An Open-Label, Single-Arm, Phase 2 Study of Extended Carfilzomib Therapy in Subjects Previously Enrolled in Carfilzomib Treatment Protocols
Phase: PHASE2
Conditions: Multiple Myeloma, Solid Tumors
Sponsor: Amgen

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Protocol PX-171-010, Amendment 3
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CLINICAL STUDY PROTOCOL
Protocol Number:
PX-171-010
Study Title:
An Open-Label, Single-Arm, Phase 2 Study of Extended 
Carfilzomib Therapy in Subjects Previously Enrolled in 
Carfilzomib Treatment Protocols
Investigational Product:
Carfilzomib for Injection
Investigational New Drug:
IND 71,057
Sponsor:
Onyx Therapeutics, Inc.
249 E. Grand Ave.
South San Francisco, CA  94080
(650) 266-0000
Original Protocol Date:
24 February 2009
Amendment 1:
11 June 2009
Amendment 2:
09 April 2010
Amendment 3:
25 March 2011
CONFIDENTIALITY STATEMENT
This document contains confidential information.  It is provided for the sole use of the Principal Investigator, 
Sub-investigators, Staff, Institutional Review Board or Independent Ethics Committee, and Regulatory 
Authorities.  By accepting this document, you agree to maintain the information as confidential and to use it 
only for the purpose of conducting the study.
NCT Number: 00884312
This NCT number has been applied to the document for 
purposes of posting on clinicaltrials.gov

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SIGNATURE PAGE
Protocol Title:
An Open-Label, Single-Arm, Phase 2 Study of Extended 
Carfilzomib Therapy in Subjects Previously Enrolled in 
Carfilzomib Treatment Protocols
Protocol Number:
PX-171-010
Sponsor:
Onyx Therapeutics, Inc.
249 E. Grand Ave.
South San Francisco, CA  94080
+1 650 266 0000
Date of Original Protocol:
24 February 2009
Amendment 1:
11 June 2009
Amendment 2:
09 April 2010
Amendment 3:
25 March 2011
Approved By:
<See Electronic Signature>
Vice President, Clinical Development
Date
<See Electronic Signature>
Vice President, Regulatory Affairs
Date
<See Electronic Signature>
, PhD
Senior Director, Biometrics
Date
APPROVALS STATEMENT
This document is signed with electronic signatures at Onyx Therapeutics, Inc. (a wholly owned subsidiary of 
Onyx Pharmaceuticals, Inc.).  Electronic signatures made by our employees, agents, or representatives, located 
anywhere in the world, are the legally binding equivalent of traditional handwritten signatures.
PPD
PPD
PPD

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PROTOCOL ACCEPTANCE PAGE
PROTOCOL NUMBER:
PX-171-010
PROTOCOL TITLE:
An Open-Label, Single Arm Phase 2 Study of Extended 
Carfilzomib Therapy in Subjects Previously Enrolled in 
Carfilzomib Treatment Protocols
PROTOCOL DATE:
24 February 2009 
AMENDMENT 1:
11 June 2009
AMENDMENT 2:
09 April 2010
AMENDMENT 3:
25 March 2011
By signing this protocol acceptance page, I confirm I have read, understood, and agree to 
conduct the study in accordance with the current protocol.
__________________________________________
Principal Investigator Name (Printed)
__________________________________________
____________
Principal Investigator Signature
Date
Please return original form to Onyx Therapeutics, Inc. or designee.  Please retain a copy for 
your study files.
This study is to be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations §§ 50, 56, and 
312, the International Conference on Harmonization E6, and any applicable regulatory 
requirements.
The study protocol and any amendments are to be reviewed by an Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) before implementation.
Written informed consent is to be obtained from each study subject prior to the conduct of 
any study procedures which exceed or differ from standard practice at the study site.
Confidential information contained in this document will not be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent 
of Onyx Therapeutics.

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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL .....................................................................................1
SIGNATURE PAGE ...........................................................................................................2
PROTOCOL ACCEPTANCE PAGE ................................................................................3
LIST OF ABBREVIATIONS .............................................................................................8
PROTOCOL SYNOPSIS:  PX-171-010 ...........................................................................10
1
INTRODUCTION .................................................................................................14
1.1
Carfilzomib Background ..............................................................................14
1.2
Phase 1 and 2 Experience with Carfilzomib in Hematologic Malignancies ...14
1.3
Phase 1 and 2 Experience with Carfilzomib in Solid Tumors........................15
1.4
Extended Carfilzomib Treatment Study Rationale ........................................17
1.5
Dose Rationale.............................................................................................17
2
STUDY OBJECTIVES..........................................................................................18
2.1
Objective......................................................................................................18
3
EXPERIMENTAL PLAN .....................................................................................18
3.1
Study Design................................................................................................18
3.2
Number of Centers .......................................................................................18
3.3
Number of Subjects......................................................................................19
3.4
Estimated Study Duration.............................................................................19
4
SUBJECT SELECTION .......................................................................................19
4.1
Inclusion Criteria..........................................................................................19
4.2
Exclusion Criteria.........................................................................................20
5
SUBJECT ENROLLMENT ..................................................................................20
6
TREATMENT PROCEDURES............................................................................21
6.1
Drug Preparation and Administration ...........................................................21
6.1.1
Carfilzomib Drug Administration ..................................................21
6.2
Dose Modification Guidelines......................................................................22
6.2.1
Dose Frequency and Dose Level Reductions..................................22
6.2.2
Dose Modifications for Hematologic Toxicities .............................23
6.2.3
Dose modifications for Non-Hematologic Toxicities......................24
6.2.4
Missed Doses.................................................................................26
6.2.5
Changes in Body Surface Area.......................................................26

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6.2.6
Other Dosing Modifications...........................................................26
6.2.7
Dose Escalation Rules....................................................................27
6.3
Safety Guidance for Investigators.................................................................27
6.3.1
Safety Guidance.............................................................................27
6.4
Concomitant Medications.............................................................................28
6.4.1
Required Concomitant Medication.................................................28
6.4.2
Allowed Concomitant Medications ................................................28
6.4.3
Excluded Concomitant Medications...............................................28
7
STUDY TESTS AND OBSERVATIONS .............................................................28
7.1
Screening (Days –30 to –1) ..........................................................................29
7.2
Cycle 1 (Day 1)............................................................................................30
7.3
Cycle 1 (Days 2, 8, 9, 15, and 16).................................................................30
7.4
Cycles 2 and Higher (Day 1) ........................................................................30
7.5
Cycles 2 and Higher (Days 2, 8, 9, 15, and 16).............................................31
7.6
Cycle 3 and Every 3 Cycles (Day 1).............................................................31
7.7
End of Study Assessments (Within 30 Days of Study Discontinuation) ........32
7.8
Tumor Response Assessment .......................................................................32
7.9
Correlative Studies.......................................................................................33
7.9.1
Cytogenetic and FISH Studies .......................................................33
8
STUDY DISCONTINUATION.............................................................................33
9
ADVERSE EVENTS .............................................................................................34
9.1
Adverse Events Definitions ..........................................................................34
9.2
Causality......................................................................................................35
9.3
Adverse Events Reporting Procedures..........................................................35
9.3.1
Disease Progression.......................................................................36
9.4
Serious Adverse Events Definitions..............................................................37
9.5
Serious Adverse Event Reporting and Documentation Requirements............38
9.6
Pregnancy ....................................................................................................38
10
STATISTICAL CONSIDERATIONS ..................................................................39
10.1
Objectives/Hypotheses .................................................................................39
10.2
Analysis Endpoints.......................................................................................39
10.2.1
Primary Endpoints (Safety)............................................................40
10.2.2
Secondary Endpoints (Efficacy/Disease Response) ........................40

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10.3
Analysis Populations....................................................................................40
10.3.1
Safety Analysis..............................................................................40
10.3.2
Disease Response Analysis............................................................40
10.4
Statistical Methods.......................................................................................40
10.4.1
Safety Analysis..............................................................................40
10.4.2
Disease Response Analysis ............................................................41
10.5
Sample Size .................................................................................................42
10.6
Guidelines for Early Study Termination .......................................................42
11
REGULATORY OBLIGATIONS ........................................................................42
11.1
Informed Consent.........................................................................................42
11.2
Compliance with Laws and Regulations .......................................................43
11.3
Pre-study Documentation Requirements.......................................................44
11.4
Subject Confidentiality.................................................................................44
12
ADMINISTRATIVE AND LEGAL OBLIGATIONS..........................................45
12.1
Protocol Amendments and Study Termination..............................................45
12.2
Study Documentation and Archives..............................................................45
12.2.1
Source Documents.........................................................................45
12.2.2
Case Report Form Completion.......................................................46
12.2.3
Archival of Records.......................................................................46
12.3
Study Monitoring and Data Collection .........................................................46
13
REFERENCES ......................................................................................................48

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LIST OF APPENDICES
Appendix A:
Schedule of Events.......................................................................................49
Appendix B:
ECOG Performance Scale (Eastern Cooperative Oncology Group)...............50
Appendix C:
NCI CTCAE Version 3.0..............................................................................51
Appendix D:
International Uniform Response Criteria for Multiple Myeloma...................52
Appendix E:
Response Criteria for Solid Tumors..............................................................54
Appendix F:
Summary of Changes ...................................................................................56
LIST OF TABLES
Table 1:
Carfilzomib for Injection Dose Levels..........................................................22
Table 2:
Dose Adjustment Guideline for Renal Dysfunction ......................................25
Table 3:
Toxicity Grading..........................................................................................35

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LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
BSA
body surface area
CBC
complete blood count
CFR
Code of Federal Regulations
CHF
congestive heart failure
CR
complete response
CRu
unconfirmed complete response
CRO
clinical research organization
CrCl
creatinine clearance
CRF
case report form(s)
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
curricula vitae
DLT
dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
FAS
full analysis set
FCBP
females of childbearing potential
FDA
Food and Drug Administration
FISH
fluorescent in situ hybridization
GCP
Good Clinical Practice 
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IV
intravenous
MM
multiple myeloma
MR
minimal response
MTD
maximum tolerated dose
NCI
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PR
partial response
QDx2
consecutive day dosing

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Abbreviation
Definition
QDx5
daily dosing for 5 consecutive days
QIU
Qualified Investigator Undertaking Form
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
sCR
stringent complete response
SD
stable disease
TLS
tumor lysis syndrome
TTP
time to tumor progression
US
United States
VGPR
very good partial response

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PROTOCOL SYNOPSIS:  PX-171-010
TITLE
An Open-Label, Single-Arm Phase 2 Study of Extended Carfilzomib 
Therapy in Subjects Previously Enrolled in Carfilzomib Treatment 
Protocols
OBJECTIVE
To evaluate the safety and efficacy of long-term or continuing 
carfilzomib treatment in subjects who have completed a previous 
carfilzomib treatment study.
STUDY DESIGN
This is a multi-center, open-label, Phase 2 study of carfilzomib to 
monitor the safety and efficacy of long-term or continuing carfilzomib 
therapy for subjects who previously completed a primary carfilzomib 
treatment study.  Only subjects who have adequately completed a 
prior carfilzomib study will be eligible for the current study.
Safety endpoints will consist of the following: (1) all reported 
Grades 3 and 4 adverse events (AEs), (2) all reported peripheral 
neuropathy AEs (Grades 1–4), (3) all serious adverse events (SAEs), 
and (4) Grades 1–4 AEs leading to either a missed carfilzomib dose, 
carfilzomib dose reduction, or discontinuation.  In the event of a 
toxicity leading to a dose reduction or discontinuation, pertinent 
laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits.
Efficacy endpoints will include time to tumor progression (TTP), 
progression-free survival (PFS), and overall survival (OS).  Data on 
the first subsequent treatment regimen following carfilzomib study 
discontinuation will also be collected.
STUDY 
POPULATION
Approximately 100 subjects from approximately 50 sites in the United 
States and Canada will be eligible for participation in the extended 
carfilzomib therapy study.  Additional subjects may be enrolled 
should the number of eligible subjects exceed 100.
INCLUSION 
CRITERIA
Subjects must meet all of the following inclusion criteria to be eligible 
to enroll in this study:
Disease Related
1. Previous completion of a carfilzomib study within 90 days prior to 
first dose of study drug for Protocol PX-171-010.
2. Disease Assessments performed within 30 days prior to first dose 
of study drug for Protocol PX-171-010.
Ethical/Other
3. Written informed consent in accordance with federal, local, and 
institutional guidelines.
4. Females of childbearing potential (FCBP) must have a negative 
serum or urine pregnancy test, with a sensitivity of at least 
50 mIU/mL, within 3 days prior to first dose of study drug for 
Protocol PX-171-010.

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5. Subjects must agree to adhere to the study visit schedule and other 
study requirements and receive outpatient treatment and 
laboratory monitoring at the institution that administers the drug.
EXCLUSION 
CRITERIA
Subjects who meet any of the following exclusion criteria are not 
eligible to be enrolled in this study:
Disease Related
1. Administration of an intervening chemotherapy between the time 
of previous carfilzomib study termination and first dose of study 
drug for Protocol PX-171-010.
Concurrent Conditions
2. Pregnant or lactating females.
3. Diagnosis of a new malignancy of a different tumor type.
PROCEDURES
After screening, eligibility determination, and enrollment; subjects 
will receive carfilzomib according to the doses and schedules as 
summarized in the Study Treatment section of the Synopsis.  Standard 
monitoring for hematologic and non-hematologic toxicity is outlined 
in Section 6.2.  Subjects may continue carfilzomib treatment until 
disease progression and discussion with Onyx Medical Monitor,
diagnosis of new malignancy, unacceptable toxicity, Investigator 
discretion, voluntary withdrawal, or commercial availability of 
carfilzomib.
Safety Measures. A complete blood count (CBC) including platelets 
and basic metabolic chemistry panel (eg, Chem 7 or 8) will be 
performed on Day 1 of each cycle.  Other general safety monitoring 
(eg, physical examinations, imaging, specialty tests, etc.) shall be in 
accordance with institutional guidelines and as clinically indicated. 
These data will not be routinely collected.
Efficacy Measures. Tumor measurements and efficacy assessments 
will be in accordance with the methods employed in the subject’s 
prior carfilzomib study.  For subjects participating in a carfilzomib 
trial without prior tumor measurements and efficacy assessments 
(eg, PX-171-008), tumor assessments employing standard institutional 
methods will be conducted at the time of screening for the current 
study.  Disease assessments (eg, extent of disease measurements and 
objective response category) will occur within 30 days prior to 
enrollment to determine eligibility, at least every 3 months throughout 
study participation, and at end of study.  Refer to Appendix D–E for 
Response Criteria.
For subjects with multiple myeloma (MM) entering the extended
study with a partial response (PR), minimal response (MR), or stable 
disease (SD); bone marrow biopsies for cytogenetic and fluorescence 
in situ hybridization (FISH) evaluation will be optional at screening.  
A bone marrow biopsy in these subjects will also be optional at end of 
study for cytogenetic and FISH evaluation if the reason for study 

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discontinuation is disease progression.  For subjects with MM 
entering the extended study with stringent complete response (sCR), 
complete response (CR), or very good partial response (VGPR), a 
bone marrow biopsy for cytogenetic and FISH analyses will also be 
optional upon the establishment of disease progression.
STUDY 
TREATMENT
Carfilzomib will be administered intravenously (IV), using the same 
method, dose level and frequency as administered in the last cycle of 
the subject’s previous carfilzomib study; carfilzomib doses will be 
administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (or the 
same dose level and frequency as administered at the last visit of the 
prior carfilzomib study) until disease progression and discussion with 
the Onyx Medical Monitor, diagnosis of new malignancy, 
unacceptable toxicity, Investigator discretion, voluntary withdrawal, 
or commercial availability of carfilzomib.  Each dose will consist of 
Carfilzomib for Injection administered on a mg/m2 basis.  Subjects 
with a body surface area (BSA) > 2.2 m2 will receive a dose based 
upon a 2.2 m2 BSA.  Dosing will be continued or modified based 
upon clinical and laboratory findings.
Decreased carfilzomib dosing frequency to include dosing on Days 1, 
2, 15 and 16 (eg, every other week dosing schedule), will be permitted 
at the discretion of the Investigator; the Onyx Therapeutics Medical 
Monitor may be consulted as needed. Carfilzomib dose reductions for 
toxicity, to a minimum dose of 11 mg/m2, will be permitted following 
discussion with the Medical Monitor, as needed.  Missed doses of 
carfilzomib will not be made up.
Dose escalations above the original dose level are permitted.  
For subjects with evidence of disease progression, the Onyx Medical 
Monitor must be consulted prior to the dose escalation or termination 
from study.
Acyclovir or valacyclovir should be given to all subjects with a 
history of herpes simplex or zoster, per institutional prophylaxis 
guidelines, unless contraindicated.
PRIMARY 
ENDPOINT
Safety
SECONDARY 
ENDPOINTS
Overall Survival (OS)
Progression Free Survival (PFS)
Time to Progression (TTP)

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STATISTICAL 
METHODS
Safety Analyses:  Safety data analysis will be conducted on all 
subjects receiving at least 1 dose of study treatment.  Analyses will 
consist of data summaries for reported AEs.  The number and 
percentage of subjects experiencing 1 or more AEs will be 
summarized by dose, relationship to study drug, and severity.
Disease Response Analyses:  Response to treatment will be tabulated 
using the criteria employed in the subject’s prior carfilzomib 
treatment study.
For subjects participating in a carfilzomib trial without explicit tumor 
measurements and defined response criteria (eg, PX-171-008), 
response to treatment will be tabulated using the appropriate method 
(eg, RECIST criteria for solid tumors). Response to treatment will be 
based on the tumor assessment conducted at the time of screening for 
the current study.
The distribution of subjects by response category will be made by 
disease cohort.  Time-to-event endpoints will be evaluated with the 
use of the Kaplan-Meier method and plots will be provided.  Analysis 
of time-to-event outcomes will be performed by disease cohort.
STUDY 
DURATION
An individual subject is considered to have completed the study 
30 days after the last administered dose of carfilzomib to allow for 
safety follow up.
Treatment with carfilzomib will continue until the earliest of the 
following:
Confirmation of disease progression, and discussion with Medical 
Monitor
- OR -
Diagnosis of a new malignancy
- OR -
Unacceptable toxicity
- OR -

Investigator discretion
- OR -
Voluntary withdrawal
- OR -
Commercial availability of carfilzomib

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1
INTRODUCTION
1.1
CARFILZOMIB BACKGROUND
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based selective inhibitor of the 
chymotrypsin-like activity of the 20S proteasome (Demo 2005). Carfilzomib is structurally 
and mechanistically different from the dipeptide boronic acid proteasome inhibitor 
bortezomib, which is currently approved for use in the treatment of patients with multiple 
myeloma (Demo 2005, Velcade 2008).  In preclinical studies, carfilzomib demonstrates 
potent anti-tumor activity in a variety of tumor models, including multiple myeloma (MM)
(Demo 2007, Ivancsits 2006, Kuhn 2007).
1.2
PHASE 1 AND 2 EXPERIENCE WITH CARFILZOMIB IN 
HEMATOLOGIC MALIGNANCIES (Carfilzomib IB 2010, Stewart 2007, 
Onyx Data on File)
Phase 1 clinical trials of carfilzomib have been conducted in subjects with hematological 
tumors, including MM, Waldenström’s macroglobulinemia, non-Hodgkin’s lymphoma 
(NHL), and Hodgkin’s lymphoma.  In a completed study (PX-171-001), carfilzomib dosing 
ranged from 1.2 mg/m2 to 20 mg/m2 daily for 5 consecutive days (QDx5) followed by 
9 days’ rest, in cycles repeated every 14 days.  Dose-limiting toxicities (DLTs) associated 
with the highest dose (20 mg/m2) were Grade 4 thrombocytopenia and Grade 3 febrile 
neutropenia, and the maximum tolerated dose (MTD) was established at 15 mg/m2.
In a completed Phase 1 Study PX-171-002, doses ranging from 1.2 mg/m2 to 27 mg/m2 are 
administered on consecutive day dosing (QDx2) twice weekly for 3 weeks, followed by 
12 days rest, in cycles repeated every 28 days.  DLTs observed at the highest dose 
(27 mg/m2) included thrombocytopenia and hypoxia, therefore the MTD was established at 
20 mg/m2.  Observations of fever, chills, and rigors, and an elevated creatinine (Grade 2) 
observed on Day 2 of the 27 mg/m2 cohort prior to dosing in this part of the study, led to the 
development of a stepped-up dosing regimen wherein carfilzomib administration is initiated 
with a dose at 20 mg/m2 followed by escalation to 27 mg/m2 after the first cycle.
The most common non-hematologic toxicity events reported from the Phase 1 studies are 
generally mild, low-grade nausea, diarrhea, dyspnea, headache, and constipation.  A Grade 3 

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or 4–thrombocytopenia may occur in subjects with preexisting low platelets, with recovery 
occurring between treatments.  Grade 3 or higher neutropenia and anemia have also been 
reported, but less frequently than thrombocytopenia.
Objective responses including partial responses (PRs) (50%–90% decreases in M-protein) 
and minimal responses (MRs) (25%–49% decreases in M-protein) were seen in several 
subjects with plasma cell dyscrasias in both studies.  The responses have been durable with 
PRs on average of 9 months.  In addition, both MM and NHL subjects have had stable 
disease (SD), exceeding 1 year in some cases.  Carfilzomib has also shown activity against 
refractory MM, solid tumors, and 1 mantle cell lymphoma subject with gastrointestinal 
lymphoma involvement that achieved an unconfirmed complete response (CRu).
The use of carfilzomib in combination with lenalidomide and dexamethasone is being 
evaluated in a Phase 1b dose escalation Study PX-171-006 in relapsed MM subjects.  
The study will evaluate the MTD of this combination regimen.
Two Phase 2 studies are ongoing, one for relapsed refractory MM and another in MM 
subjects relapsed following 1–3 prior therapies.  In these studies, tumor lysis syndrome 
(TLS) has been observed in 4 of 77 subjects treated at the 20 mg/m2 dose.  Guidelines for the 
investigator were subsequently implemented for the prevention and management of TLS in 
ongoing studies.
In May 2009, a MM arm was added to the PX-171-007 study to explore carfilzomib given as 
a 30-minute infusion.  MM subjects receiving carfilzomib administered over 30 minutes have 
dose escalated to 20/36 mg/m2 (4 subjects) and 20/45 mg/m2 (3 subjects) without 
dose-limiting toxicities.
1.3
PHASE 1 AND 2 EXPERIENCE WITH CARFILZOMIB IN SOLID 
TUMORS (Carfilzomib IB 2010, Stewart 2007, Onyx Data on File)
Carfilzomib is also being studied as a single agent in a Phase 1b/2 Study PX-171-007 in 
advanced stage solid tumor subjects who have failed available therapies. Subjects are treated 
with carfilzomib on the QDx2 schedules using the stepped-up dosing regimen previously 
described.  A Phase 1b dose escalation portion has been completed, demonstrating that 

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administration of 20 mg/m2 on Days 1and 2 followed by 36 mg/m2 on subsequent days is 
well tolerated.
A Simon 2-stage open label study of 70 patients with 5 cohorts was initiated as the Phase 2 
portion in April 2008.  The cohorts were stratified according to solid tumor disease type.  
The objective of this portion of the trial was to estimate overall response to 4 cycles of 
carfilzomib.  This portion would only proceed to stage 2 if 1 PR or better occurred after 
16 weeks in a cohort.
Seventy-nine patients had been enrolled on study through May 2009 in the Phase 1 
(14 patients) and Phase 2 (65 patients) parts.  The median number of carfilzomib cycles given 
was 2 (range 1-12). Of the 1064 doses administered ~68% were at the 36 mg/m2 dose level.  
One PR was observed in a renal cell patient; 11 patients achieved stable disease.  The most 
common AEs included fatigue, headache, diarrhea, nausea, and constipation.  There was a 
low incidence of peripheral neuropathy and severe hematologic toxicity.
Dose escalation to evaluate and determine an MTD with a 30-minute infusion of carfilzomib 
is ongoing in patients with solid tumors and multiple myeloma. At this time, there is limited 
safety data available to comment on differences, if any, associated with a 30-minute infusion 
versus a 10-minute infusion of carfilzomib.
A drug-drug interaction Study PX-171-008 has been initiated where 15 subjects with 
advanced solid tumors will be assessed to determine the effect of carfilzomib on the 
pharmacokinetics of midazolam, a sensitive substrate for human CYP3A4. In addition, renal 
and biliary excretions will be assessed in this study.
The safety data from the solid tumor study indicate that the non-hematologic toxicities are 
similar to those seen in the Phase 1 studies.  The most common events reported regardless of 
relationship to study drug are fatigue, diarrhea, and headache.
Further information about the Phase 1 and 2 studies is presented in the Investigator’s 
Brochure (IB).

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1.4
EXTENDED CARFILZOMIB TREATMENT STUDY RATIONALE
For all of the aforementioned primary carfilzomib treatment studies, the maximum duration 
of treatment ranges from 1 to 18 cycles.  The purpose of the extended carfilzomib treatment 
study is to evaluate the safety and efficacy of long-term carfilzomib treatment for patients 
who have completed a carfilzomib study.
1.5
DOSE RATIONALE
Carfilzomib will be administered intravenously (IV) using the same method, dose level and 
frequency as administered in the last cycle of the subject’s previous carfilzomib study.  
A carfilzomib dosing schedule on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (or the same 
dose level and frequency as administered at the last visit of the prior carfilzomib study) will 
be employed and evaluated for long-term safety and efficacy.  Subjects will remain at the 
same dose level and frequency as their previous study because the dose has been shown to be 
tolerable in the individual subject.
The option will be available to reduce the dosing frequency to Days 1, 2, 15, and 16 of a 
28-day cycle (eg, twice a week, every other week).  Reductions in dosing frequency will be 
made at the discretion of the Investigator in consultation with the Medical Monitor.
Dose escalations beyond the original dose level up to the maximum tolerated dose 
established in primary carfilzomib studies may be permitted following discussion with the 
Medical Monitor for subjects whose disease progresses on the extended carfilzomib 
treatment regimen.

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2
STUDY OBJECTIVES
2.1
OBJECTIVE
To evaluate the safety and efficacy of long-term or continuing carfilzomib dosing in subjects 
who have completed a previous carfilzomib treatment study.
3
EXPERIMENTAL PLAN
3.1
STUDY DESIGN
This is a multicenter, open-label, Phase 2 study of carfilzomib to monitor the safety and 
efficacy of long-term or continuing carfilzomib therapy for subjects who previously 
completed a primary carfilzomib treatment study.  Only subjects who have completed a prior 
carfilzomib treatment study will be eligible for the current study.
Safety endpoints will consist of the following: (1) all reported Grades 3 and 4 adverse events 
(AEs), (2) all reported peripheral neuropathy AEs (Grades 1–4), (3) all serious adverse 
events (SAEs), and (4) Grades 1–4 AEs leading to either a missed carfilzomib dose, 
carfilzomib dose reduction, or discontinuation.  In the event of a toxicity leading to a dose 
reduction or discontinuation, pertinent laboratory measurements and concomitant 
medications will be collected and monitored as unscheduled visits.
Efficacy endpoints will include time to tumor progression (TTP), progression-free survival 
(PFS), and overall survival (OS).  Data on the first subsequent treatment regimen following 
extended carfilzomib therapy study discontinuation will also be collected.
3.2
NUMBER OF CENTERS
Approximately 50 study centers in the United States (US) and Canada will be eligible for 
participation in the current study.  Additional study sites selected to participate in future 
studies may also be included.

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3.3
NUMBER OF SUBJECTS
Approximately 100 subjects will be eligible for enrollment in this open-label multicenter 
study.  Additional subjects from future studies may also be enrolled to further establish long-
term safety of carfilzomib.
3.4
ESTIMATED STUDY DURATION
An individual subject is considered to have completed the study 30 days after the last 
administered dose of study drug in order to allow for safety follow up.  Treatment with 
carfilzomib will continue until the earliest of the following:

Confirmation of disease progression, and discussion with Medical Monitor
- OR -

Diagnosis of a new malignancy
- OR -

Unacceptable toxicity
- OR -

Investigator discretion
- OR -

Voluntary withdrawal
- OR -

Commercial availability of carfilzomib
4
SUBJECT SELECTION
4.1
INCLUSION CRITERIA
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study:
1. Previous completion of a carfilzomib study within 90 days prior to first dose of study 
drug for Protocol PX-171-010.
2. Disease Assessments performed within 30 days prior to first dose of study drug for 
Protocol PX-171-010.
Ethical/Other
3. Written informed consent in accordance with federal, local, and institutional guidelines
4. Females of childbearing potential (FCBP)* must have a negative serum or urine 
pregnancy test, with a sensitivity of at least 50 mIU/mL, within 3 days prior to first dose 
of extended carfilzomib therapy study drug.

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5. Subjects must agree to adhere to the study visit schedule and other study requirements 
and receive outpatient treatment and laboratory monitoring at the institution that 
administers the drug.
* Females of childbearing potential (FCBP): Defined as sexually mature females who have not undergone a 
hysterectomy or who have not been postmenopausal for at least 24 consecutive months (ie, who have had 
menses at some time in the preceding 24 consecutive months), or had a bilateral oophorectomy are 
considered to be females of childbearing potential.
4.2
EXCLUSION CRITERIA
Subjects who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1. Administration of an intervening chemotherapy between the time of previous carfilzomib 
study termination and first dose of study drug for Protocol PX-171-010.
Concurrent Conditions
2. Pregnant or lactating females.
3. Diagnosis of a new malignancy of a different tumor type.
5
SUBJECT ENROLLMENT
The screening period for a particular subject commences at the point which the subject signs 
the informed consent.  Consent must be signed before any study-specific tests may be 
performed.
Subject demographics, including previous carfilzomib study unique identifier, will be 
captured in a study enrollment form.  Tumor measurements and efficacy assessments 
(eg, extent of disease measurements and objective response category) relevant to the 
subject’s tumor type will be collected in accordance to the method(s) employed in the 
subject’s previous carfilzomib study protocol.  Refer to Appendix D–E for Response Criteria.  
For subjects participating in a carfilzomib trial without explicit tumor measurements and 
defined response criteria (eg, PX-171-008), response to treatment will be tabulated using the 
appropriate method (eg, RECIST criteria for solid tumors).  Response to treatment will be 
based on the tumor assessment conducted at the time of screening for the current study.  
Disease assessments will be required within 30 days prior to study enrollment, at least every 
3 months throughout the extended treatment period (Day 1), and at end of study visit. 

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After a subject has been screened and has successfully fulfilled all eligibility criteria, the site 
representative will fax the inclusion/exclusion checklist and all other required documentation 
to Onyx Therapeutics.
Subjects will retain their study-specific number from the previous study.  This number will 
be used to identify the subject throughout the study and must be used on all study 
documentation related to that subject.
The number of subjects may be expanded to include eligible subjects from future studies, to 
further establish safety and efficacy, if needed.
6
TREATMENT PROCEDURES
6.1
DRUG PREPARATION AND ADMINISTRATION
6.1.1
CARFILZOMIB DRUG ADMINISTRATION
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials 
which, when reconstituted with an appropriate volume of Water for Injection, contains 
2 mg/mL of carfilzomib.  The product is supplied in labeled carton(s) and is shipped and 
stored between 2°C–8°C (36°F–46°F).  Details of the description, formulation, preparation, 
storage, and accountability of Carfilzomib for Injection may be found in a separate Pharmacy 
Manual.
Carfilzomib will be administered IV, using the same method, frequency, and at the same 
dose level as administered in the last cycle of the subject’s previous carfilzomib study; in this 
study, carfilzomib doses will be administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle 
(or the same dose level and frequency as administered at the last visit of the prior carfilzomib
study) until disease progression or unacceptable toxicity.  Each dose will consist of 
Carfilzomib for Injection administered on an mg/m2 basis.  Subjects with a body surface area 
(BSA) > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA.
Dosing will be continued or modified based upon clinical and laboratory findings.
The dose will be administered at a facility capable of managing hypersensitivity reactions.  
If a carfilzomib dose is delayed by more than 1 day, it will not be made up.

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Subjects should be well hydrated prior to dosing with carfilzomib.  Blood chemistries, 
including creatinine, complete blood counts (CBC), and platelet count must be obtained and 
reviewed by the Principal Investigator or qualified designee prior to carfilzomib dosing for 
all treatment cycles, and the values must meet the guidelines below for retreatment.  
Electrolyte abnormalities that are clinically significant should be corrected prior to dosing.
Subjects should have a dedicated line for drug administration.  Before and after carfilzomib 
administration, the line must be flushed with 20 mL of normal saline.  If a dedicated line is 
not possible, the existing line must be flushed with a minimum of 20 mL of normal saline 
before and after carfilzomib administration.
6.2
DOSE MODIFICATION GUIDELINES
6.2.1
DOSE FREQUENCY AND DOSE LEVEL REDUCTIONS
Subjects enrolled in this protocol will begin treatment at the same carfilzomib dose level, 
frequency and method as the last dose received on their previous study.  Dose levels are as 
follows:
Table 1:
Carfilzomib for Injection Dose Levels
Carfilzomib Dose Levels
11 mg/m2
15 mg/m2  
20 mg/m2
27 mg/m2
36 mg/m2*
45 mg/m2*
56 mg/m2*
* Dose level for 30-minute infusion
Dose frequency reductions will be allowed at the discretion of the Investigator in 
consultation with the Medical Monitor.  The dose frequency can be reduced to carfilzomib 
administration on Days 1, 2, 15, and 16 (eg, every other week dosing) of a 28-day cycle, and 
continued until conditions in section 3.4 are met.

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Dose level reductions, to a minimum dose of 11 mg/m2, for toxicity will also be permitted; 
the Medical Monitor may be consulted as needed.  Missed doses of carfilzomib will not be 
made up.  Doses of carfilzomib may be rescheduled by up to 48 hours if the scheduled 
administration falls upon a holiday.  Anticipated delays of a scheduled carfilzomib dose by 
more than 1 day should be discussed beforehand with the Medical Monitor. A dose 
reduction guideline diagram is as follows:
6.2.2
DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITIES
Study drug will be withheld from subjects with:

Grade 3 neutropenia (ANC < 1000/mm3)

Grade 4 thrombocytopenia with active bleeding
Grade 4 anemia and thrombocytopenia (without active bleeding) do not require the 
carfilzomib dose to be withheld.  However, subjects should receive supportive measures in 
accordance with institutional guidelines.  For patients with Grade 4 thrombocytopenia 
without evidence of bleeding, study drug dosing may occur following consultation with the 
Medical Monitor.

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Subjects with reversible and manageable hematologic toxicity (eg, effects have diminished to 
baseline or better at the time of the next scheduled treatment) will continue to receive 
carfilzomib at the same dose level. For the purposes of this study, ‘baseline’ refers to the 
subject’s status at the start of this Protocol (PX-171-010).
If required by continued or worsening toxicity, dose level and/or frequency reductions will be 
permitted after discussion with the Medical Monitor.  The minimum dose level will be 
11 mg/m2.  Dose reductions below 11 mg/m2 will not be permitted.  The minimum dose 
frequency will be carfilzomib administration on Days 1, 2, 15 and 16 (eg, every other week).  
Less frequent dosing will not be permitted.  If toxicity continues, the subject should be 
removed from the study.
For subjects whose dose level/frequency is reduced due to study drug-related hematologic 
toxicity, dose level/frequency re-escalation may be considered if the subject tolerates the 
reduced dose and at the Investigator’s discretion in consultation with the Medical Monitor.
If there is no resolution of toxicity after 2 weeks of withholding treatment (up to 3 weeks for 
infection treatment), the subject will be withdrawn from the study.
6.2.3
DOSE MODIFICATIONS FOR NON-HEMATOLOGIC TOXICITIES
Study drug should be held for drug-related ≥ Grade 3 events until resolution to ≤ Grade 1 or 
return to baseline status. For the purposes of this study, ‘baseline’ refers to the subject’s 
status at the start of this Protocol (PX-171-010).
After resolution to ≤ Grade 1 or return to baseline status of the event, subsequent treatment 
with carfilzomib may resume at full dose at the Investigator’s discretion.
If required by continued or worsening toxicity, dose level and/or frequency reductions will be 
permitted after discussion with the Medical Monitor.  The minimum dose level will be 
11 mg/m2.  Dose reductions below 11 mg/m2 will not be permitted.  The minimum dose 
frequency will be carfilzomib administration on Days 1, 2, 15, and 16 (eg, every other week).  
Less frequent dosing will not be permitted.  If the toxicity continues, the subject should be 
removed from the study.

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For subjects whose dose level/frequency is reduced due to study drug-related toxicity, dose 
level/frequency re-escalation may be considered if the subject tolerates the reduced regimen 
and at the Investigator’s discretion in consultation with the Medical Monitor.
If there is no resolution of toxicity after 2 weeks of withholding treatment (up to 3 weeks for 
infection treatment), the subject will be withdrawn from the study.
6.2.3.1
Decreased Creatinine Clearance
Carfilzomib should be held for calculated creatinine clearance (CrCl) < 15 mL/min.  
For subjects who enter this study with a CrCl < 15 mL/min, study drug should be held if 
CrCl drops ≥ 50% from baseline.  When the CrCl returns to baseline, carfilzomib treatment 
should resume at 1 dose level reduction (ie, from 27 to 20 mg/m2, from 20 to 15 mg/m2, or 
from 15 to 11 mg/m2.  If the CrCl is still ≥ 50% below baseline after 2 weeks the subject 
should be withdrawn from the study.
Subjects on routine hemodialysis may receive carfilzomib at the same dose as the previous 
carfilzomib study.
The Cockroft and Gault formula will be used to calculate the CrCl as follows:  Creatinine 
Clearance = {[(140 – age) × Mass (kg)] / [Creatinine (mg/dL) × 72]} × 0.85 if female.
Table 2:
Dose Adjustment Guideline for Renal Dysfunction
Renal Dysfunction
Recommended Action
Normal to Mild 
(CrCl > 50 mL/min)
Full dose
Moderate  to Severe
(CrCl 15–50 mL/min)
Full dose
Upon study entry, CrCl 
< 15 mL/min and CrCl drops 
below 50% of baseline
Hold carfilzomib until CrCl returns to 
baseline; restart at 1 level dose reduction
6.2.3.2
Infections
Subjects with active or suspected infections should have treatment withheld until the 
infection has resolved and anti-infective treatment has been completed.  After the infection 
has resolved and anti-infective treatment has been completed, treatment may continue at the 

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original dose.  If there is no resolution of the infection after 3 weeks, the subject will be 
withdrawn from the study.
6.2.3.3
Congestive Heart Failure
Any subject with symptoms of new or worsening congestive heart failure (CHF), whether or 
not drug related, must have the dose held until resolution of the CHF.  After the CHF has 
resolved or returned to baseline, treatment may continue at a reduced dose with the approval 
of the Medical Monitor, or the subject may be withdrawn from the study.  If there is no 
resolution of CHF after 2 weeks, the subject will be withdrawn from the study.
6.2.3.4
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Carfilzomib does not need 
to be held in the following cases:

Grade 3 nausea, vomiting, or diarrhea (unless persisting > 3 days with adequate 
treatment of anti-emetics or anti-diarrheals)

Grade 3 fatigue (unless persisting for > 14 days)

Alopecia

≥ Grade 3 hyperglycemia attributed to dexamethasone
Other exceptions may be discussed with the Medical Monitor on a case-by-case basis.
6.2.4
MISSED DOSES 
Missed doses will not be replaced during a cycle.  If a subject misses greater than 2 doses of 
any cycle for reasons other than toxicity, the subject will be discontinued.
6.2.5
CHANGES IN BODY SURFACE AREA
Dose adjustments do not need to be made for weight gains/losses of ≤20%.  Subjects with a 
BSA of > 2.2 m2 will receive carfilzomib based on 2.2 m2 BSA.
6.2.6
OTHER DOSING MODIFICATIONS
Dose modifications and delays different from those stated in the protocol, for management of 
toxicities, may be permitted but must be decided jointly by the Principal Investigator and the 
Medical Monitor or designee.

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6.2.7
DOSE ESCALATION RULES
Dose escalations beyond the original dose level up to the maximum tolerated dose 
established in primary carfilzomib studies may be permitted following discussion with the 
Medical Monitor.
6.3
SAFETY GUIDANCE FOR INVESTIGATORS
6.3.1
SAFETY GUIDANCE
Based upon the experience in Phase 1 studies with carfilzomib, the following observations 
must be noted:
Physicians administering carfilzomib in subjects with compromised renal function should 
hydrate appropriately and treat according to calculated CrCl, not on serum creatinine.  It is 
recommended that electrolyte abnormalities judged as clinically significant by the Principal 
Investigator (or qualified designee) be corrected to ≤ Grade 1 or baseline.  Renal function and 
serum creatinine should be monitored prior to dosing.  Carfilzomib must be held if a subject 
presents with a CrCl < 15 mL/min with the following exception:  for subjects with CrCl 
<15 mL/min at study entry, study drug must be held if CrCl drops ≥ 50% from baseline. 
Subjects who develop an active infection requiring systemic treatment should not be dosed 
with carfilzomib until the infection has resolved and the treatment course has been 
completed.  Subjects with ≥ Grade 3 neutropenia should not be treated with carfilzomib.
Carfilzomib dosing must be held for Grade 4 thrombocytopenia with bleeding.  If platelet 
counts do not recover, the dose of carfilzomib may be reduced or held according to the Dose 
Reductions/Adjustments rules outlined in Section 6.2.2.  For Grade 4 thrombocytopenia 
without evidence of active bleeding, platelet transfusions may be used per study site policies 
and at the discretion of the Investigator or treating physician.
Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation, sometimes 
requiring the use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement should 
be administered to prevent dehydration.

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6.4
CONCOMITANT MEDICATIONS
Concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.
6.4.1
REQUIRED CONCOMITANT MEDICATION
All subjects with a history of herpes viral infection should receive acyclovir or valacyclovir
prophylaxis according to institutional guidelines and the investigator’s discretion.
6.4.2
ALLOWED CONCOMITANT MEDICATIONS
Commercially available bisphosphonates are permitted.  Subjects may receive antiemetics 
and antidiarrheals as necessary, but these should not be administered unless indicated.  
Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically.
Subjects may receive platelet transfusions in accordance with institutional guidelines.  
Red blood cell (RBC) transfusions or supportive care with erythropoietin or darbepoetin alfa, 
in accordance with institutional guidelines, is also permitted.
Subjects who received 4 mg dexamethasone prior to carfilzomib dosing on an ongoing basis 
during their previous carfilzomib treatment protocol may continue to receive 4 mg 
dexamethasone prior to carfilzomib dosing on the current protocol at the investigator’s 
discretion.
The addition of certain approved agents with known antitumor activity is permitted if there is 
concern for disease progression and per Investigator discretion in consultation with the Onyx 
Medical Monitor.
6.4.3
EXCLUDED CONCOMITANT MEDICATIONS
Other investigational agents should not be used during the study.
7
STUDY TESTS AND OBSERVATIONS
Protocol-required tests, observations, and procedures are summarized in the Schedule of 
Events, Appendix A.

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Safety Measures
A CBC including platelets and basic metabolic chemistry panel (eg, Chem 7 or 8) will be 
performed on Day 1 of each cycle.  Other general safety monitoring (eg, physical 
examinations, imaging, specialty tests, etc.) shall be in accordance with institutional 
guidelines and as clinically indicated.  These data will not be routinely recorded on case 
report forms (CRFs).
Pregnancy Test
Females of Child Bearing Potential (FCBP) must have a negative serum or urine pregnancy 
test, with a sensitivity of at least 50 mIU/mL within 3 days prior to dosing. All subjects must 
be informed that he/ she needs to use a dual effective method of birth control while in this 
study, such as oral contraceptives plus use of a physical barrier (ie, condom) for the full 
duration of the study, plus 3 additional months.
7.1
SCREENING (DAYS –30 TO –1)
The following screening assessments must be performed between Days –30 and –1:
1. Obtain written informed consent prior to carrying out any study procedure
2. Obtain previous PX-171 protocol unique identifier (patient study number)
3. Determine eligibility according to Inclusion/Exclusion criteria (see Section 4)
4. Perform Disease Assessments, ie, extent of disease measurements (per method employed 
in previous protocol); and response category (see Appendix D–E). 
Note: If disease assessments are performed previously within 30 days of first dose 
of extended carfilzomib therapy study drug, a second disease assessment will not be 
required.
5. Perform routine physical examination
6. Perform pregnancy test for FCBP
7. Obtain height, weight, and BSA
8. Obtain Eastern Cooperative Oncology Group (ECOG) performance status and 
neuropathy grade
9. OPTIONAL:  Bone marrow aspirate and/or biopsy sample collection for cytogenetic and 
fluorescent in situ hybridization (FISH) analysis (only for MM subjects whose disease 
status at study entry is PR, MR or SD).
10. Record peripheral neuropathy AEs (all grades)
11. Record Grade 3 and 4 AEs, and all SAEs

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12. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction 
or discontinuation.
13. Record any concomitant chemotherapy agents
7.2
CYCLE 1 (DAY 1)
The following assessments must be completed on Cycle 1, Day 1:
1. Serum chemistry – basic chemistry panel (Chem 7 or 8), pre-dose.  Laboratory values 
may be obtained within 24 hours prior to treatment for convenience.  Results must be 
reviewed prior to dosing.
2. CBC and platelet count – pre-dose.  Laboratory values may be obtained within 24 hours 
prior to treatment for convenience.  Results must be reviewed prior to dosing.
3. Administer carfilzomib dose IV
4. Record peripheral neuropathy AEs (all grades)
5. Record Grade 3 and 4 AEs, and all SAEs
6. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction, 
or discontinuation. In the event of a toxicity leading to a dose reduction or 
discontinuation, pertinent laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits
7. Record any concomitant chemotherapy agents
7.3
CYCLE 1 (DAYS 2, 8, 9, 15, AND 16)
The following assessments must be completed on Cycle 1 on Days 2, 8, 9, 15, and 16 (or the 
same dose level and frequency as administered at the last visit of the prior carfilzomib study):
1. Administer carfilzomib dose IV
2. Record peripheral neuropathy AEs (all grades)
3. Record Grade 3 and 4 AEs, and all SAEs
4. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction, 
or discontinuation. In the event of a toxicity leading to a dose reduction or 
discontinuation, pertinent laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits.
5. Record any concomitant chemotherapy agents
7.4
CYCLES 2 AND HIGHER (DAY 1)
The following assessments must be completed on Cycle 2 and higher (Day 1):
1. Serum chemistry – basic panel (Chem 7 or 8), pre-dose; laboratory values must be 
reviewed prior to dosing.
2. CBC and platelet count, pre-dose; laboratory values must be reviewed prior to dosing.

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3. Obtain weight and BSA
4. Administer carfilzomib dose IV
5. Record peripheral neuropathy AEs (all grades)
6. Record Grade 3 and 4 AEs, and all SAEs
7. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction, 
or discontinuation. In the event of a toxicity leading to a dose reduction or 
discontinuation, pertinent laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits.
8. Record any concomitant chemotherapy agents
7.5
CYCLES 2 AND HIGHER (DAYS 2, 8, 9, 15, AND 16)
The following assessments must be completed on Cycle 2 and higher on Days 2, 8, 9, 15, and 
16 (or the same dose level and frequency as administered at the last visit of the prior 
carfilzomib study):
1. Administer carfilzomib dose IV
2. Record peripheral neuropathy AEs (all grades)
3. Record Grade 3 and 4 AEs, and all SAEs
4. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction, 
or discontinuation. In the event of a toxicity leading to a dose reduction or 
discontinuation, pertinent laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits.
5. Record any concomitant chemotherapy agents
7.6
CYCLE 3 AND EVERY 3 CYCLES (DAY 1)
The following assessments must be completed on Cycle 3 and every 3 cycles (Day 1):
1. Serum chemistry – basic panel (Chem 7 or 8), pre-dose; laboratory values must be 
reviewed prior to dosing. 
2. CBC and platelet count, pre-dose; laboratory values must be reviewed prior to dosing. 
3. Perform Disease Assessments, ie, extent of disease measurements (per method employed 
in previous protocol); and response category (see Appendix D–E).  
Note:  If disease assessments, per standard institutional practices, occur more frequently 
than every 3 months (eg every month or every 2 months), the most recent assessment 
may be reported.
4. Administer carfilzomib dose IV
5. Record peripheral neuropathy AEs (all grades)

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6. Record Grade 3 and 4 AEs, and all SAEs
7. Record AE (any Grade) leading to a missed carfilzomib dose, carfilzomib dose reduction, 
or discontinuation. In the event of a toxicity leading to a dose reduction or 
discontinuation, pertinent laboratory measurements and concomitant medications will be 
collected and monitored as unscheduled visits.
8. Record any concomitant chemotherapy agents
7.7
END OF STUDY ASSESSMENTS 
(WITHIN 30 DAYS OF STUDY DISCONTINUATION)
The following assessment must be completed within 30 days of administration of last dose of 
study drug and prior to initiation of any new therapy:
1. Perform complete physical examination
2. Perform Disease Assessments, ie, extent of disease measurements (per method employed 
in previous protocol); and response category (see Appendix D–E).
3. OPTIONAL: Bone marrow aspirate and/or biopsy for cytogenetic and FISH analysis 
(only required for MM subjects whose reason for study discontinuation is PD).
4. Record peripheral neuropathy AEs (all grades)
5. Record Grade 3 and 4 AEs, and all SAEs
6. Record any concomitant chemotherapy agents
7.8
TUMOR RESPONSE ASSESSMENT
Efficacy Measures
Tumor measurements and efficacy assessments will be in accordance with the methods 
employed in the subject’s prior carfilzomib study.  For subjects participating in a carfilzomib 
trial without prior tumor measurements and efficacy assessments (eg, PX-171-008), tumor 
assessments will be conducted at the time of screening for the current study using the 
appropriate method (eg, RECIST criteria for solid tumors); these assessments will be used as 
the subjects’ baseline disease assessments for determining response and progression while on 
the current Protocol (PX-171-010). Disease assessments (eg, Extent of Disease 
Measurements and objective response category) will occur within 30 days prior to enrollment 
to determine eligibility, at least every 3 months throughout study participation, and at end of 
study.  Subjects will be evaluated for disease response according to the parameters employed 
in their previous carfilzomib study.  Refer to Appendix D–E for Response Criteria.

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7.9
CORRELATIVE STUDIES
7.9.1
CYTOGENETIC AND FISH STUDIES
A bone marrow biopsy and/or aspirate for determining percent plasma cell involvement, 
including metaphase cytogenetic and FISH studies are optional for all MM subjects entering 
with a PR, MR, or SD.  Samples for cytogenetic and FISH analysis will also be optional for 
all MM subjects who discontinue study due to PD.  Bone marrow cytogenetic and FISH 
analyses will be carried out at the site’s local laboratory, per standard of practice, or in a 
Central Reference Laboratory.
8
STUDY DISCONTINUATION
Subjects may withdraw from the study at any time.  Subjects who discontinue from the study 
will be monitored for AEs as described in Appendix C (NCI-CTCAE Version 3.0).
The Sponsor, Onyx Therapeutics, Inc. may elect to discontinue the study at any time.
The Investigator may remove a subject from the study for the following reasons:

Noncompliance with study procedures

Need of treatment with medications not allowed by the study protocol

Subject no longer consents to participate in the study

Intercurrent illness that interferes with study assessments

Incidence or severity of AEs in this study indicates a potential health hazard to
the subject

Confirmation of PD, and discussion with the Medical Monitor
Onyx Therapeutics or designee must be notified within 24 hours if a subject is withdrawn 
from the study.
If the reason for withdrawal is the occurrence of an AE, the subject will be followed by the 
Investigator until such events resolve, stabilize, and, according to the Investigator’s 
judgment, there is no need of further follow-up.  The reason for withdrawal from the study 
will be documented in the CRF.
If a subject is withdrawn for PD, the date of the laboratory test or procedure indicating 
disease progression will be used as the date of PD.  The CRFs must have appropriate source 

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documentation to demonstrate that a subject has progressed.  Bone marrow aspirate or biopsy 
samples for cytogenetic analysis are optional for all MM subjects who discontinue due to PD.
9
ADVERSE EVENTS
9.1
ADVERSE EVENTS DEFINITIONS
An AE is any untoward medical occurrence in a study subject administered an investigational 
product and that does not necessarily have a causal relationship with this treatment.
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current Investigator’s Brochure or prescribing information for a marketed 
compound. Also, reports which add significant information on specificity or severity of a 
known, already documented AE constitute unexpected AEs. For example, an event more 
specific or more severe than described in the Investigator’s Brochure would be considered 
“unexpected”.
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), 
symptom, or disease temporally associated with participation in an investigational study, 
whether or not considered treatment-related.  In addition to new events, any increase in the 
severity or frequency of a pre-existing condition that occurs after the subject signs a consent 
form for participation is considered an AE.  This includes any side effect, injury, toxicity, or 
sensitivity reaction.
Whenever possible, the CTCAE Version 3.0 (see Appendix D) should be used to describe the 
event and for assessing the severity of AEs.  Any event representing a change in the CTCAE 
grade needs to be reported on the AE CRF.  This includes any change in a laboratory value.
For AEs not adequately addressed in the CTCAE, the severity table below may be used:

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Table 3:
Toxicity Grading
GRADE 1 – Mild:
Transient or mild discomfort; no limitation in activity; 
no medical intervention/therapy required.
GRADE 2 – Moderate:
Mild to moderate limitation in activity – some assistance may be needed; 
no or minimal medical intervention/therapy required.
GRADE 3 – Severe:
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible.
GRADE 4 – Life Threatening:
Extreme limitation in activity, significant assistance required; 
life threatening (immediate risk of death); significant medical intervention/ 
therapy required; hospitalization or hospice care probable.
GRADE 5 – Fatal
Death
Any condition, laboratory abnormality, or physical finding with an onset date prior to the 
subject signing consent for study participation is considered to be pre-existing in nature and 
part of the subject’s medical history.
9.2
CAUSALITY
Relationship of the AE to the study drug should be defined as follows:

None

Unlikely

Possible

Probable
9.3
ADVERSE EVENTS REPORTING PROCEDURES
The following AEs will be reported and monitored for this study:

Peripheral Neuropathy (all grades)

All Grade 3 and 4 AEs

Any AEs resulting in a missed dose, dose reduction, or treatment discontinuation

All SAEs
AEs (eg, any new event or worsening in severity or frequency of a pre-existing condition or 
laboratory finding) with an onset date after the subject signs consent for study participation 
must be promptly documented on the AE CRF.  Details of the event must include severity, 
relationship to study drug, duration, action taken, and outcome.  SAEs will be recorded on

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the AE CRF and on the SAE reporting form (see Section 9.5, Serious Adverse Event 
Reporting and Documentation Requirements).
AEs will be collected from the time the subject signs informed consent through 30 days 
following the last dose of study drugs, or initiation of a new anti-cancer therapy.  In addition, 
the Investigator should report any AE (per instructions described above) that may occur after 
this time period that is believed to have a reasonable possibility of being associated with 
study drug.
All AEs that are considered related to study drug must be followed to resolution or 
stabilization if improvement is not expected.  AEs which completely resolve and then recur 
should be recorded as a new AE.  For subjects who complete the end-of-treatment visit less 
than 30 days following their last dose of protocol-defined therapy, a follow up of ongoing 
AEs should be attempted by telephone, and documented in the subject’s source file.  
AEs continuing at 30 days after the last dose should have a comment in the source by the 
Investigator that the event has stabilized or is not expected to improve.
The Principal Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and determining that documentation of the event is adequate.  AEs will be 
assigned a severity grade using the NCI-CTCAE grading scale Version 3.0.  Any laboratory 
finding requiring a therapeutic intervention should also be considered as an AE and reported 
accordingly.
The Principal Investigator may delegate these duties to Sub-Investigators and must assure 
that these Sub-Investigators are qualified to perform these duties under the supervision of the 
Principal Investigator and that they are listed on the Form FDA 1572 or Canadian Qualified 
Investigator Undertaking Form (QIU).
9.3.1
DISEASE PROGRESSION
Discontinuation of treatment due to either progression or deterioration due to the primary 
malignancy should be recorded on the Treatment Discontinuation CRF as “Disease 
Progression” and not as an AE or an SAE, unless the event meets the SAE reporting criteria 
described in Section 9.4.

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In addition to an increase in M-protein, natural disease progression of multiple myeloma 
typically displays specific clinical signs and symptoms such as elevated Calcium, Renal 
insufficiency, Anemia, and Bone disease (known as the “CRAB” features) (Durie 2006).  
Signs and symptoms clearly associated with progression should not be listed as AEs unless 
judged by the Investigator to be atypical or accelerated or if the Investigator considers the 
sign or symptom to be caused by the study drug.  If there is any uncertainty regarding 
causality, the event should be recorded in the CRF as an AE or SAE as appropriate.
All deaths during treatment or within 30 days of the last dose of study drug are to be reported 
as SAEs (see Section 9.4).  The corresponding entry for progression-related deaths on the AE 
CRF should use the verbatim term “Disease Progression” rather than the specific sign or 
symptom that may have been the immediate cause of death.  Additional details of the event 
(such as the primary and contributory causes of death) should be reported on the Death CRF.
9.4
SERIOUS ADVERSE EVENTS DEFINITIONS
An SAE is one that meets one or more of the following criteria:

Death

Life threatening experience defined as any adverse experience that places the subject, 
in the view of the Investigator, at immediate risk of death at the time of occurrence; 
ie, it does not include a reaction that, had it occurred in a more severe form, might 
have caused death.

Requires inpatient hospitalization or prolongation of an existing hospitalization 
(except scheduled hospitalizations for non-acute, unrelated cause such as an elective 
surgery)

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect in the offspring of an exposed subject

Important medical events that may not result in death, be life threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, it jeopardizes the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.
Any death occurring within 30 days of the subject receiving study drug, regardless of the 
subject having discontinued from the study must be reported to the sponsor as an SAE.

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9.5
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS
Onyx Therapeutics, Inc. must be notified by telephone or fax of the occurrence of any SAE 
within 24 hours of the Investigator, designee, or site personnel knowledge of the event.  
To report an SAE, call or fax an SAE form to:
Attn: i3 Research
Fax: (866) 880-9343
SAE hotline: (888) 750-8020
E-mail: i3drugsafetyPV@i3drugsafety.com
Telephone reports must be followed by a written report within 24 hours.  Follow-up reports 
must be submitted in a timely fashion as additional information becomes available. 
The Investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local regulations, of all SAEs.  
The sponsor may request additional source documentation pertaining to the SAE sent to 
Onyx.  If a subject is permanently withdrawn from the study because of a SAE, this 
information must be included in the initial or follow-up SAE report form as well as the Study 
Discontinuation CRF.
All SAEs occurring from the time that the subject signs consent for study participation or up 
to 30 days after the last administered dose of study drug will be reported.  All SAEs 
regardless of relationship to study drug must be followed to resolution or to stabilization if 
improvement or resolution is not expected.
9.6
PREGNANCY
The subject must immediately inform her doctor:

If she becomes pregnant while taking the drug

If she misses her menstrual period, or experiences unusual menstrual bleeding

If she stops using birth control

If she thinks, FOR ANY REASON, that she may be pregnant

The subject understands that if her doctor is not available, she can call 
1-888-668-2528 for information on emergency contraception

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If a subject or spouse or partner of a subject becomes pregnant while enrolled in this clinical 
trial or up to 3 months following administration of carfilzomib, Onyx must be notified within 
24 hours of the Investigator, designee, or site personnel learning of the pregnancy.  If the 
subject is pregnant, carfilzomib and all other study drug(s) must be withheld until the 
Medical Monitor is notified, and the case is discussed.  Subjects, spouses, or partners will be 
followed through the outcome of the pregnancy.  The Investigator will be required to 
complete a Pregnancy Information Form and fax the information to:
Attn: i3 Research
Fax:  (866) 880-9343
SAE hotline:  (888) 750-8020
E-mail:  i3drugsafetyPV@i3drugsafety.com
10
STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study.  Specific 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
Plan (SAP).  If, after the study has begun but prior to the final analysis, changes are made to 
the protocol that affect principal features of the primary or key secondary analyses, then the 
protocol and/or SAP will be amended, as required.  Any other changes made to the planned 
analyses after the protocol and SAP have been made final, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR) of the study.  
Post hoc exploratory analyses will be clearly identified in the CSR as such.  
10.1
OBJECTIVES/HYPOTHESES
The objectives of the study are stated in Section 2.  The present protocol will not test any 
prespecified hypotheses, but will summarize safety and disease response data so that an 
assessment of each may be made.
10.2
ANALYSIS ENDPOINTS
The safety and disease response endpoints that will be evaluated are listed below, followed 
by descriptions of the derivations of selected endpoints.  

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10.2.1
PRIMARY ENDPOINTS (SAFETY)

Reported peripheral neuropathy AEs (all Grades)

Reported Grades 3 and 4 AEs

SAEs

Grades 1 through 4 AEs leading to a missed carfilzomib dose or a carfilzomib dose 
reduction or discontinuation
10.2.2
SECONDARY ENDPOINTS (EFFICACY/DISEASE RESPONSE)

Overall survival (OS)

Progression-Free Survival (PFS)

Time to Progression (TTP)
10.3
ANALYSIS POPULATIONS
10.3.1
SAFETY ANALYSIS
The safety population consists of all enrolled subjects who received at least 1 dose of 
carfilzomib after enrollment in PX-171-010.
10.3.2
DISEASE RESPONSE ANALYSIS
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of the disease response data in this study.  The FAS population is a subset of all enrolled 
subjects, with subjects excluded for the following reasons:

No post-baseline endpoint data subsequent to at least 1 dose of study treatment on the 
PX-171-010 protocol (applicable only to PX-171-008 subjects).

Lack of baseline data for those analyses that require baseline data
10.4
STATISTICAL METHODS
10.4.1
SAFETY ANALYSIS
Safety and tolerability will be assessed by clinical review of all relevant parameters 
associated with (1) peripheral neuropathy (all Grades) (2) all reported Grade 3 and 4 AEs, 
(3) Grades 1–4 AEs resulting in a missed carfilzomib dose, dose delay or discontinuation, 
and (4) reported SAEs.
Treatment-emergent AEs are defined as AEs that start on or after the first day study 
treatment is administered and within 30 days of the last administration of study treatment.  

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AEs will be summarized by the number and percentage of subjects who experienced the 
event, according to system organ class and preferred term.  A subject reporting multiple cases 
of the same AE will be counted once within each system organ class and similarly counted 
once within each preferred term.  Unless otherwise specified, the denominator for these 
calculations will be based on the number of subjects in each disease cohort (solid tumor or 
MM) who receive at least 1 administration of carfilzomib on the extended study, irrespective 
of the total number of doses or treatment cycles administered.  These conventions will be 
appropriately modified to calculate AE incidence rates separately for each cycle that study 
therapy is administered.  AE incidence rates may also be calculated based on other measures 
of subject exposure (eg, total number of treatment cycles administered).  AEs will also be 
summarized by NCI-CTCAE Version 3.0 severity grade and by relationship to each study 
drug.  For AEs not adequately addressed by the NCI-CTCAE, the severity grading described 
in Section 9.1 may be used (see Table 3).  Additional summaries may also be provided for 
SAEs, and events resulting in the permanent discontinuation of therapy.  Summaries will be 
provided by disease cohort All AEs will be included in individual subject listings.
10.4.2
DISEASE RESPONSE ANALYSIS
The analysis of disease response will be based on the FAS populations defined in 
Section 10.3.2.  The assessment of disease response will be based on duration of OS, PFS, 
and TTP.  For patients previously enrolled in PX-171-008, response may be first noted in 
PX-171-010.  Durations will be calculated from the date of disease response documented in 
the subjects’ prior carfilzomib protocol, or in PX-171-010 for subjects previously enrolled in 
PX-171-008, to the first documentation of the endpoint’s occurrence in the extended trial.
Depending on the completeness of the available follow-up data, analysis of each endpoint 
will be performed based on the Kaplan-Meier method.  The date of progression will be 
determined using the progression criteria described in Appendix D–E.  The date of censoring 
for subjects who end the study without documented progression will correspond to the date 
the last disease assessment was performed.  Analysis will be performed separately by disease 
cohort (MM or solid tumor).

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10.5
SAMPLE SIZE
The total number of subjects to be enrolled in the study is dependent upon the number of
subjects who have completed the primary carfilzomib treatment protocols.  It is anticipated 
that approximately 100 subjects will be enrolled in this study.  Formal power calculation was 
not used to determine the sample size.
10.6
GUIDELINES FOR EARLY STUDY TERMINATION
Safety will be monitored throughout the trial.  If any significant safety issues arise, the 
sponsor will be notified and if necessary, a decision to modify or terminate the study will be 
made.
11
REGULATORY OBLIGATIONS
11.1
INFORMED CONSENT
No Investigator may involve a human being as a subject in research unless the Investigator 
has obtained the legally effective informed consent of the subject or the subject’s legally 
authorized representative.  An Investigator shall seek such consent only under circumstances 
that provide the prospective subject or the subject’s legally authorized representative 
sufficient opportunity to consider whether or not to participate, and that minimize the 
possibility of coercion or undue influence.  The information that is given to the subject or the 
representative shall be in a language understandable to the subject or representative.
Onyx Therapeutics or its designated representative will provide the Investigator with a 
sample consent form.  Local and/or institutional requirements may require disclosure of 
additional information in the informed consent.  Any changes to the consent form must be 
submitted to the Onyx Therapeutics or its designated representative for approval, prior to 
submission to the IRB/IEC.  The IRB/IEC will review the consent form for approval.  A copy 
of the approved form must be submitted to the Onyx or its designated representative prior to 
initiation of the study.
Before implementing any study procedure, informed consent shall be documented by the use 
of a written consent form approved by the IRB/IEC and signed and dated by the subject or 
the subject’s legally authorized representative at the time of consent.  A copy of the signed 

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informed consent will be given to the subject or subject’s legally authorized representative.  
The original signed consent must be maintained by the Investigator and available for 
inspection by Onyx Therapeutics, its designated representative, or regulatory authority at any 
time.
11.2
COMPLIANCE WITH LAWS AND REGULATIONS
The study will be conducted in accordance with US Food and Drug Administration (FDA) 
and International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice 
(GCP), the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
IRB or IEC requirements.
This study must have the approval of a properly constituted IRB or IEC.  Before the 
investigational drug is shipped to the Investigator, the Investigator or designee will provide 
Onyx Therapeutics with a copy of the IRB/IEC approval letter stating that the study protocol 
and any subsequent amendments and informed consent form have been reviewed and 
approved.
The Investigator or designee will be responsible for obtaining annual IRB/IEC re-approval 
throughout the duration of the study.  Copies of the Investigator’s annual report to the 
IRB/IEC and copies of the IRB/IEC continuance of approval must be submitted to Onyx 
Therapeutics or designee.
The Investigator is also responsible for notifying their IRB/IEC of any significant AEs that 
are serious and/or unexpected.
Onyx Therapeutics will provide study sites with any Investigational New Drug (IND) safety 
reports generated, changes to the IB, and any safety updates.  The Investigator is responsible 
for immediately notifying their IRB/IEC of any such updates.
Onyx Therapeutics will initiate in writing any substantive changes to this protocol as a 
protocol amendment.  The amendment will be submitted to the IRB/IEC, together with a 
revised informed consent form, if applicable.  Written documentation of IRB/IEC approval 

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must be received before the amendment is implemented.  Upon completion of the trial, the 
Investigator must provide the IRB/IEC with a summary of the trial’s outcome.
11.3
PRE-STUDY DOCUMENTATION REQUIREMENTS
Before the start of the study, the following documents must be on file with Onyx 
Therapeutics or its designated representative:

An original US Form FDA 1572 or Canadian Qualified Investigator Undertaking 
Form (QIU) for the site, signed by the Principal Investigator

Current Curriculum Vitae (CV) for the Principal Investigator and all 
Sub-Investigators

Original financial disclosure forms for the Principal Investigator and all 
Sub-Investigators listed on the US Form FDA 1572 or Canadian QIU

Current IRB/IEC membership list and/or Department of Health and Human Services 
number

Copies of all appropriate laboratory certifications and laboratory normal ranges

IRB/IEC approval of the protocol
o
The approval letter must identify the Onyx Therapeutics protocol number or title 
and date of protocol

IRB/IEC-approved informed consent and approval letter
o
The approval letter must identify the Onyx Therapeutics protocol number or title 
of protocol and date of the informed consent
o
The informed consent must also be reviewed and approved by Onyx Therapeutics

IRB/IEC approval of any advertising materials to be used for study recruitment, if 
applicable
o
Advertising materials must also be approved by Onyx Therapeutics

Health Insurance Portability and Accountability Act (HIPAA) forms, if required

Original signed Investigator agreement

Original signed and dated protocol acceptance form
11.4
SUBJECT CONFIDENTIALITY
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician.

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The Investigator/Institution will permit direct access to source data and documents by 
Onyx Therapeutics its designee, the FDA, Health Canada, and other applicable regulatory 
authorities.  The access may consist of trial-related monitoring, audits, IRB/IEC reviews, 
and regulatory authority inspections, including FDA and Health Canada.
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 Code of Federal Regulation 
(CFR) 164.508.
12
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
PROTOCOL AMENDMENTS AND STUDY TERMINATION
All protocol amendments will be implemented by Onyx Therapeutics and must receive 
IRB/IEC approval before implementation, except where necessary to eliminate an immediate 
hazard to subjects.  The Investigator or designee must send a copy of the approval letter from 
the IRB, along with the revised informed consent form, to Onyx Therapeutics.
Both Onyx Therapeutics and the Investigator reserve the right to terminate the study 
according to the study contract.  The Investigator or designee should notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification to 
Onyx Therapeutics.
12.2
STUDY DOCUMENTATION AND ARCHIVES
12.2.1
SOURCE DOCUMENTS
Source records are original documents, data, and records (eg, medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated instruments, 
laboratory data) that are relevant to the clinical trial.  The Investigator will prepare and 
maintain adequate and accurate source documents.  These documents are designed to record 
all observations and other pertinent data for each subject enrolled in this clinical trial.  
Source records must be adequate to reconstruct all data transcribed onto the CRFs.

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12.2.2
CASE REPORT FORM COMPLETION
All required data must be recorded on the CRFs provided by Onyx Therapeutics or its 
designee.  All CRFs must be completed by designated study personnel.  The completed CRFs 
must be reviewed, signed, and dated by the Investigator or designee in a timely fashion.
12.2.3
ARCHIVAL OF RECORDS
According to 21 CFR 312.62(c), the Investigators shall retain records required to be 
maintained under this part for a period of 2 years following the date a marketing application 
is approved for the drug for the indication for which it is being investigated.  If no application 
is to be filed or if the application is not approved for such indication, the Investigator shall 
retain these records until 2 years after the investigation is discontinued and the FDA, Health 
Canada, or applicable regulatory authorities are notified.
The Investigator must retain protocols, amendments, IRB/IEC approvals, copies of the 
Form FDA 1572 or Canadian QIU, signed and dated consent forms, medical records, CRFs, 
drug accountability records, all correspondence, and any other documents pertaining to the 
conduct of the study.
12.3
STUDY MONITORING AND DATA COLLECTION
Following prequalification and initiation of the study site, periodic monitoring visits will be 
made by Onyx Therapeutics, and/or its designated representative.  The Investigator must 
provide sufficient space and allocate sufficient time for the monitor to inspect subject source 
records, CRFs, drug accountability records, and regulatory documents.
The purpose of trial monitoring is to verify the following:

The rights and well-being of human subjects are protected.

The reported data are accurate, complete, and verifiable from source documents.

The conduct of the trial is in compliance with the currently approved protocol, 
amendment(s), ICH GCPs, FDA CFR, and any other applicable regulatory 
requirements.
The monitor shall submit a written report to Onyx Therapeutics after each trial site visit or 
trial-related communication.  Reports shall include a summary of what the monitor reviewed 

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and significant findings, deviations and deficiencies, conclusions, actions taken or to be taken 
to ensure site compliance.
The Investigator must also permit trial-related audits, IRB/IEC review, and regulatory 
inspections providing direct access to data and source documents pertaining to this study if so 
requested.
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data:

Routine study site monitoring

CRF review against source documents

Data management quality control checks

Sponsor medical review
A contract research organization (CRO) will be responsible for the data management of this 
clinical trial.  Onyx Therapeutics or its designee will be responsible for the design and 
distribution of the CRFs.  Onyx Therapeutics or its designee will be responsible for the 
monitoring of the CRFs.  CRFs will be returned to the CRO.  The CRO, and/or Onyx 
Therapeutics, and/or its designee will generate queries in the event of incomplete or 
inconsistent data to be reconciled by the study site.

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13
REFERENCES
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EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998 Sep; 
102(5):1115–23.
Carfilzomib for Injection [Investigator Brochure], Version 8. South San Francisco, CA: 
Onyx Therapeutics, Inc.; 24 February 2010.
Data on File, Onyx Therapeutics, Inc.
Demo SD, Buchholz TJ, Laidig GL, Parlati F, Shenk KD, Smyth MS, et al. Biochemical and 
cellular characterization of the novel proteasome inhibitor PR-171. Blood 2005;106:455a, 
Abstract 1588.
Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, et al. Antitumor activity of 
PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383–91.
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International 
uniform response criteria for multiple myeloma. Leukemia 2006 Sep; 20(9): 1467–73. 
Errata in: Leukemia 2006 Dec; 20(12):2220. Leukemia 2007 May; 21(5):1134.
Ivancsits D, Nimmanapali R, Sun M, Shenk K, Demo SD, Bennett MK, et al. 
The proteasome inhibitor PR-171 inhibits cell growth, induces apoptosis, and overcomes de 
novo and acquired drug resistance in human multiple myeloma cells. Blood 2006;106:452a.
Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of 
carfilzomib, a novel, irreversible inhibitor of the ubiquitin proteasome pathway, against 
pre-clinical models of multiple myeloma. Blood 2007;110:3281–90.
Stewart KA, O’Connor OA, Alsina M, Trudel S, Urquilla PR, Vallone MK, et al. Phase I 
evaluation of carfilzomib (PR-171) in hematological malignancies: responses in multiple 
myeloma and Waldenstrom’s macroglobulinemia at well-tolerated doses. J Clin Oncol 2007; 
ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement): 8003.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. European Organization for 
Research and Treatment of Cancer, National Cancer Institute of the United States, National 
Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16.
Velcade® (bortezomib) [full prescribing information]. Cambridge, MA: Millennium 
Pharmaceuticals, Inc.; 2008.

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APPENDIX A:
SCHEDULE OF EVENTS
Visit
Screening
(Day –30 to –1)
Cycle 1
Every Cycle
Cycle 3 and
Every 3 Cycles
End of Study
(Within 30 days of last dose
of study drug)
Written Informed Consent
X
Inclusion/Exclusion Criteria
X
Obtain Previous PX-171 Protocol Unique Identifier
X
Pregnancy Test1
X
Routine Physical Examination
X
X
Height, Weight, and BSA2
X
Day 1
ECOG Performance and Neuropathy Grade
X
Bone Marrow Sample for Cytogenetics and FISH3
X
X
CBC + Platelet Count and Serum Chemistry6
Day 1
Day 1
Day 1
Carfilzomib Dosing (the same dose level and frequency as 
administered at the last visit of the prior Onyx study)
Days 1, 2, 8, 9, 15, 16, or 
same dose level and 
frequency as prior study
Days, 1, 2, 8, 9, 15, 16, or 
same dose level and 
frequency as prior study
Days, 1, 2, 8, 9, 15, 16, or 
same dose level and 
frequency as prior study
Disease Assessments (Extent of disease measurements and 
response), per method employed in previous protocol4
X
Day 1
X
Peripheral Neuropathy AEs (all Grades)
X
X
X
X
X
Grade 3 and 4 AEs, SAEs or AEs Resulting in Missed Dose or 
Dose Reduction (all Grades)5
X
X
X
X
X
Record any concomitant chemotherapy reagent
X
X
X
X
X
1
Females of childbearing potential must have a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL, within 3 days prior to dosing.
2
Height done at screening visit only; BSA calculated Day 1 of every cycle.  However, dose adjustments not needed for weight gains/losses of ≤20%.
3
Screening bone marrow aspirate or biopsy for cytogenetics and FISH is optional and is for MM subjects whose disease status at study entry is PR or less.  A Bone marrow sample is 
also optional for all MM subjects at the end of study if there is evidence of disease progression.
4
If disease assessments are done previously within 30 days of first dose of extended study drug, they will not be required again at screening. If disease assessments per standard 
institutional practices occur more frequently than every 3 months (eg, every month or every 2 months), the most recent assessment may be reported.
5
Record all AEs leading to missed dose, dose reduction or discontinuation.  Record all Grade 3 and 4 AEs from time of consent through 30 days post last administered dose of study drug 
or initiation of a new anti-cancer therapy.
6
CBC + Platelet Count and Serum Chemistry data will not be routinely recorded on CRFs.

Onyx Therapeutics, Inc.
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Appendix B: ECOG Performance Scale
(Eastern Cooperative Oncology Group)
Grade
Description
0
Normal activity, fully active, able to carry on all pre-disease 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 
(eg, 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
Death

Onyx Therapeutics, Inc.
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APPENDIX C:
NCI CTCAE VERSION 3.0
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer 
Institute (NCI) Version 3.0
Publish Date:  December 12, 2003
http://ctep.cancer.gov/forms/CTCAEv3.pdf

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APPENDIX D:
INTERNATIONAL UNIFORM RESPONSE CRITERIA FOR 
MULTIPLE MYELOMA
Summary Table
Response 
Subcategory
Response Criteria
sCR
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence.1
CR
Negative immunofixation on the serum and urine, disappearance of any soft tissue 
plasmacytomas, and < 5% plasma cells in bone marrow
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% 
or greater reduction in serum M-protein with urine M-protein level < 100 mg per 24 hours
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 unmeasurable, a ≥ 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein and serum FLC are unmeasurable,2 then ≥50% reduction in 
plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell 
percentage was ≥ 30%
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of 
soft tissue plasmacytomas is also required
SD
Not meeting criteria for CR, VGPR, PR, MR or PD
PD
Progressive Disease requires any one or more of the following:
Increase of ≥ 25% from baseline in:
--- serum M-component and /or (the absolute increase must be ≥ 0.5 g/dL)
--- urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h)
Only in subjects without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels.  The absolute increase must be > 10 mg/dL.
Bone marrow plasma cell percentage: the absolute % must be ≥ 10%
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of existing bone lesions or soft tissue plasmacytomas
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) 
that can be attributed solely to the plasma cell proliferative disorder
Source: Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform 
response criteria for multiple myeloma. Leukemia 2006 Sep;20(9): 1467–73. Errata in: Leukemia 2006 
Dec;20(12):2220. Leukemia 2007 May;21(5):1134.
1 Presence/absence of clonal cells is based upon the /ratio.  An abnormal /ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  An abnormal ratio 
reflecting presence of an abnormal clone is /of > 4:1 or < 1:2.
2 Measurable disease: serum M protein >1 g/dL, urine M-protein > 200 mg/24 h, or serum involved FLC levels 
> 10 mg/dL with a normal /ratio.
All response categories require 2 consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic 
studies were performed. Radiographic studies are not required to satisfy these response requirements.

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Minimal Response 
Response 
Subcategory
Response Criteria
MR
25%–49% reduction in the level of serum M-protein or a 50%–89% reduction in 24 hours
urinary M-protein, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks.
For subjects with non-secretory myeloma only, 25%–49% reduction in plasma cells in a 
bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a 
minimum of 6 weeks.
25%–49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination)
Source: Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, et al. Criteria for evaluating 
disease response and progression in subjects with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for 
Blood and Marrow Transplant. Br J Haematol 1998 Sep; 102(5):1115–23.

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APPENDIX E:
RESPONSE CRITERIA FOR SOLID TUMORS
Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions
Partial Response (PR):
At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of one 
or more new lesions
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since the treatment started
Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of tumor marker level
Incomplete Response/
Stable Disease (SD):
Persistence of one or more non-target lesion(s) or/and maintenance of tumor 
marker level above the normal limits
Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions1 
1 Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should be confirmed later on by the review 
panel (or study chair).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started).  In general, the subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Incomplete Response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD

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
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status.
Source: Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to 
evaluate the response to treatment in solid tumors. European Organization for Research and Treatment 
of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl 
Cancer Inst 2000;92:205–16.

Onyx Therapeutics, Inc.
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Carfilzomib for Injection
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APPENDIX F:
SUMMARY OF CHANGES
PROTOCOL PX-171-010, AMENDMENT 3
Revisions have been made to the requirements for subjects with MM to undergo bone 
marrow aspirate and/or biopsy sample collection (for cytogenetic and fluorescent in situ 
hybridization [FISH] analysis): These procedures have been changed to optional at all time 
points, rather than required. An addition has been made to dose levels to accommodate 
subjects rolled over from previous studies. For clarity, updates to AE recording (in the event 
of a toxicity leading to a dose reduction or discontinuation), and AE reporting following the 
last dose of study, have also been made in this document.
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document. Specific changes are described 
in the table below. Changes noted in specific sections were also made in the protocol 
summary and elsewhere in the document, as applicable. Revised text is presented in bold 
format.

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Section No.
Amendment 2
Amendment 3
Rationale
Synopsis: PROCEDURES
Efficacy Measures
For subjects with multiple myeloma 
(MM) entering the extended study with a 
partial response (PR), minimal response 
(MR), or stable disease (SD); bone 
marrow biopsies for cytogenetic and 
fluorescence in situ hybridization (FISH) 
evaluation will be required at screening.  
A bone marrow biopsy in these subjects 
will also be required at end of study for 
cytogenetic and FISH evaluation if the 
reason for study discontinuation is 
disease progression.
For subjects with multiple myeloma 
(MM) entering the extended study with a 
partial response (PR), minimal response 
(MR), or stable disease (SD); bone 
marrow biopsies for cytogenetic and 
fluorescence in situ hybridization (FISH) 
evaluation will be optional at screening.  
A bone marrow biopsy in these subjects 
will also be optional at end of study for 
cytogenetic and FISH evaluation if the 
reason for study discontinuation is 
disease progression.
Revision. To allow bone marrow biopsies 
for cytogenetic and fluorescence in situ 
hybridization (FISH) to be optional, 
rather than required.  To accommodate 
subjects where bone marrow biopsies are 
unfeasible or unsafe to obtain.
Synopsis: PROCEDURES
Efficacy Measures
For subjects with MM entering the 
extended study with stringent complete 
response (sCR), complete response (CR), 
or very good partial response (VGPR), a 
bone marrow biopsy for cytogenetic and 
FISH analyses will only be required
upon the establishment of disease 
progression.
For subjects with MM entering the 
extended study with stringent complete 
response (sCR), complete response (CR), 
or very good partial response (VGPR), a 
bone marrow biopsy for cytogenetic and 
FISH analyses will also be optional upon 
the establishment of disease progression.
Revision. To allow bone marrow biopsies 
for cytogenetic and fluorescence in situ 
hybridization (FISH) to be optional, 
rather than required, upon the 
establishment of disease progression for 
subjects with MM. To accommodate 
subjects where bone marrow biopsies are 
unfeasible or unsafe to obtain.
Section 6.2.1 Dose 
Frequency and Dose Level 
Reductions
Carfilzomib Dose Levels
11 mg/m2
15 mg/m2  
20 mg/m2
27 mg/m2
36 mg/m2*
45 mg/m2*
* Dose level for 30-minute infusion
Carfilzomib Dose Levels
11 mg/m2
15 mg/m2
20 mg/m2
27 mg/m2
36 mg/m2*
45 mg/m2*
56 mg/m2*
* Dose level for 30-minute infusion
Addition. A dose level is added since 
subjects can escalate up to 56 mg/m2
based on dose levels administered in 
PX-171-007.
Section 6.4.1 Required 
Concomitant Medication
A proton-pump inhibitor will be used 
orally daily to prevent peptic disease.
Deleted
Revision. Proton-pump inhibitors are not 
a required concomitant medication.

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Section No.
Amendment 2
Amendment 3
Rationale
Section 7 Study Tests and 
Observations
These data will not be routinely 
collected.
These data will not be routinely recorded 
on CRFs.
Clarification. These data may be 
collected, but will not be routinely 
recorded on CRFs. 
Section 7.1 Screening 
(Days -30 to -1)
Bone marrow aspirate and/or biopsy 
sample collection for cytogenetic and 
fluorescent in situ hybridization (FISH) 
analysis (only for MM subjects whose 
disease status at study entry is PR, MR or 
SD).
OPTIONAL:  Bone marrow aspirate 
and/or biopsy sample collection for 
cytogenetic and fluorescent in situ 
hybridization (FISH) analysis (only for 
MM subjects whose disease status at 
study entry is PR, MR or SD).
Revision. To allow bone marrow 
biopsies for cytogenetic and fluorescence 
in situ hybridization (FISH) to be 
optional at Screening, rather than 
required, for MM subjects whose disease 
status at study entry is PR, MR or SD.
To accommodate subjects where bone 
marrow biopsies are unfeasible or unsafe 
to obtain.
Section 7.1 Screening 
(Days -30 to -1)
Section 7.2 
Cycle 1 (Day 1)
Section 7.3 
Cycle 1 (Days 2, 8, 9, 15, 
and 16)
Section 7.4
Cycles 2 and Higher 
(Day 1)
Section 7.5
Cycles 2 and Higher 
(Days 2, 8, 9, 15, and 16)
Section 7.6
Cycles 3 and Every 
3 Cycles (Day 1)
Section 7.7 End of Study 
Assessments
Record Grade 3 and 4 AEs, including 
SAEs
Record Grade 3 and 4 AEs, and all SAEs
Clarification.  All SAEs are to be 
recorded.

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Section No.
Amendment 2
Amendment 3
Rationale
Section 7.2 
Cycle 1 (Day 1)
Section 7.3 
Cycle 1 (Days 2, 8, 9, 15, 
and 16)
Section 7.4
Cycles 2 and Higher 
(Day 1)
Section 7.5
Cycles 2 and Higher 
(Days 2, 8, 9, 15, and 16)
Section 7.6
Cycles 3 and Every 
3 Cycles (Day 1)
Record AE (any Grade) leading to a 
missed carfilzomib dose, carfilzomib 
dose reduction, or discontinuation.
Record AE (any Grade) leading to a 
missed carfilzomib dose, carfilzomib 
dose reduction, or discontinuation. In the 
event of a toxicity leading to a dose 
reduction or discontinuation, pertinent 
laboratory measurements and 
concomitant medications will be 
collected and monitored as 
unscheduled visits.
Addition. To include 
information/instructions regarding 
collection of laboratory measurements 
and concomitant medications in the event 
of toxicity leading to dose reduction or 
discontinuation. 
Section 7.7 End of Study 
Assessments
Section 8 Study 
Discontinuation
Bone marrow aspirate and/or biopsy for 
cytogenetic and FISH analysis 
(only required for MM subjects whose 
reason for study discontinuation is PD).
OPTIONAL: Bone marrow aspirate 
and/or biopsy for cytogenetic and FISH 
analysis (only required for MM subjects 
whose reason for study discontinuation is 
PD).
Revision. To allow bone marrow 
biopsies for cytogenetic and fluorescence 
in situ hybridization (FISH) to be 
optional, rather than required, for MM 
subjects whose reason for study 
discontinuation is PD. To accommodate 
subjects where bone marrow biopsies are 
unfeasible or unsafe to obtain.
Section 7.9.1 Cytogenic 
and FISH Studies
Appendix A Footnote
A bone marrow biopsy and/or aspirate for 
determining percent plasma cell 
involvement, including metaphase 
cytogenetic and FISH studies, are 
mandatory for all MM entering with a 
PR, MR, or SD. Samples for cytogenetic 
and FISH analysis will also be required
for all MM subjects who discontinue 
study due to PD.
A bone marrow biopsy and/or aspirate for 
determining percent plasma cell 
involvement, including metaphase 
cytogenetic and FISH studies are 
optional for all MM subjects entering 
with a PR, MR, or SD. Samples for 
cytogenetic and FISH analysis will also 
be optional for all MM subjects who 
discontinue study due to PD.
Revision. To allow bone marrow 
biopsies for cytogenetic and fluorescence 
in situ hybridization (FISH) to be 
optional, rather than required, for MM 
subjects entering with a PR, MR, or SD 
and for MM subjects who discontinue 
study due to PD. To accommodate 
subjects where bone marrow biopsies are 
unfeasible or unsafe to obtain.

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Section No.
Amendment 2
Amendment 3
Rationale
Section 9.3 Adverse Events 
Reporting Procedures
AEs will be collected from the time the 
subject signs informed consent through
30 days following the last dose of study 
drugs.
AEs will be collected from the time the 
subject signs informed consent through 
30 days following the last dose of study 
drugs, or initiation of a new anti-cancer 
therapy.
Addition. To include 
information/instruction regarding 
collection of AEs. AEs should not 
continue to be recorded /collected if a 
subject initiates a new anti-cancer 
therapy.
Appendix A Footnote 
CBC + Platelet Count and Serum 
Chemistry data will not be routinely 
collected.
CBC + Platelet Count and Serum 
Chemistry data will not be routinely 
recorded on CRFs.
Clarification. These data may be 
collected, but will not be routinely 
recorded on CRFs.

 
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