URGXFW&DUILO]RPLE
6WDWLVWLFDO$QDO\VLV3ODQ
'DWH2FWREHU
3DJH
$SSHQGL[$+DQGOLQJRI'DWHV,QFRPSOHWH'DWHVDQG0LVVLQJ'DWHVIRU$GYHUVH
(YHQWVDQG&RQFRPLWDQW0HGLFDWLRQV
7KHIROORZLQJGDWDZLOOEHLPSXWHGXVLQJWKHIROORZLQJDOJRULWKP
x
$GYHUVH(YHQWV
x
&RQFRPLWDQW0HGLFDWLRQV
,PSXWDWLRQ5XOHVIRU3DUWLDORU0LVVLQJ6WDUW'DWHV
6WDUW'DWH 
6WRS'DWH 
&RPSOHWH
\\\\PPGG 
3DUWLDO
\\\\PP 
3DUWLDO
\\\\ 
PLVVLQJ 
VW
GRVH 
VW
GRVH 
VW
GRVH
\\\\PP 
VW
GRVH
\\\\PP 
VW
GRVH
\\\\ 
VW
GRVH
\\\\ 
3DUWLDO
\\\\PP 
 VWGRVH
\\\\PP 
 
 
 
 
QD 
 
 
VWGRVH
\\\\PP 
 
 
 
 
 
3DUWLDO
\\\\ 
 VWGRVH
\\\\ 
 
 
 
 
QD 
 
 
VWGRVH
\\\\ 
 
 
 
 
 
0LVVLQJ 
 
 
 
 
 
 
 
 ,PSXWHWKHGDWHRIILUVWGRVH
 ,PSXWHWKHILUVWGD\RIWKHPRQWK
 ,PSXWH-DQXDU\RIWKH\HDU
 ,PSXWH-DQXDU\RIWKHVWRS\HDU
1RWH,IWKHVWDUWGDWHLPSXWDWLRQOHDGVWRDVWDUWGDWHWKDWLVDIWHUWKHVWRSGDWHWKHQGR
QRWLPSXWHWKHVWDUWGDWH
,PSXWDWLRQUXOHVIRUSDUWLDORUPLVVLQJVWRSGDWHV
x
)RUSDUWLDOVWRSGDWHPP\\\\LPSXWHWKHODVWGD\RIWKHPRQWK
x
)RUSDUWLDOVWRSGDWH\\\\LPSXWH'HFHPEHURIWKH\HDU
x
)RUFRPSOHWHO\PLVVLQJVWRSGDWHGRQRWLPSXWH
x
,IWKHVWRSGDWHLPSXWDWLRQOHDGVWRDVWRSGDWHWKDWLVDIWHUWKHGHDWKGDWHWKHQ
LPSXWHWKHVWRSGDWHDVWKHGHDWKGDWH
x
,IWKHVWRSGDWHLPSXWDWLRQOHDGVWRDVWRSGDWHWKDWLVEHIRUHWKHVWDUWGDWHWKHQ
WKHUHLVDGDWDHUURUDQGGRQRWLPSXWHWKHVWRSGDWHLHVHWWKHVWRSGDWHDV
PLVVLQJ