Clinical trial NCT01832727
Conditions: Multiple Myeloma
Keywords: multiple myeloma oprozomib OPZ ONX 0912 Onyx proteasome inhibitor oprozomib tablets
Sponsor: Amgen
Start date: 2013-07-02; Completion date: 2019-06-25
Enrollment: 65 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives are:

Phase 1b:

* To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oprozomib given orally, once daily, on 2 different schedules.
* To evaluate safety and tolerability

Phase 2:

* To estimate the overall response rate (ORR).
* To evaluate safety and tolerability

Detailed description:
The purpose of the Phase 1b portion of the study was to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), safety, and pharmacokinetics (PK) of oprozomib administered orally once daily in combination with dexamethasone, in participants with relapsed and/or refractory multiple myeloma, using a 3 + 3 dose-escalation scheme with and without step-up dosing. The MTD was defined as the highest dose level at which fewer than 33% of participants had a dose-limiting toxicity (DLT).

Arms: arm 1: Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 2: Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. arm 3: Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 4: Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts. arm 5: Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 6: Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 7: Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 8: Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. arm 9: The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
Interventions: intervention 1: Oprozomib intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days. intervention 2: Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

Protocol documents:
Prot_000.pdf: 
Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 1 of 154 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and 
Dexamethasone in Patients With Relapsed and/or Refractory 
Multiple Myeloma 
Protocol No.: 
2012-001 
Name of the 
Investigational Product: 
Oprozomib Tablets and Oprozomib Extended Release (ER) 
Tablets 
Indication: 
Relapsed and/or Refractory Multiple Myeloma 
IND Number: 
117,851 
NCT Number 
NCT01832727 
Development Phase: 
Phase 1b/2 
Sponsor: 
Onyx Therapeutics 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
(805) 447-1000
Study Medical Monitor: 
, MD 
Medical Director, Clinical Development 
1120 Veterans Blvd 
South San Francisco, CA 94080 USA 
Phone:  
 
Email:  
 
Investigator(s): 
Date of Original Protocol: 14 December 2012 
Amendment 1 Date: 
18 March 2013 
Amendment 2 Date: 
25 June 2013 
Amendment 3 Date: 
26 June 2014 
Amendment 4 Date 
08 February 2018 
Confidentiality Statement 
This material is the property of Onyx Therapeutics, a wholly owned subsidiary of Onyx 
Pharmaceuticals, an Amgen subsidiary.  The material is highly confidential and is to be used 
only in connection with matters authorized by a senior representative of Onyx Therapeutics, 
and no part of it is to be disclosed to a third party without the express prior written 
permission of Onyx Therapeutics. 
NCT Number: NCT01832727
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


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CONFIDENTIAL 
Compliance Statement 
This study will be conducted in accordance with Protocol 2012-001, the relevant Onyx 
Therapeutic policies and procedures, the International Council for Harmonisation (ICH), 
Good Clinical Practice (GCP) guidelines, and the applicable country and regional regulatory 
requirements. 


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CONFIDENTIAL 
PROTOCOL ACCEPTANCE PAGE 
Issue/Date:  Protocol Number 2012-001 / Amendment 4 / 08 February 2018 
I have read this protocol for Study Number 2012-001, entitled: 
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients with 
Relapsed and/or Refractory Multiple Myeloma 
As investigator, I understand and agree to conduct this study as outlined herein. 
Investigator Name (print) 
Investigator Signature 
Date 
Signature on this page assures the sponsor that, to the best of the investigator’s knowledge, the affiliated 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all governing regulatory 
obligations and the International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) 
and country and regional (local) requirements while conducting this clinical investigation.  Once signed, the 
original of this form should be detached from the protocol and returned to Onyx or its designee (please retain a 
copy for your files). 


Onyx Therapeutics, Inc. 
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CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
Name of 
sponsor/company: 
Onyx Therapeutics 
Name of finished product: Oprozomib Tablets and Oprozomib Extended Release (ER) Tablets 
Name of active 
ingredient: 
Oprozomib 
Title of study and 
protocol number: 
2012-001:  Phase 1b/2, Multicenter, Open-label Study of Oprozomib and 
Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma 
Phase of development: 
Phase 1b/2 
Study objectives: 
Primary Objectives 
Phase 1b 
 
To determine the maximum tolerated dose (MTD) and recommended Phase 
2 dose (RP2D) of oprozomib (OPZ) given orally, once daily, on 2 different 
schedules: 5 consecutive days every 14 days (bimonthly; 5/14) or 2 
consecutive days every 7 days (weekly; 2/7) for a 14-day treatment cycle, 
both schedules given in combination with dexamethasone 
 
To evaluate safety and tolerability 
Phase 2 
 
To estimate the overall response rate (ORR), defined as the proportion of 
subjects with the best overall response of stringent complete response 
(sCR), complete response (CR), near complete response (nCR), very good 
partial response (VGPR), and partial response (PR) as defined by the 
International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) and modified European Group for Blood and Marrow 
Transplantation (EBMT) criteria 
 
To evaluate safety and tolerability 
Secondary Objectives 
 
To evaluate pharmacokinetics (PK) of Oprozomib Tablets and Oprozomib 
ER Tablets 
 
To estimate clinical benefit rate (CBR), defined as ORR plus minimal 
response (MR), as defined by the EBMT criteria 
 
To estimate the duration of response (DOR) 
 
To estimate progression-free survival (PFS) 
 
To estimate time to progression (TTP) 
Exploratory Objectives: 
 
To evaluate pharmacodynamics (PDn) and proteomic biomarkers 
 
To evaluate genomic biomarkers that may predict for response and 
resistance following treatment with proteasome inhibitors 
Study design:  
This study is an open-label, Phase 1b/2, multicenter study in which subjects will 
receive oprozomib administered orally once daily in combination with 20 mg of 
dexamethasone, as follows: 
 
Days 1–5 of a 14-day cycle in combination with dexamethasone on Days 1, 
2, 8, and 9; or 
 
Days 1, 2, 8, and 9 of a 14-day cycle in combination with dexamethasone 
on Days 1, 2, 8, and 9. 
Treatment will be administered in 14-day cycles until disease progression, 
unacceptable toxicity, or study treatment discontinuation for any reason. 


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OPZ = oprozomib; Dex = dexamethasone 
Phase 1b:  The Phase 1b portion of the study will determine the MTD, safety, 
PK/PDn, and recommended Phase 2 dose (RP2D) of oprozomib administered 
orally once daily in combination with dexamethasone, in subjects with relapsed 
and/or refractory multiple myeloma, using a 3 + 3 dose-escalation scheme with or 
without step-up dosing.  A dose-escalation plan is being followed in Phase 1b to 
determine the recommended Phase 2 dose for each treatment schedule.  The MTD 
is defined as the highest dose level at which fewer than 33% of subjects have 
dose-limiting toxicity (DLT).  For each of the 2 schedules being studied, groups 
of 3 to 6 subjects will be enrolled into dose-escalation cohorts.  As long as fewer 
than 33% of subjects experience DLTs in a given cohort, escalation will continue 
by 30 mg increments of oprozomib onto the next designated cohort(s).  A 
minimum of 6 subjects must be treated at each MTD to establish the dose as the 
MTD with and without step-up dosing. 
Subjects will be evaluated for DLTs according to the National Cancer Institute- 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.  
Subjects with stable disease (SD) or better may continue treatment.  Intrasubject 
dose escalation to the recommended Phase 2 dose may be permitted once that 
dose has been determined and after discussion between the treating physician and 
the Sponsor study medical monitor. 
Phase 2:  The Phase 2 portion will use the Phase 2 dose determined for each 
schedule, unless the sponsor determines that, based on Phase 1b data, 1 or both of 
the schedules should not proceed with development. 
Oprozomib Tablet 
In the Phase 1b portion of the study, oprozomib doses in combination with 
dexamethasone will be escalated in sequential groups of 3 subjects with expansion 
up to 6 subjects if a DLT is observed.  The initial cohort of the study with 
Oprozomib Tablets will be entered at a dose level of 210 mg oprozomib and 20 mg 
dexamethasone for both schedules.  All subsequent cohorts will be escalated or 
de- escalated by 30 mg of oprozomib until the MTD is reached. 
In the event that the initial cohort that received the 210 mg dose is found to exceed 
the MTD (the highest dose at which a DLT is observed in fewer than 2 of 
6 subjects), dosing will proceed at 180 mg or lower, as agreed with the Cohort 
Safety Review Committee. 


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Oprozomib ER Tablet 
A new oprozomib tablet will be introduced into the study with Amendment 3.  
The Oprozomib ER Tablet is being developed to have a more consistent 
dissolution profile by decreasing variability through an improved release process.  
In addition, administration of a single tablet, instead of multiple tablets as in the 
case of Oprozomib Tablets, will be used in doses up to 270 mg. (Currently, all 
doses given are composed of multiple Oprozomib Tablets.  For example, the 
270 mg dose is made up of three 90 mg Oprozomib Tablets.) The use of fewer 
tablets provides a smaller surface-to-volume ratio, resulting in a slower dissolution 
in vitro, and is predicted to have a lower maximum plasma concentration (Cmax) 
and similar area under the curve (AUC). 
The current gastrointestinal (GI) toxicity is likely mediated by local proteasome 
inhibition and variability (caused by prior formulation and multiple tablets) in the 
release of drug substance in the current formulation.  Thus, it is hypothesized that 
the formulation change and single-tablet dosage may decrease local intraluminal 
oprozomib levels at any one location in the GI tract and thereby decrease GI 
toxicity.  Preliminary PK data on file from the single-agent oprozomib study 
suggest systemic toxicity is related to Cmax; therefore, a lower Cmax may reduce 
systemic toxicity. 
Switch from Oprozomib Tablets to Oprozomib ER Tablets 
When subjects switch from Oprozomib Tablets to Oprozomib ER Tablets, 
intensive PK sampling should be obtained on Day 1 in the cycle prior to switching 
and on Day 1 of the following cycle (i.e., first day with Oprozomib ER Tablet) at 
the scheduled time points described above.  The time between the 2 days of PK 
collection for switching to the Oprozomib ER tablet will be 1 cycle or 14 days. 
The introduction of Oprozomib ER Tablets into the study and determination of 
MTD of this formulation for the 5/14 and 2/7 schedules are described below: 
5/14 Schedule 
For the 5/14 once-daily dosing schedule, Oprozomib ER Tablets will be introduced 
with step-up dosing as described below.  Determination of the MTD for step-up 
dosing will proceed in the following manner: 
 The first cohort will enroll 6 subjects using step-up dosing.  Subjects will 
receive 1 cycle at the 150 mg dose and then step-up to the 180 mg dose for 
subsequent cycles (150/180 mg).  The DLT period will begin in Cycle 2 (the 
first cycle of dosing at the step-up dose level). 
 For the next cohort, 6 subjects will be dosed with continuous dosing of 
180 mg of Oprozomib ER Tablets and assessed for DLTs to determine safety 
of this dose level. 
 Further escalation will be based on the following: 
o If < 2 DLTs are observed in the continuous dosing cohort of 180 mg in 
Cycle 1, dose escalation may continue but will revert to step-up dosing (i.e., 
150/210 mg, 150/240 mg, etc.) unless an alternate RP2D has been 
determined by the CSRC and sponsor. 
o If > 2 DLTs are observed, further escalation will not be conducted. 
2/7 Schedule 
For the 2/7 once-daily dosing schedule, Oprozomib ER Tablets will be introduced 
into subsequent cohorts where no subjects have been enrolled unless the MTD for 
continuous dosing for Oprozomib Tablets has been previously determined prior to 
the introduction of the new tablets.  One of the following 2 scenarios will be 
utilized to introduce Oprozomib ER Tablets into the dose escalation schema: 
 If the MTD for continuous dosing has not been established for Oprozomib 
Tablets, Oprozomib ER Tablets will be introduced at the next new dose level 


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CONFIDENTIAL 
 
specified by the preexisting dose-escalation plan.  Dose escalation will 
continue in 30 mg increments until the MTD for continuous dosing for 
Oprozomib ER Tablets is established, as determined by the CSRC and 
sponsor. 
 If the MTD for continuous dosing has been established with Oprozomib 
Tablets, Oprozomib ER tablets will be introduced at the MTD in a cohort of 
6 subjects.  Escalation beyond this dose can only occur using step-up dosing 
as described below if there are < 2 DLTs in the 6 subjects in this cohort 
enrolled with Oprozomib ER Tablets as determined by the CSRC and 
sponsor. 
Once the MTD for continuous dosing for Oprozomib ER Tablets has been 
established, step-up dosing will be introduced into dose escalation.  Subsequent 
2/7 cohorts will be dosed at the 240 mg for 1 cycle then step-up to the dose level to 
be studied.  The rationale for this initial dose is based on safety and tolerability of 
this dose level in the current study, as no DLTs were observed in this cohort of 3 
evaluable subjects at this dose level.  The 240 mg dose is 2 dose levels below the 
single agent MTD, which was found to be 300 mg in Study 2011-001.  Subjects on 
active treatment will continue with Oprozomib ER Tablets under protocol 
Amendment 4.  No changes in drug product, dosage, or treatment regimen 
occurred in this protocol amendment from the previous version. 
Determination of the MTD for step-up dosing will be evaluated in the following 
manner: 
 The first step-up dosing cohort will start with 1 cycle of 240 mg, and then 
starting with Cycle 2, subjects will step-up to the MTD from continuous 
dosing for subsequent cycles. 
 All subsequent cohorts will also begin dosing at 240 mg for 1 cycle and then 
will be escalated in Cycle 2 to the step-up dose level to be studied, by 30 mg 
increments until the MTD is defined with Oprozomib ER Tablets, unless an 
alternate R2PD is determined by the CSRC and the sponsor.  The DLT 
period will begin in Cycle 2 (the first cycle of dosing at the step-up dose 
level). 
Phase 2:  The Phase 2 portion of the study will include approximately 40 subjects 
at the recommended dose for each schedule, to better characterize the safety and 
tolerability, activity, and PK/PDn of the regimen and treatment schedule.  The 
Phase 2 portion of the study for 1 or both treatment schedules will be initiated at 
the sponsor’s discretion. 
Dose-Limiting Toxicities:  During the Phase 1b portion, assessment of DLTs will 
occur at the following times: 
 The first 14 days of treatment with continuous dosing (Cycle 1), or 
 The first 14 days of treatment with the step-up dose to be studied (Cycle 2) 
Any subject who develops DLT after receiving at least 1 dose of oprozomib during 
the DLT assessment period will be considered evaluable.  Any subject who does 
not develop a DLT but has not received all planned doses of oprozomib and 
dexamethasone during the DLT assessment period will be considered unevaluable 
and will be replaced. 
“Study drug-related” is defined as a reasonable likelihood of clinical causality 
based on time of event, biology, and dechallenge improvement, and that the 
adverse event (AE) was not likely explained by the subject’s clinical state, 
underlying disease, concomitant medication, or study/non-study procedure.  For 
the purposes of this study, a DLT is defined as any of the following treatment-
related events occurring in the first 14 days of treatment, with treatment at the 
dose to be studied (i.e., Cycle 1 for continuous dosing or Cycle 2 for step-up 
dosing): 


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Any ≥ Grade 3 nonhematologic AE with the following exceptions or 
qualifications: 
 ≥ Grade 4 abnormalities in serum creatinine or electrolytes will be considered 
a DLT 
 ≥ Grade 3 acute kidney injury, defined as serum creatinine > 3 × baseline or 
> 4.0 mg/dL of any duration will be considered a DLT 
 Grade 3 nausea, vomiting, diarrhea, or constipation will be considered a DLT 
only if lasting for > 7 days despite optimal supportive care, including (at a 
minimum) a 5-hydroxytryptamine type-3 (5-HT3) antagonist and aprepitant for 
nausea and vomiting, loperamide (e.g., Imodium), and diphenoxylate/atropine 
(e.g., Lomotil) for diarrhea 
 Grade 3 fatigue lasting > 14 days will be considered at DLT 
 Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours will not 
be considered a DLT 
 ≥ Grade 3 dexamethasone-related toxicities will not be considered DLTs 
Any of the following hematologic AEs will be considered a DLT: 
 Grade 4 neutropenia:  Absolute neutrophil count (ANC) < 500 cells/mcL 
lasting ≥ 7 days 
 Febrile neutropenia:  Any single temperature ≥ 38.3°C or a sustained 
temperature of ≥ 38.0°C for more than 1 hour with ≥ Grade 3 neutropenia 
(ANC < 1000 cells/mcL) 
 Grade 3/4 thrombocytopenia, as follows: 
o Grade 3 thrombocytopenia of any duration with Grade 2 bleeding or 
requiring platelet transfusion 
o Grade 4 lasting ≥ 7 days 
o Grade 4 lasting < 7 days with Grade 2 bleeding, or if platelet counts are 
lower than 10,000 cells/mcL, requiring a platelet transfusion 
The following will not be considered a DLT: 
 Grade 4 anemia 
 Grade 4 thrombocytopenia lasting < 7 days with platelet counts above 
10,000 cells/mcL without clinically significant bleeding and with or without 
transfusion 
Pharmacokinetics:  Blood samples for determination of plasma concentrations of 
oprozomib and its metabolite(s) will be drawn at the time points specified in the 
PK/PDn appendices according to continuous or step-up dosing; blood volumes are 
detailed in the Laboratory Manual.  At a minimum, the following PK parameters 
will be calculated:  Cmax, time to maximum concentration (Tmax), and AUC.  
Samples may also be used for biomarker assessment. 
When subjects switch from Oprozomib Tablet to Oprozomib ER Tablet, they will 
have intensive PK collection on Day 1 of the cycle prior to switching, and on 
Day 1 of the subsequent cycle when the new formulation is administered. 
Pharmacodynamics and Proteomics:  Blood samples for the determination of 
proteasome inhibition by oprozomib and proteomic analyses will be drawn at the 
time points specified in the PK/PDn appendices; blood volumes are detailed in the 
Laboratory Manual. 
Genomics:  Analysis of genetic and gene expression biomarkers that may predict 
response and resistance following treatment with proteasome inhibitors will be 
conducted on all subjects who consent to optional genomic biomarker analysis.  
These analyses will be performed on a sample of bone marrow aspirate, blood, and 
saliva obtained at baseline.  No additional bone marrow samples will be required 


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for the baseline analysis.  At the time of progression, analysis will also be 
performed on a sample of the bone marrow aspirate. 
Activity:  Response assessments will be performed every 4 weeks based on 
IMWG-URC and EBMT (for nCR and MR) criteria.  Overall response rate and 
CBR will be determined based on subjects’ best overall response. 
Safety:  All subjects will be closely monitored for AEs and study drug tolerability.  
The safety and tolerability of oprozomib will be assessed through documentation 
of AEs graded according to NCI-CTCAE (Version 4.03), blood counts, serum 
chemistries, vital signs, and electrocardiograms (ECGs). 
Duration of 
study/treatment periods: 
The total study duration is expected to be approximately 36 months.  
Approximately 22 to 26 months may be required to enroll all subjects in both 
phases. 
Phase 1b:  It is estimated that enrollment will take approximately 8–16 months.  
Subjects will be treated in 14-day cycles until disease progression, unacceptable 
toxicity, or study treatment discontinuation for any reason.  Subjects must 
complete a visit approximately 4 weeks after the last cycle of treatment to allow 
for safety follow-up within 30 days after the last dose of oprozomib. 
Phase 2:  It is estimated that enrollment will take approximately 10–12 months.  
Subjects will be treated in 14-day cycles and may continue treatment until disease 
progression, unacceptable toxicity, or study treatment discontinuation for any 
reason.  Subjects with progression will be considered to have completed the study 
30 days after the last dose of oprozomib. 
Note:  For subjects who discontinue treatment for reasons other than progression 
in either study phase, disease assessments will no longer be required under 
protocol Amendment 4.. 
Number of investigational 
sites: 
Approximately 12 sites in the United States (US)  
Approximately 4 sites in France 
Study population: 
The study population will consist of multiple myeloma patients requiring therapy 
who have relapsed and/or are refractory to their last therapy and have been treated 
with at least 1, but not more than 5, lines of multiple myeloma therapy.  Prior 
therapy must have consisted of at least 1 regimen that included lenalidomide 
and/or bortezomib.  Patients should be considered to be appropriate candidates 
for a clinical study by their treating physicians. 
 Relapsed patients must have previously achieved ≥ MR on at least 1 line of 
therapy as assessed by the treating physician. 
 Refractory patients are allowed, but it is not required that patients be 
refractory to their last therapy. 
 Primary refractory patients are allowed in the Phase 1b portion of the study 
only. 
Sample size: 
For the Phase 1b portion of the study, it is estimated that approximately 60 subjects 
(approximately 30 subjects per treatment schedule) will be required to determine 
the recommended Phase 2 dose for each treatment schedule.  This is based on an 
estimate that up to 5 cohorts will be enrolled per treatment schedule, with up to 
6 evaluable subjects per cohort. 
The Phase 2 portion of each dose schedule will be initiated at the sponsor’s 
discretion.  Approximately 80 additional evaluable subjects (approximately 
40 subjects per treatment schedule) will be enrolled at the recommended dose.  
The total sample size for the study will depend on the number of dose levels 
required to establish the recommended dose for each schedule and the number of 
schedules initiated in the Phase 2 portion of the study. 


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Planned number of 
subjects: 
The total number of subjects planned for this study is approximately 140 subjects. 
Test product, dose, and 
mode of administration: 
Oral Oprozomib Tablet in strengths of 60, 90, and 120 mg 
Oral Oprozomib ER tablet in strengths of 150,180, 210, 240, and 270 mg 
Oral dexamethasone 20 mg in tablet strengths of 4 and 6 mg 
Reference therapy, dose, 
and mode of 
administration: 
Not applicable 
Type of control: 
Not applicable 
Treatment regimen: 
Oprozomib will be administered at the assigned dose for each cohort, as follows: 
 Days 1–5 of a 14-day cycle with 20 mg dexamethasone on Days 1, 2, 8, and 
9, or 
 Days 1, 2, 8, and 9 of a 14-day cycle with 20 mg dexamethasone on Days 1, 
2, 8, and 9 
All subjects with SD or better may continue treatment until disease progression, 
unacceptable toxicity, or study treatment discontinuation for any reason. 
Main inclusion criteria: 
1. Diagnosis of multiple myeloma with measureable disease as indicated by 1 or 
more of the following: 
a. Serum M-protein ≥ 500 mg/dL 
b. Urine M-protein ≥ 200 mg/24 hours 
c. Only for subjects without measurable serum and urine M-protein, serum 
free light chain:  Involved free light chain (FLC) level ≥ 10 mg/dL, 
provided serum FLC ratio is abnormal 
2. Patients requiring therapy who have relapsed and/or are refractory to their last 
therapy and have been treated with at least 1, but not more than 5, lines of 
multiple myeloma therapy.  Prior therapy must have consisted of at least 
1 regimen that included lenalidomide and/or bortezomib.  Patients should be 
considered to be appropriate candidates for a clinical study by their treating 
physicians.  Relapsed patients must have previously achieved ≥ MR on at least 
1 line of therapy, as assessed by the treating physician.  Refractory patients are 
allowed, but it is not required that patients be refractory to their last therapy.  
Primary refractory patients are allowed in the Phase 1b portion of the study 
only. 
3. Males and females ≥ 18 years of age 
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2 
5. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal 
(ULN) in the absence of Gilbert’s disease or hemolysis, aspartate 
aminotransferase (AST) ≤ 3 times ULN, and alanine aminotransferase (ALT) 
≤ 3 times ULN 
6. Absolute neutrophil count ≥ 1000 cells/mcL, hemoglobin ≥ 7.0 g/dL, and 
platelet count ≥ 30,000 cells/mcL: 
a. Patients must not have received platelet transfusions for at least 1 week 
prior to Screening. 
b. Screening ANC must be independent of granulocyte colony-stimulating 
factor and granulocyte-macrophage colony-stimulating factor (G-CSF and 
GM-CSF) support for at least 1 week and of pegylated G-CSF for 
≥ 2 weeks prior to first dose. 
c. Patients may receive red blood cell (RBC) transfusions or receive 


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supportive care with erythropoietin or darbepoetin in accordance with 
institutional guidelines. 
7. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute 
calculated using the formula of Cockcroft and Gault ([140 − Age] × Mass (kg) 
/ [72 × creatinine mg/mL]).  Multiply result by 0.85 if female. 
8. Uric acid, if elevated, must be corrected to within laboratory normal range 
before dosing. 
9. Patients must sign a written informed consent form in accordance with federal, 
local, and institutional guidelines. 
10. Female patients of childbearing potential must have a negative serum or urine 
pregnancy test within 3 days prior to receiving the first dose of study drug and 
agree to use effective methods of contraception during the study and for 
3 months following the last dose of study drug.  Postmenopausal females 
(> 45 years old and without menses for > 1 year) and surgically sterilized 
females are exempt from these requirements.  Male patients must use an 
effective barrier method of contraception during the study and for 3 months 
following the last dose if sexually active with a female of childbearing 
potential. 
11. Prior carfilzomib is not required but is allowed if a patient had at least 2 cycles 
of carfilzomib alone or in combination with a dose of at least 20/27 mg/m2, as 
long as the patient: 
a. Had at least a partial response to prior carfilzomib therapy 
b. Was not removed from carfilzomib therapy due to toxicity, unless 
approved by the medical monitor 
c. Was not removed from carfilzomib therapy for progressive disease nor 
experienced progressive disease within 6 months after any prior 
carfilzomib therapy 
Main exclusion criteria: 
1. Radiation therapy within 2 weeks prior to first dose; localized radiation 
therapy within 1 week prior to first dose 
2. Immunotherapy/standard myeloma therapy within 2 weeks prior to first dose 
(except for antibody therapy, where 6 weeks are required, and alkylator 
therapy, where 3 weeks are required); prior stem cell transplant (SCT) therapy 
(autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 
16 weeks).  Patients with prior allogeneic SCT should not have evidence of 
moderate-to-severe graft-versus-host disease (GvHD). 
3. Plasmapheresis is not permitted at any time during the Screening period or 
while the subject is receiving study treatment.  If a subject has started 
screening procedures requiring plasmapheresis, or is anticipated to require 
plasmapheresis during or after the Screening period, this patient will be 
considered ineligible and should not be enrolled. 
4. Glucocorticoid therapy within 14 days prior to enrollment that exceeds a 
cumulative dose of 160 mg of dexamethasone or equivalent 
5. Participation in an investigational therapeutic study within 3 weeks prior to 
first dose 
6. Prior oprozomib exposure 
7. Known hypersensitivity/toxicity or intolerance to dexamethasone 
8. Major surgery within 3 weeks prior to first dose 
9. Congestive heart failure ([CHF] New York Heart Association Class III to IV), 
symptomatic ischemia, conduction abnormalities uncontrolled by 
conventional intervention, or myocardial infarction within 6 months prior to 
first dose 
10. Uncontrolled hypertension or uncontrolled diabetes 


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11. Active infection requiring systemic antibiotics, antivirals, or antifungals 
within 2 weeks prior to first dose 
12. Known or suspected human immunodeficiency virus (HIV) infection or 
patients who are HIV seropositive 
13. Active hepatitis A, B, or C infection 
14. History of previous clinically significant GI bleed in the last 6 months prior to 
first dose 
15. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of 
the first dose 
16. Other malignancy within the past 3 years, with the exception of adequately 
treated basal cell carcinoma of the skin, squamous cell skin cancer, thyroid 
cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate 
cancer of Gleason Score of 6 or less with stable prostate specific antigen 
levels, or cancer considered cured by surgical resection 
17. Plasma cell leukemia 
18. Female patients who are pregnant or nursing 
19. Inability to swallow medication, inability or unwillingness to comply with the 
drug administration requirements, or GI condition that could interfere with the 
oral absorption or tolerance of treatment 
20. Any contraindication to oral hydration (e.g., significant preexisting 
comorbidity or fluid restriction) 
21. Any clinically significant psychiatric or medical condition that in the opinion 
of the investigator could increase patient risk or interfere with protocol 
adherence or a patient’s ability to give informed consent 
Schedule of treatment 
and assessments: 
Refer to Appendix A, Appendix B, Appendix C, and Appendix D in the study 
protocol for the schedule of study assessments. 
Criteria for evaluation: 
Efficacy variables: 
Disease response assessments will be done every 4 weeks for the first year through 
Cycle 26 and then every 8 weeks thereafter according to the IMWG-URC.  In 
addition, nCR and MR will be assessed as per the modified EBMT criteria. 
Safety variables: 
The safety and tolerability of oprozomib will be assessed using the following 
measures:  AEs graded according to the NCI-CTCAE (Version 4.03), blood 
counts, serum chemistries, vital signs, and ECGs. 
Other variables: 
Pharmacokinetics:  Blood samples will be drawn for plasma concentration of 
oprozomib and its metabolite(s) at various time points during the study based on 
whether subjects are treated with continuous or step-up dosing.  Pharmacokinetic 
parameters, including but not limited to Cmax, Tmax, and AUC, will be calculated. 
Pharmacodynamics:  Blood samples will be drawn for PDn assessments of 
proteasome inhibition in whole blood and peripheral blood mononuclear cells 
(PBMCs) via a fluorogenic substrate assay or enzyme-linked immunosorbent 
assay. 
Proteomics:  Analysis of proteomic biomarkers that may predict for response 
following treatment with oprozomib will be performed.  Proteomic biomarkers 
will be measured in PBMCs and plasma.  Global proteomic profiling using mass 
spectrometry will be conducted on plasma samples and isolated PBMCs taken 
before and after study drug administration and analyzed for changes in specific 
protein levels (e.g., cytokines). 
Genomics:  Analysis of genetic and gene expression biomarkers that may predict 
for response and resistance following treatment with proteasome inhibitors will be 
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Biomarker analyses will be performed on bone marrow aspirates, blood, and saliva 
samples.  Whole genome sequencing (WGS), whole exome sequencing (WES), 
whole transcriptome sequencing, and/or other methods of nucleic acid 
quantification will be conducted on isolated tumor (CD138+) cells from bone 
marrow samples taken at baseline and disease progression.  In addition, WGS or 
WES will be performed on a normal tissue sample (e.g., saliva or CD3+ T cells 
isolated from PBMCs) to distinguish germ line mutations from somatic mutations 
in tumor cell samples.  Data will be analyzed to characterize whether drug 
response is related to alterations in genes regulated by or involved in activation of 
NF-KappaB transcription factors as well as in genes involved in immunoglobulin 
production and plasma cell protein homeostasis.  Immunoglobulin levels in tumor 
cells will be quantified by enzyme-linked immunosorbent assay (ELISA) or other 
protein quantification methods.  These data will also be used to derive hypotheses 
about mechanisms of drug response, resistance, and safety. 
Statistical Methods: 
The design of the Phase 1b portion of the study will focus on determining the 
MTD, RP2D, and safety of oprozomib (along with assessing selected PK/PDn 
parameters) and will employ a 3+3 design that will allow for possible dose de-
escalation.  A listing of subjects who experience a DLT during the Phase 1b 
portion will be generated along with the results associated with the PK/PDn 
parameters being considered. 
All subjects who receive at least 1 dose of study treatment will be considered 
evaluable for both the efficacy and the safety analyses (Safety Population).  
Additional efficacy analyses will be performed using the response-evaluable 
population, defined as subjects who are included in the safety evaluable 
population, have a baseline disease assessment and at least 1 postbaseline disease 
assessment, or dropped out due to AE prior to first postbaseline disease 
assessment. 
Efficacy endpoints include evaluation of response at each dose level and at the 
recommended Phase 2 dose for each schedule.  An estimate of the ORR at the 
recommended dose(s) and its 1-sided 95% exact binomial confidence interval will 
be determined by each schedule.  Additionally, the ORR and CBR will be 
determined along with the associated 2-sided 95% exact binomial confidence 
intervals for each cohort and schedule.  Analyses for time-to-event(s) endpoints 
(DOR, PFS, and TTP) will be performed using the Kaplan-Meier method.  
Medians and other quartiles for each time-to-event endpoint will be estimated with 
the corresponding 2-sided 95% confidence intervals.  Time to response will be 
assessed using descriptive statistics. 
Extent of exposure to the study treatment will be summarized using descriptive 
statistics.  The number and percentage of subjects experiencing 1 or more AEs 
will be summarized by relationship to study treatment and severity.  Laboratory 
parameters, vital signs, and ECGs will be summarized using descriptive statistics. 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................................. 1 
PROTOCOL ACCEPTANCE PAGE ............................................................................................ 3 
PROTOCOL SYNOPSIS ............................................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................. 14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 20 
1. 
INTRODUCTION ............................................................................................................ 23 
1.2 
PROTEASOME BACKGROUND ...................................................................... 23 
1.3 
RELEVANT NONCLINICAL BACKGROUND ............................................... 24 
1.4 
RELEVANT CLINICAL BACKGROUND ........................................................ 26 
1.4.1 
STUDY 2009-003:  SOLID TUMORS................................................. 26 
1.4.2 
STUDY 2011-001:  HEMATOLOGIC MALIGNANCIES ................. 30 
1.4.3 
STUDY 2012-001:  OPROZOMIB IN COMBINATION WITH 
DEXAMETHASONE IN MULTIPLE MYELOMA ........................... 31 
1.4.4 
STUDY OPZ003:  OPROZOMIB IN COMBINATION WITH 
LENALIDOMIDE AND DEXAMETHASONE IN MULTIPLE 
MYELOMA .......................................................................................... 32 
1.4.5 
ADDITIONAL STUDIES WITH OPROZOMIB ................................ 32 
1.5 
STUDY DESIGN RATIONALE ......................................................................... 33 
1.5.1 
DOSE RATIONALE ............................................................................ 33 
1.5.2 
SCHEDULE RATIONALE .................................................................. 35 
1.6 
STUDY RATIONALE ......................................................................................... 36 
2. 
STUDY OBJECTIVES .................................................................................................... 37 
2.1 
PRIMARY OBJECTIVES ................................................................................... 38 
2.2 
SECONDARY OBJECTIVES ............................................................................. 38 
2.3 
EXPLORATORY OBJECTIVES ........................................................................ 38 
3. 
EXPERIMENTAL PLAN ................................................................................................ 38 
3.1 
STUDY DESIGN ................................................................................................. 38 
3.1.1 
PHASE 1B PORTION .......................................................................... 39 
3.1.2 
DOSE-ESCALATION PLAN .............................................................. 40 
3.1.3 
PHASE 2 PORTION ............................................................................. 44 
3.2 
NUMBER OF CENTERS .................................................................................... 44 
3.3 
NUMBER OF SUBJECTS .................................................................................. 44 


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3.3.1 
PHASE 1B PORTION .......................................................................... 44 
3.3.2 
PHASE 2 PORTION ............................................................................. 45 
3.4 
ESTIMATED STUDY DURATION ................................................................... 45 
4. 
PATIENT SELECTION .................................................................................................. 46 
4.1 
INCLUSION CRITERIA ..................................................................................... 46 
4.2 
EXCLUSION CRITERIA .................................................................................... 48 
5. 
SUBJECT ENROLLMENT ............................................................................................. 49 
6. 
TREATMENT PROCEDURES ....................................................................................... 50 
6.1 
DRUG ADMINISTRATION ............................................................................... 50 
6.1.1 
SWITCHING TO OPROZOMIB ER TABLETS FROM OPROZOMIB 
TABLETS ............................................................................................. 51 
6.2 
PHASE 1B............................................................................................................ 51 
6.2.1 
SAFETY CONSIDERATIONS FOR PHASE 1B ................................ 51 
6.2.2 
DOSE-ESCALATION RULES ............................................................ 52 
6.3 
DOSE-LIMITING TOXICITY ............................................................................ 52 
6.4 
DOSE REDUCTIONS/ADJUSTMENTS ............................................................ 54 
6.4.1 
OPROZOMIB DOSING DELAYS, MODIFICATIONS, AND 
REINTRODUCTION ........................................................................... 54 
6.4.1.1 
Dose Modification for Hematologic Toxicities ...................... 54 
6.4.1.2 
Dose Reduction for Nonhematologic Toxicities .................... 55 
6.4.1.3 
Infections ................................................................................ 57 
6.4.1.4 
Congestive Heart Failure ........................................................ 57 
6.4.1.5 
Conditions Not Requiring Dose Reduction ............................ 57 
6.4.1.6 
Dosing Delays ......................................................................... 57 
6.4.2 
DEXAMETHASONE:  DOSING DELAYS, MODIFICATIONS, AND 
REINTRODUCTION ........................................................................... 58 
6.4.3 
MISSED DOSES .................................................................................. 60 
6.5 
SAFETY GUIDANCE FOR INVESTIGATORS................................................ 60 
6.6 
CONCOMITANT MEDICATIONS .................................................................... 61 
6.6.1 
REQUIRED/RECOMMENDED CONCOMITANT 
MEDICATIONS/TREATMENTS ........................................................ 62 
6.6.2 
ALLOWED CONCOMITANT MEDICATIONS ................................ 64 
6.6.3 
EXCLUDED CONCOMITANT MEDICATIONS .............................. 65 
7. 
STUDY TESTS AND OBSERVATIONS ....................................................................... 65 


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7.1 
VITAL SIGNS ASSESSMENTS......................................................................... 65 
7.2 
CENTRAL ECG ASSESSMENTS ...................................................................... 66 
7.3 
NEUROLOGIC ASSESSMENTS ....................................................................... 66 
7.4 
PHARMACOKINETIC, PHARMACODYNAMIC, AND PROTEOMIC 
STUDIES ............................................................................................................. 67 
7.4.1 
PHASE 1B:  PHARMACOKINETIC STUDIES ................................. 67 
7.4.2 
PHASE 1B:  PHARMACODYNAMIC AND PROTEOMIC 
STUDIES .............................................................................................. 69 
7.4.3 
PHASE 2:  PHARMACOKINETIC STUDIES .................................... 69 
7.4.4 
PHASE 2:  PHARMACODYNAMIC AND PROTEOMIC 
STUDIES .............................................................................................. 70 
7.4.5 
GENOMIC EVALUATIONS ............................................................... 71 
7.5 
LABORATORY EVALUATIONS FOR SAFETY ............................................ 71 
7.6 
DISEASE RESPONSE ASSESSMENTS ............................................................ 73 
7.7 
ASSESSMENTS AT END OF STUDY TREATMENT OR EARLY 
DISCONTINUATION ......................................................................................... 73 
8. 
STUDY TREATMENT DISCONTINUATION ............................................................. 73 
9. 
ADVERSE EVENTS ....................................................................................................... 74 
9.1 
ADVERSE EVENTS DEFINITIONS ................................................................. 74 
9.2 
CAUSALITY ....................................................................................................... 76 
9.3 
ADVERSE EVENTS REPORTING PROCEDURES ......................................... 76 
9.3.1 
GENERAL PROCEDURES ................................................................. 76 
9.3.2 
DISEASE PROGRESSION .................................................................. 77 
9.4 
SERIOUS ADVERSE EVENTS DEFINITIONS ................................................ 78 
9.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS ............................................................................................... 78 
9.6 
PREGNANCY ..................................................................................................... 79 
10. 
STATISTICAL CONSIDERATIONS ............................................................................. 82 
10.1 
STUDY ENDPOINTS ......................................................................................... 82 
10.2 
SAMPLE SIZE CONSIDERATIONS ................................................................. 83 
10.3 
STATISTICAL ANALYSIS ................................................................................ 84 
10.3.1 
ANALYSIS POPULATIONS ............................................................... 84 
10.3.2 
EFFICACY ANALYSIS ....................................................................... 84 
10.3.3 
SAFETY ANALYSIS ........................................................................... 85 


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10.4 
PHARMACOKINETIC, PHARMACODYNAMIC, AND PROTEOMIC 
ANALYSES ......................................................................................................... 86 
10.4.1 
PHARMACOKINETIC ANALYSES .................................................. 86 
10.4.2 
PHARMACODYNAMIC AND PROTEOMIC ANALYSES ............. 87 
10.4.3 
GENOMIC ANALYSES ...................................................................... 87 
11. 
INVESTIGATIONAL PRODUCT .................................................................................. 88 
11.1 
OPROZOMIB DRUG PRODUCT ...................................................................... 88 
11.1.1 
DESCRIPTION ..................................................................................... 88 
11.1.2 
FORMULATION .................................................................................. 88 
11.1.3 
HOW SUPPLIED.................................................................................. 89 
11.1.4 
STORAGE CONDITIONS ................................................................... 89 
11.2 
ACCOUNTABILITY........................................................................................... 89 
11.3 
DEXAMETHASONE DRUG PRODUCT .......................................................... 90 
11.3.1 
DESCRIPTION ..................................................................................... 90 
11.3.2 
HOW SUPPLIED.................................................................................. 90 
11.3.3 
STORAGE CONDITIONS ................................................................... 90 
11.3.4 
ACCOUNTABILITY ........................................................................... 90 
12. 
REGULATORY OBLIGATIONS ................................................................................... 91 
12.1 
INFORMED CONSENT ...................................................................................... 91 
12.2 
COMPLIANCE WITH LAWS AND REGULATIONS ..................................... 91 
12.3 
SUBJECT CONFIDENTIALITY ........................................................................ 92 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................... 93 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION ....................... 93 
13.2 
STUDY DOCUMENTATION AND ARCHIVES .............................................. 93 
13.2.1 
SOURCE DOCUMENTS ..................................................................... 93 
13.2.2 
CASE REPORT FORM COMPLETION ............................................. 93 
13.2.3 
ARCHIVAL OF RECORDS................................................................. 94 
13.3 
STUDY MONITORING AND DATA COLLECTION ...................................... 94 
14. 
REFERENCES ................................................................................................................. 96 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON 
THE 5 CONSECUTIVE DAY BIMONTHLY SCHEDULE (DAYS 1 TO 5 OF 
EACH 14-DAY TREATMENT CYCLE), PHASE 1B ................................................ 98 


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APPENDIX B 
SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON 
THE 5 CONSECUTIVE DAY BIMONTHLY SCHEDULE (DAYS 1-5 OF EACH 
14-DAY TREATMENT CYCLE), PHASE 2 ............................................................. 105 
APPENDIX C 
SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON 
THE 2 CONSECUTIVE DAY WEEKLY SCHEDULE (DAYS 1, 2, 8, AND 9 OF 
EACH 14-DAY TREATMENT CYCLE), PHASE 1B .............................................. 108 
APPENDIX D 
SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON 
THE 2 CONSECUTIVE DAY WEEKLY SCHEDULE (DAYS 1, 2, 8, AND 9 OF 
EACH 14-DAY TREATMENT CYCLE), PHASE 2 ................................................. 116 
APPENDIX E 
SCHEDULE OF STUDY ASSESSMENTS:  DISEASE RESPONSE 
EVALUATIONS ......................................................................................................... 119 
APPENDIX F 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ....................................................................................... 121 
APPENDIX G 
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES WITH 
NARROW THERAPEUTIC RANGE ........................................................................ 122 
APPENDIX H 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA ..................... 123 
APPENDIX I 
BLOOD SAMPLES FOR PHARMACOKINETIC AND 
PHARMACODYNAMIC/PROTEOMIC ANALYSES:  SAMPLING TIMES ........ 126 
APPENDIX J 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 129 
APPENDIX K 
EXAMPLE ELECTRONIC SERIOUS ADVERSE EVENT 
CONTINGENCY REPORT FORM ........................................................................... 131 
APPENDIX L 
EXAMPLE AMGEN PREGNANCY NOTIFICATION 
WORKSHEET ............................................................................................................ 134 
APPENDIX M 
EXAMPLE AMGEN LACTATION NOTIFICATION 
WORKSHEET ............................................................................................................ 135 
APPENDIX N 
SUMMARY OF CHANGES IN PROTOCOL 2012-001 
AMENDMENT 4 ........................................................................................................ 136 
 
List of Tables 
 
Table 1: 
Phase 1 Response Rates for Subjects with Multiple Myeloma by Schedule and 
Formulation ................................................................................................................ 31 
Table 2: 
Phase 1 Response Rates for Subjects with Waldenström Macroglobulinemia by 
Schedule and Formulation .......................................................................................... 31 
Table 3: 
Dose-Escalation Schemes Using Oprozomib Tablets for 5 Consecutive Days 
Bimonthly and Using Oprozomib Tablets and Oprozomib Extended Release Tablets 
for 2 Consecutive Day Weekly Schedules ................................................................. 43 
Table 4: 
Dose-Escalation Schemes Using Oprozomib Extended Release Tablets:  
5 Consecutive Day Bimonthly Schedule .................................................................... 43 


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Table 5: 
Dose-Escalation Schemes for Oprozomib Extended Release Tablets:  2 Consecutive 
Day Weekly Schedule ................................................................................................ 44 
Table 6: 
Dose-Escalation Rules ................................................................................................ 52 
Table 7: 
Guidelines for Dose Modification for Hematologic Toxicities ................................. 55 
Table 8: 
Guidelines for Dose Modification for Nonhematologic Toxicities ........................... 56 
Table 9: 
Treatment Guidelines for Dexamethasone-related Toxicity ...................................... 59 
Table 10: Dose Decrements for Dexamethasone ....................................................................... 59 
Table 11: Full Chemistry Panels ................................................................................................ 72 
Table 12: Adverse Event Severity Grades .................................................................................. 75 
Table 13: Date of Progression or Censoring for Duration of Response and Progression Free 
Survival ...................................................................................................................... 85 
 
List of Figures 
 
Figure 1 
Dosing Regimens ....................................................................................................... 39 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
2/7 
2 consecutive days every 7 days 
5/14 
5 consecutive days every 14 days 
5-HT3 
5-hydroxytryptamine type-3 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APEX trial 
Assessment of Proteasome Inhibition for Extending Remissions Investigators trial 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-inf 
area under the curve extrapolated to infinity 
AUC0-τ 
area under the curve at the last measurable time point 
BPNS 
Brief Peripheral Neuropathy Screen 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
Cmax 
maximum plasma concentration 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
Case Report Form 
CSRC 
Cohort Safety Review Committee 
CYP3A 
cytochrome P450 3A 
Dex 
Dexamethasone 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EBMT 
European Group for Blood and Marrow Transplantation 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
ER 
extended release 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 


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Abbreviation 
Definition 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GvHD 
graft-versus-host disease 
H0 
null hypothesis 
HA 
alternative hypothesis 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
investigator’s brochure 
IC50 
50% inhibition concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMWG-URC 
International Myeloma Working Group - Uniform Response Criteria 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPD 
maximum protocol dose 
MR 
minimal response 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
nCR 
near complete response 
NF-κB 
nuclear factor kappa light chain enhancer of activated B cells 
NHL 
non-Hodgkin lymphoma 
NSCLC 
non-small cell lung cancer 
OPZ 
Oprozomib 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PDn 
pharmacodynamics 
PDn/P 
blood draw for pharmacodynamic and proteomic analyses 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 


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Abbreviation 
Definition 
PR 
partial response 
PRN 
pro re nata (as needed) 
QRS interval 
beginning of the Q wave to the termination of the S wave, representing the time for 
ventricular depolarization 
QT 
the interval from the beginning of the Q wave to the beginning of the T wave, measured 
from the beginning of the QRS complex to the end of the T wave 
QTc 
corrected QT interval 
QTc prolongation 
prolongation of the interval between the start of the Q wave and the end of the T wave in 
the heart’s electrical cycle (A prolonged QT interval is a biomarker for ventricular 
tachyarrhythmias and a risk factor for sudden death) 
RBC 
red blood cell 
RP2D 
Recommended Phase 2 Dose 
RR 
R to R interval:  the interval from the beginning of one R wave to the beginning of the 
next 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SCT 
stem cell transplant 
SD 
stable disease 
SFLC 
serum free light chain 
SPEP 
serum protein electrophoresis 
STD10 
severely toxic dose to 10% of test animals 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum plasma concentration 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal range 
UPEP 
urine protein electrophoresis 
US 
United States 
VGPR 
very good partial response 
WBC 
white blood cell 
WD 
withdrawal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
WM 
Waldenström macroglobulinemia 


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1. 
INTRODUCTION 
This is a Phase 1b/2 clinical trial of the oral proteasome inhibitor oprozomib in combination 
with dexamethasone in subjects with a relapsed and/or refractory multiple myeloma.  See 
Section 3 for a complete description of the study design.  The study began in July 2013.  The 
maximum tolerated dose (MTD) of oprozomib was not reached on either schedule but is 
currently ongoing. 
The protocol has been amended as new data have become available and ongoing safety results 
have been reviewed.  A summary of changes for all amendments is included in Appendix K of 
each version of the protocol and the main purpose for each amendment is summarized below. 
Version 
Main Purpose of Amendment 
Amendment 1 
 Changed the starting dose from 150 mg to 210 mg 
 Changed the inclusion/exclusion criteria 
Amendment 2 
 Provided guidance to investigators regarding prophylaxis, monitoring, and 
treatment of tumor lysis syndrome 
 Updated DLT criteria 
Amendment 3 
 Introduce the Oprozomib ER tablet broadly in the study. 
 Introduce step-up dosing in the dose escalation to determine if tolerability and 
safety are improved.  This approach is based on preclinical data suggesting this 
schedule may be better tolerated than continuous dosing (see Section 1.3). 
 Include the use of the results of the safety and tolerability of step-up dosing in 
the determination of the recommended Phase 2 dose. 
 Provide additional safety guidance and exclusion criteria regarding GI 
hemorrhage as toxicities were observed in subjects treated with oprozomib on 
the 5/14 schedule (5 consecutive days every 14 days bimonthly) at 240 mg. 
DLT = dose-limiting toxicity 
The main purpose of the current amendment (Amendment 4) is to: 
Pare down data collection for subjects on active treatment due to the completion of this 
study’s analysis and abbreviated clinical study report. 
1.2 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a 
wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation 
system.  Ubiquitinated proteins are cleaved within the proteasome by 1 or more of 3 separate 


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N-terminal threonine protease activities:  a chymotrypsin-like activity, a trypsin-like activity, and 
a caspase-like activity. 
1.3 
RELEVANT NONCLINICAL BACKGROUND 
Oprozomib is a tripeptide epoxyketone-based inhibitor of the 20S proteasome that primarily 
targets the chymotrypsin-like activity.  Oprozomib (formerly ONX 0912) is a structural 
analogue of carfilzomib (Kyprolis), an intravenously administered tetrapeptide epoxyketone that 
received accelerated approval in the United States (US) for the treatment of patients with 
multiple myeloma who have received at least 2 prior therapies, including bortezomib and an 
immunomodulatory agent, and have demonstrated disease progression on or within 60 days of 
completion of the last therapy (Kyprolis Prescribing Information [Onyx Pharmaceuticals 2012]).  
Like carfilzomib, oprozomib is an irreversible and highly selective proteasome inhibitor that 
binds most potently to the chymotrypsin-like subunit of the proteasome (50% inhibition 
concentration [IC50] 50–80 nM) (Zhou 2009).  In addition, when measured against a broad panel 
of proteins containing metallo-, aspartyl, and serine proteases, oprozomib demonstrated minimal 
reactivity against these nonproteasomal proteases. 
Exposure to oprozomib is associated with potent proapoptotic activity across a broad panel of 
tumor-derived cell lines in culture.  The antitumor efficacy of oprozomib has been tested in 
immunocompromised mice implanted with a variety of human tumor cell lines, including 
models of both solid (colorectal adenocarcinoma, non-small cell lung cancer [NSCLC]) and 
hematologic (multiple myeloma, non-Hodgkin lymphoma [NHL]) tumors.  Oprozomib has 
shown an equivalent antitumor activity to carfilzomib in preclinical models where both 
compounds have been tested (Zhou 2009). 
In Good Laboratory Practice (GLP)-compliant toxicity studies, oprozomib was administered to 
rats orally for 2 complete cycles of daily dosing for 5 days with 9 days rest, at doses of 120, 180, 
and 240 mg/m2 (20, 30, and 40 mg/kg).  Administration at 180 mg/m2 (30 mg/kg) resulted in 
mortality in 1 of 26 animals during the first cycle of dosing.  Surviving animals received a 
second cycle of oprozomib administration without additional severe toxicities, and this dose was 
determined to be the severely toxic dose to 10% of test animals (STD10).  Proteasome inhibition 
was > 90%, as measured in whole blood 1 hour after the first dose.  Mortality of > 10% was 


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noted at the next highest dose level (240 mg/m2) and was also noted in the first cycle of dosing.  
In this study, mortality was restricted to females, where exposure (as determined by 
pharmacokinetics [PK]) was 3-fold to 5-fold higher than in males on the first day of dosing.  The 
apparent cause of death could not be determined, but histologic analysis of the surviving 
animals showed mucosal hyperplasia in the small intestines. 
Oprozomib was administered orally to dogs at 60, 120, and 200 mg/m2 (3, 6, and 10 mg/kg) using 
the same schedule of administration.  A dose of 120 mg/m2 (6 mg/kg) was determined to be the 
highest nonseverely toxic dose (HNSTD).  Mortality or early sacrifice was noted in 3 of 
14 animals at the highest dose (200 mg/m2).  Clinical observations in these animals preceding 
death were emesis, decreased activity, lethargy, high body temperatures, cold to touch, weight loss, 
decreased food consumption, and brown/pink nasal discharge, and in 1 of the animals, irregular 
gait.  The apparent cause of death for these animals was attributed to mucosal hemorrhage and 
atrophy of the small and large intestines, which was associated with frequent watery diarrhea and 
occasionally with the presence of blood in the stool. 
In both rats and dogs, all doses of oprozomib resulted in > 80% inhibition of proteasome activity 
in whole blood as measured 1 hour after the first dose.  In both rats and dogs, exposure, as 
measured by area under the curve (AUC), showed a greater than dose-proportional increase 
when the dose was increased above the STD10/HNSTD. 
In a cardiovascular safety pharmacology study conducted in male and female dogs, a single dose 
of oprozomib at 120 mg/m2 was not associated with cardiovascular toxicity. 
Hypotension, beginning approximately 4 hours after dose administration, was noted in all 
animals at 200 and 400 mg/m2 and was dose-dependent in severity.  In all but 1 animal, this was 
accompanied by an increase in heart rate.  There were no observed corrected QT (QTc) 
prolongations in any animals. 
Schedules with and without step-up dosing were conducted in rats.  Rats did not tolerate a 
schedule of 50 mg/kg given on the 2 consecutive day weekly schedule.  Rats did tolerate up to 
60 mg/kg daily when initiated at a lower dose of 30 mg that was then stepped-up to 50 mg on 
Week 2 and then 60 mg on Week 3.  This suggests increased tolerability using a step-up 
approach.  This is consistent with preclinical and clinical observations showing that CFZ 


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tolerability was increased with step-up schedule. 
Oprozomib does not absorb light within the range of natural sunlight (molar extinction 
coefficient less than 1000 L mol-1 cm-1 for wavelengths between 290 to 700 nm), and therefore 
is unlikely to have any adverse photoeffects. 
Further information about the preclinical pharmacology and toxicology of oprozomib is 
presented in the Investigator’s Brochure (IB). 
1.4 
RELEVANT CLINICAL BACKGROUND 
The following enrollment safety and efficacy information for the Oprozomib studies below as of 
31 March 2014 is as follows: 
1.4.1 
STUDY 2009-003:  SOLID TUMORS 
Once-Daily Dosing Group 
The first-in-human clinical study (Study 2009-003 using Oprozomib in Capsules) was initiated 
in May 2010 and was an open-label, dose-escalation study in subjects with recurrent or relapsed 
advanced solid tumors.  The primary objectives of this ongoing study were to evaluate the 
safety, tolerability, and MTD of oprozomib.  Samples for PK and pharmacodynamics (PDn) 
analysis were also collected at various time points during Cycles 1 and 2.  The dose for the 
initial cohort was 30 mg orally, once daily, for 5 consecutive days every 14 days (bimonthly), 
with cycles repeated every 14 days.  Doses were escalated in subsequent cohorts by 30 mg as 
follows:  60, 90, 120, 150, and 180 mg.  A once-daily dosing schedule was used for the first 
6 cohorts treated. 
Twenty-five subjects received oprozomib on a 5 consecutive day bimonthly schedule with 
once-daily dosing (n = 3 for each dose from 30 to 120 mg, n = 7 for the 150 mg cohort, and 
n = 6 for the 180 mg cohort).  All 25 subjects who received a once-daily dose of Oprozomib in 
Capsules were included in the safety population.  The median duration of study treatment in the 
once-daily dosing group was 29 days (range:  5–249 days).  The median number of 14-day 
treatment cycles was 3 (range:  1–18 cycles), and the median total dose received was 1650 mg 
(range:  150–7740 mg).  All subjects are off study; reasons for study discontinuation included 


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progressive disease (18 subjects, 72.0%), withdrawal of consent (3 subjects, 12.0%), adverse 
event (AE)/toxicity (1 subject, 4.0%), and “Other” reasons (3 subjects, 12.0%).  The latter 
category includes subject decision in 1 subject and lack of clinical benefit in 2 subjects. 
One subject in the 180 mg cohort experienced a dose-limiting toxicity (DLT) of Grade 3 
vomiting and dehydration, and a second subject in the same dose cohort experienced a DLT of 
Grade 3 hypophosphatemia, prompting the expansion of the 150 mg cohort to 7 subjects in total.  
The MTD for the once-daily dosing group receiving the powder in capsule formulation was 
determined to be 150 mg. 
Twenty-four subjects (96.0%) experienced at least 1 treatment-emergent AE.  The most frequent 
AEs seen in ≥ 25% of subjects included nausea (23 subjects, 92.0%), vomiting (20 subjects, 
80.0%), fatigue (14 subjects, 56.0%), diarrhea (13 subjects, 52.0%), decreased appetite 
(11 subjects, 44.0%), and abdominal pain, dehydration, and anemia (7 subjects each, 28.0%). 
The majority of treatment-emergent AEs were gastrointestinal and Grade 1 or Grade 2 in 
severity.  The only ≥ Grade 3 AEs occurring in more than 1 subject were Grade 3 dehydration 
(3 subjects, 12.0%) and Grade 3 vomiting, hyponatremia, and hypophosphatemia (2 subjects 
each, 8.0%).  One subject (4.0%) experienced a Grade 4 treatment-emergent AE of 
hyperuricemia that resolved after 13 days; no action was taken with study drug. 
Seven subjects (28.0%) experienced at least 1 treatment-emergent serious adverse event (SAE).  
There were no Grade 4 or Grade 5 SAEs in the once-daily dosing group.  Grade 3 dehydration 
(experienced by 2 subjects, 8.0%) was the only SAE experienced by more than 1 subject. 
One subject (4.0% overall) in the 150 mg cohort discontinued study treatment due to the 
occurrence of Grade 3 nausea and vomiting which did not require hospitalization. 
Clinically significant laboratory abnormalities reported as AEs included Grade 3 anemia (n = 1), 
hypophosphatemia (n = 2), and lymphocytopenia (n = 1).  As mentioned previously, there was 
also 1 Grade 4 AE of hyperuricemia. 
Plasma concentrations of oprozomib following oral administration typically reached a maximum 
within 120 minutes and were undetectable within 24 hours.  Exposure to oprozomib appears to 


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increase in a dose-proportional manner up to 150 mg.  The diol, PR-176, is a major plasma 
metabolite for all subjects.  The bioavailability of oprozomib is reflected by potent target 
inhibition at levels similar to those observed with carfilzomib (Badros 2010, 
Papadopoulos 2011, Zhou 2009).  Proteasome inhibition ≥ 80% was observed in both whole 
blood and peripheral mononuclear cells for two-thirds of the subjects receiving doses ≥ 90 mg. 
Twice-daily Dosing Group 
In an effort to reduce gastrointestinal toxicity, subjects enrolled under Amendment 4 received 
oprozomib as a split daily dose, 4 to 6 hours apart.  Nineteen subjects have received treatment on 
a 5 consecutive day bimonthly schedule with twice-daily dosing (n = 4 for the 120 mg cohort; 
n = 3 for the 150 mg cohort; n = 7 for the 180 mg cohort; and n = 5 for the 210 mg cohort). 
All 19 enrolled subjects received at least 1 dose of Oprozomib in Capsules and comprised the 
safety population.  The median duration of study treatment in the twice-daily dosing group was 
47 days (range:  5–116 days).  The median number of 14-day treatment cycles was 4 (range:  
1–8 cycles), and the median total dose received was 3000 mg (range:  1050−6300 mg).  All 
subjects are off study; reasons for study discontinuation included progressive disease 
(11 subjects, 57.9%), AE/toxicity (3 subjects, 15.8%), symptomatic deterioration (1 subject, 
5.3%), and “Other” reasons (4 subjects, 21.1%), the latter including subject decision/preference 
(3 subjects) and lack of clinical benefit and toxicity (1 subject). 
One subject in the 180 mg cohort experienced a DLT of Grade 3 hypophosphatemia, prompting 
the expansion of the 180 mg cohort to 7 subjects (1 subject did not complete Cycle 1 for reasons 
other than DLT and was therefore replaced).  No additional DLTs were observed in this cohort.  
Two additional DLTs were recorded in the 210 mg cohort (120 mg, 90 mg), including 1 subject 
with Grade 5 gastrointestinal hemorrhage and 1 subject with Grade 3 hallucinations.  The MTD 
for the once-daily dosing group receiving the powder in capsule formulation was determined to 
be 180 mg. 
Nineteen subjects (100.0%) experienced at least 1 treatment-emergent AE.  The AEs most 
frequently seen in ≥ 25% of subjects included vomiting (18 subjects, 94.7%); nausea 
(17 subjects, 89.5%); diarrhea (14 subjects, 73.7%); fatigue, constipation, and decreased appetite 


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(7 subjects each, 36.8%); and pyrexia, dysgeusia, and anemia (5 subjects each, 26.3%). 
Most AEs were gastrointestinal and Grades 1 and 2 in severity, although 1 subject in the 210 mg 
cohort died within 30 days of discontinuing study drug due to a gastrointestinal bleed.  Grade 3 
anemia, fatigue, and lymphocyte count decreased were the only ≥ Grade 3 AEs occurring in 
more than 1 subject.  Four subjects (21.1%) experienced Grade 3 anemia, and 2 subjects 
(10.5%) experienced Grade 3 lymphocyte count decreased and Grade 3 fatigue, respectively.  
No Grade 4 AE occurred in the twice-daily dosing group. 
A lower incidence of gastrointestinal AEs was reported in Cycle 2 when subjects were fed 
(11 subjects, 57.9%) compared with Cycle 1 when subjects fasted (19 subjects, 100%).  Fewer 
subjects participated in Cycle 2 than Cycle 1 due to discontinuations.  Notable differences 
included less vomiting (Cycle 2:  9 subjects, 47.4%; Cycle 1:  14 subjects, 73.7%); less nausea 
(Cycle 2:  4 subjects, 21.1%; Cycle 1:  13 subjects, 68.4%); less diarrhea (Cycle 2:  6 subjects, 
31.6%; Cycle 1:  10 subjects, 52.6%); and less pyrexia (Cycle 2:  1 subject, 5.3%; Cycle 1: 
4 subjects , 21.1%).  No other apparent differences in the incidence of other AEs were reported 
in Cycle 2 compared with Cycle 1.  Additional data, ideally with a more robust crossover 
design, will be needed to assess the true effect of food on GI tolerability especially in light of 
preclinical data suggesting improved tolerability over time, such as the data supporting a step-up 
dosing regimen. 
A total of 8 subjects (42.1%) experienced at least 1 treatment-emergent SAE.  No SAE was 
experienced by more than 1 subject. 
Three subjects (15.8%) discontinued study treatment due to AEs.  One subject in the 120 mg 
cohort discontinued study treatment due to Grade 1 vomiting.  One subject in the 180 mg 
cohort discontinued study treatment due to SAEs of Grade 3 nausea and vomiting.  As 
mentioned previously, 1 subject in the 210 mg cohort was discontinued from study due to a 
Grade 5 gastrointestinal bleed.  There were no treatment-emergent laboratory abnormalities 
≥ Grade 4. 
Preliminary PDn in subjects’ whole blood samples demonstrates that the levels of proteasome 
inhibition with the twice-daily dose are similar to those with the equivalent single dose. 


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1.4.2 
STUDY 2011-001:  HEMATOLOGIC MALIGNANCIES 
Safety 
As of 21 January 2014, the Phase 1b portion of Study 2011-001 had completed enrollment; 
61 response-evaluable subjects with hematologic malignancies had received Oprozomib in 
Capsules in split dosing, or Oprozomib Tablets with daily dosing, on a 5 consecutive day 
bimonthly (5/14) schedule or a 2 consecutive day weekly (2/7) schedule in Phase 1.  In the 
Phase 1 portion of the study (as of 21 January 2014): 
 Thirty-two (32) subjects have been enrolled on the 5 consecutive day bimonthly schedule.  
Dose-limiting toxicities for the 5/14 schedule observed at the maximum administered 
dose (MAD) of 270 mg were tumor lysis syndrome (TLS) and Grade 3 vomiting.  The 
MTD was defined as 240 mg, and this was selected for the Phase 2 portion of the study 
for the 5/14 schedule.  Due to toxicities, including fatal GI bleeding in 2 subjects, and a 
high rate of discontinuations observed at this dose level, the dose under evaluation in 
Phase 2 has been reduced.  The Phase 2 portion of the study will reopen using a step-up 
dose approach starting with 150 mg as the initial dose level, with an increase to 180 mg in 
Cycle 2. 
 Twenty-nine (29) subjects have been enrolled on the 2 consecutive day weekly schedule.  
Dose-limiting toxicities for the 2/7 schedule observed at the MAD of 330 mg were Grade 
3 diarrhea and Grade 4 thrombocytopenia.  The MTD was defined as 300 mg, a step-up 
dosing regimen using 240 mg as the initial dose level, with an increase to 300 mg in 
Cycle 2, was selected for the Phase 2 portion of the study for the 2/7 schedule. 
The Phase 2 portion of the study (as of 21 January 2014): 
 A total of 13 subjects have been enrolled in the 5/14 schedule. 
 No subjects have been enrolled in the 2/7 schedule. 
Nineteen subjects experienced serious adverse events (SAEs) across both schedules.  The 
11 treatment-related SAEs comprised 4 GI events (diarrhea, nausea/vomiting, 
fatigue/dehydration/nausea, and dehydration), 2 hematological events (anemia and neutropenia), 
2 cases of TLS, 1 infection (pneumonia), and 1 general event (fatigue/dehydration/nausea; 
events could be counted in more than 1 category).  All of these are expected events based on the 
Oprozomib Investigator’s Brochure (Version 6).  There were 2 cases of renal failure.  There 
were also 2 Grade 5 GI hemorrhages at the 240 mg dose on the 5-consecutive-days bimonthly 
schedule. 


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Efficacy 
Response rates for subjects with multiple myeloma (n = 43) and subjects with Waldenström 
macroglobulinemia (WM; n = 18) by schedule and formulation are summarized in Table 1 and 
Table 2. 
Table 1: 
Phase 1 Response Rates for Subjects with Multiple Myeloma by 
Schedule and Formulation 
Formulation/Schedule (n) 
Dose Range (mg) 
ORR (≥ PR) 
Clinical Benefit Rate (≥ MR) 
PIC 5/14 (10) 
120–210 
40% 
50% 
Tablets 5/14 (18) 
150–270 
27.8% 
38.9% 
Tablets 2/7 (15) 
150−330 
20.0% 
46.7% 
ORR = overall response rate; PIC = powder in capsule. 
Table 2: 
Phase 1 Response Rates for Subjects with Waldenström Macroglobulinemia 
by Schedule and Formulation 
Formulation/Schedule (n) 
Dose Range (mg) 
ORR (≥ MR) 
Major Response (≥ PR) 
Tablets 5/14 (11) 
150–270 
63.6% 
54.5% 
Tablets 2/7 (7) 
150–330 
42.9% 
14.3% 
ORR = overall response rate; PIC = powder in capsule. 
The Phase 2 portion of Study 2011-001 is ongoing.  Eight response-evaluable subjects have 
received Oprozomib Tablets on the 5 consecutive day bimonthly schedule with once daily 
dosing in Phase 2; 7 subjects had SD, and 1 subject was off study prior to any disease response 
assessment. 
1.4.3 
STUDY 2012-001:  OPROZOMIB IN COMBINATION WITH 
DEXAMETHASONE IN MULTIPLE MYELOMA 
2012-001 is the study on which this protocol amendment is based.  See Section 3.1 for 
information on study methodology. 
Safety 
The 2012-001 Phase 1b/2 study assessing safety and activity of Oprozomib Tablets in 
combination with dexamethasone is currently enrolling in the Phase 1b portion of the study. 
 As of May 2014, 12 subjects have been enrolled and treated at doses of 180 mg 
(n = 5) to 210 mg (n = 7) on the 5/14 schedule, and 4 subjects remain on study.  Three 


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subjects have experienced DLTs at the 210 mg dose, including 1 subject with a 
subarachnoid hemorrhage, 1 subject with Grade 3 transaminitis, and 1 subject with Grade 4 
thrombocytopenia.  In addition, 1 subject had 3 SAEs (esophagitis, urinary tract infection, 
and pneumonia). 
 As of May 2014, 13 subjects have been enrolled and treated at doses of 180 mg 
(n = 3), 210 mg (n = 3), 240 mg (n = 3), to 270 mg (n = 4) on the 2/7 schedule, and 
7 subjects remain on study.  One DLT of Grade 4 thrombocytopenia has been observed. 
Efficacy 
Three response-evaluable subjects received Oprozomib Tablets on a 5 consecutive day 
bimonthly schedule with daily dosing, and all 3 subjects had SD as their best response.  Seven 
response-evaluable subjects have received Oprozomib Tablets administered orally, once daily, 
on a 2 consecutive day weekly schedule.  Four subjects had SD as the best response and 
3 subjects had a partial response ([PR] confirmed or unconfirmed). 
1.4.4 
STUDY OPZ003:  OPROZOMIB IN COMBINATION WITH 
LENALIDOMIDE AND DEXAMETHASONE IN MULTIPLE 
MYELOMA 
Safety 
The OPZ003 Phase 1b/2 study, assessing oprozomib in combination with lenalidomide and 
dexamethasone, is currently enrolling in the Phase 1b portion of the study in newly diagnosed 
subjects with multiple myeloma.  As of 21 January 2014, three subjects have been enrolled.  
Two subjects remain on study.  One subject, a 65-year-old female, experienced a 
treatment-related SAE of syncope during treatment at the 210 mg dose level.  The subject 
discontinued treatment, and the SAE resolved.  Subsequently, the subject experienced a second 
event of syncope.  The dose level in this study has since been de-escalated to 180 mg and 
syncope has been identified as an event of interest for oprozomib. 
Efficacy 
No efficacy data are available at this time. 
1.4.5 
ADDITIONAL STUDIES WITH OPROZOMIB 
Oprozomib is being studied in other Phase 1/2 trials intended to characterize the safety and 


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activity in combination with other anti-myeloma and solid tumor agents.  Please see the 
Investigator’s Brochure for additional details. 
1.5 
STUDY DESIGN RATIONALE 
The objectives of this Phase 1b/2 study (Protocol 2012-001) are to define the MTD (Phase 1b), 
evaluate safety and tolerability (Phases 1b and 2), and evaluate the activity, PK, PDn, and 
biomarkers (Phases 1b and 2), and select the Recommended Phase 2 Dose (RP2D) of oprozomib 
administered in combination with dexamethasone in subjects with relapsed and/or refractory 
multiple myeloma with and without step-up dosing.  All treatments will be administered orally, 
and all subjects will be treated in 14-day treatment cycles.  Oprozomib Tablets or Extended 
Release (ER) Tablets will be administered in single daily doses unless otherwise determined by 
the sponsor. 
Two schedules will be evaluated: 
1. Treatment for 5 consecutive days bimonthly (Days 1, 2, 3, 4, and 5 of a 14-day cycle) 
with dexamethasone on Days 1, 2, 8, and 9 with both continuous and step-up dosing of 
oprozomib; and 
2. Treatment for 2 consecutive days weekly (Days 1, 2, 8, and 9 of a 14-day cycle) with 
dexamethasone on Days 1, 2, 8, and 9 with both continuous and step-up dosing of 
oprozomib. 
Treatment cycles will be repeated until disease progression, unacceptable toxicity, or study 
treatment discontinuation for any reason (see Section 8). 
The rationale for administration of oprozomib in combination with dexamethasone is provided 
in Section 1.5.1. 
1.5.1 
DOSE RATIONALE 
Oprozomib Tablet 
The starting dose of 210 mg (for the initial cohort of the study) given once daily on either the 
5 consecutive day bimonthly or the 2 consecutive day weekly schedule in subjects with 
hematologic malignancies is supported by the clinical data collected for subjects exposed to 
Oprozomib Tablets in current and completed clinical studies. 


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Preliminary safety results from Study 2011-001 demonstrate the following: 
 Subjects have tolerated 180 mg tablets in the 5 consecutive day bimonthly schedule 
without the occurrence of 2 DLTs and with no other significant safety concerns. 
 Subjects have tolerated up to 240 mg tablets in the 2 consecutive day weekly schedule 
without the occurrence of 2 DLTs and with no other significant safety concerns. 
 Subjects were able to tolerate up to 210 mg total daily dose with Oprozomib in 
Capsules administered on the 5 consecutive day bimonthly schedule without 
occurrence of DLTs or the occurrence of other significant safety concerns. 
In a previous study with bortezomib in relapsed refractory multiple myeloma subjects, the 
addition of steroids to a proteasome inhibitor has demonstrated a reduction in GI toxicity when 
compared to single agent (Jagannath 2006).  In Study 2011-001, the addition of low doses of 
dexamethasone appeared to reduce GI toxicity.  It is anticipated that Oprozomib Tablets will 
have lower GI toxicity in combination with dexamethasone than single-agent oprozomib, and 
therefore Oprozomib Tablets may be safely administered at the same level as oprozomib 
monotherapy. 
As of 14 April 2014, three DLTs have been observed in the 5/14 once-daily dosing schedule at 
210 mg using Oprozomib Tablets:  1 subarachnoid hemorrhage, 1 prolonged Grade 4 
thrombocytopenia, and 1 Grade 3 transaminitis.  The 180 mg cohort has expanded to 5 subjects 
without any DLTs.  One additional subject will be enrolled to establish 180 mg as the MTD 
with Oprozomib Tablets. 
Oprozomib ER Tablet 
A new oprozomib tablet will be introduced into the study with Amendment 3.  The Oprozomib 
ER Tablet is being developed to have a more consistent dissolution profile by decreasing 
variability through an improved release process.  In addition, administration of a single 
Oprozomib ER Tablet, instead of multiple tablets as in the case of Oprozomib Tablets, will be 
used in doses up to 270 mg.  (Currently, all doses given are composed of multiple Oprozomib 
Tablets.  For example, the 270 mg dose is made up of three 90 mg Oprozomib Tablets.)  The use 
of fewer tablets provides a smaller surface-to-volume ratio, resulting in a slower dissolution in 
vitro, and is predicted to have a lower maximum plasma concentration (Cmax) and similar AUC.  
The current GI toxicity is likely mediated by local proteasome inhibition and variability (caused 


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by prior formulation and multiple tablets) in the release of drug substance in the current 
formulation.  Thus, it is hypothesized that the formulation change and single-tablet dosage may 
decrease local intraluminal oprozomib levels at any one location in the GI tract and thereby 
decrease GI toxicity.  Preliminary PK data on file from the single-agent oprozomib study 
suggest systemic toxicity is related to Cmax; therefore, a lower Cmax may reduce systemic 
toxicity. 
Switching from Oprozomib Tablets to Oprozomib ER Tablets 
When current subjects switch over to Oprozomib ER Tablets, they will continue the same dose 
and schedule that they were receiving with the Oprozomib Tablet.  Intensive PK sampling 
should be obtained on Day 1 in the cycle prior to switching and on Day 1 of the following cycle 
(i.e., first day with Oprozomib ER Tablet) at the scheduled time points described in Section 7.4 
for Cycle 1, Day 1 for patients on the step-up dosing regimen (i.e., predose to 7 hours postdose).  
The time between the 2 days of PK collection for switching to the Oprozomib ER tablet will be 
1 cycle or 14 days. (see Section 7.4.1 for PK sampling requirements before and after the switch). 
Step-Up Dosing 
Step-up dosing has been better tolerated than continuous dosing in animal studies (see 
Section 1.3).  Carfilzomib has been approved using a step-up dosing regimen that minimizes 
adverse events associated with initial doses.  Based on this information, cohorts re-escalating 
after identification of the MTD with Oprozomib Tablets will receive step-up dosing. 
Protocol Amendment 4 
No changes in drug product, dosage, or treatment regimen occurred in this protocol 
amendment from the previous version. 
1.5.2 
SCHEDULE RATIONALE 
The optimal schedule of administration of oprozomib is under investigation.  Early development 
focused on the 5 consecutive day bimonthly (either once or twice daily) schedule in 14-day 
treatment cycles.  The most significant AEs noted with the 5 consecutive day bimonthly 
schedule are related to GI toxicities.  To potentially address those toxicities, a 2 consecutive 


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day weekly schedule is also being examined.  Preclinical studies have shown that oprozomib 
administered once daily for 2 consecutive days has activity against a number of tumor cell lines.  
Therefore, for subjects enrolled in this study, the MTD will be determined for both the 
5 consecutive day bimonthly schedule and for the 2 consecutive day weekly schedule.  The 
Phase 2 portion of this study will be initiated at the sponsor’s discretion using the recommended 
dose determined from 1 or both dosing schedules.  The Phase 2 portion of the study will 
evaluate the safety and tolerability, PK, PDn, and activity of oprozomib; these data will be used 
to plan for the further development of oprozomib. 
1.6 
STUDY RATIONALE 
The clinical activity of proteasome inhibition in hematologic malignancies has been 
demonstrated in the clinical setting, including multiple myeloma.  Specifically, bortezomib, 
which is a covalent, slowly reversible inhibitor that primarily targets the chymotrypsin-like 
activity of the proteasome, was the first of the proteasome inhibitors that was shown to be 
cytotoxic to several tumor types.  Because of the benefit of bortezomib observed in subjects with 
relapsed or refractory myeloma in Phase 1 and 2 studies, the drug received accelerated approval 
by the US Food and Drug Administration (FDA) and was made available to patients with 
advanced myeloma in May 2003 (Dispenzieri 2005).  Full approval of bortezomib for multiple 
myeloma was based on the results of the Assessment of Proteasome Inhibition for Extending 
Remissions (APEX) trial (Richardson 2005). 
Carfilzomib (Kyprolis), which received accelerated approval in July 2012, is an irreversible 
inhibitor of the epoxyketone class (proteasome) that is selective and structurally distinct from 
bortezomib (O’Connor 2009).  Proteasome inhibition by bortezomib is slowly reversible.  
Consequently, proteasome inhibition is more sustained with carfilzomib than with 
bortezomib (Demo 2007; Suzuki 2011).  In comparison to bortezomib, carfilzomib exhibits 
equal potency, but greater selectivity for the chymotrypsin-like activity of the proteasome.  In 
cell culture, carfilzomib is more cytotoxic than bortezomib following brief treatments that 
mimic the in vivo PK of both molecules (Demo 2007). 
Phase 1 development of carfilzomib included 2 studies, PX-171-001 and PX-171-002, that 
explored 2 different dosing schedules (daily dosing for 5 consecutive days within Week 1 and 


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9 days rest; and daily dosing for 2 consecutive days for 3 weeks [Days 1, 2, 8, 9, 15, 16] and 
12 days rest). 
Data collected in these 2 studies suggested that the 2 consecutive day weekly schedule was 
better tolerated and demonstrated clinically meaningful response rates.  Subsequent Phase 2 and 
Phase 3 carfilzomib studies have utilized this dosing schedule and have provided data indicating 
both tolerability and efficacy in advanced stage, heavily pretreated multiple myeloma subjects. 
Oprozomib, an orally available structural analogue of carfilzomib, is a synthetic small-molecule 
peptide that specifically functions as an irreversible and highly selective inhibitor of the 
chymotrypsin-like activity of the 20S proteasome, which leads to the accumulation of protein 
substrates within the cell and induction of apoptosis.  The studies discussed above demonstrate 
the treatment potential for proteasome inhibition in multiple myeloma.  There is also a continued 
need for more effective agents and those that can be administered orally, which would improve 
compliance and patient convenience and potentially prolong treatment duration. 
Dexamethasone will be administered in this study based on data from the SUMMIT trial 
(Richardson 2003) and an expanded access trial (Mikhael 2009), in which dexamethasone was 
shown to have synergistic effects with proteasome inhibitors.  Preclinical studies also suggest 
the potential therapeutic advantage of dexamethasone combined with carfilzomib (Kuhn 2007) 
and bortezomib (Hideshima 2001) in multiple myeloma.  In earlier clinical studies, 
dexamethasone was shown to mitigate GI AEs temporally associated with single-agent 
oprozomib. 
2. 
STUDY OBJECTIVES 
The Phase 1b portion of this study will determine the MTD of oprozomib in subjects with 
multiple myeloma when administered orally once daily, in combination with dexamethasone.  A 
dose-escalation plan is being followed in Phase 1b to determine the recommended Phase 2 dose 
for each treatment schedule.  The Phase 2 portion will use the recommended Phase 2 dose 
determine for each schedule, unless the sponsor determines that based on Phase1b data, 1 or both 
of the schedules should not proceed with development.  The Phase 2 portion of this study will 
further evaluate the safety and activity of oprozomib in combination with dexamethasone. 


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2.1 
PRIMARY OBJECTIVES 
Phase 1b 
 To determine the MTD and the RP2D of oprozomib given orally, once daily, on 2 different 
schedules:  5 consecutive days every 14 days (bimonthly, 5/14) or 2 consecutive days every 
7 days (weekly; 2/7) for a 14-day treatment cycle, both schedules given in combination with 
dexamethasone 
 To evaluate safety and tolerability 
Phase 2 
 To estimate the overall response rate (ORR), defined as the proportion of subjects with the 
best overall response of stringent complete response (sCR), complete response (CR), near 
complete response (nCR), very good partial response (VGPR), and partial response (PR), as 
defined by the International Myeloma Working Group- Uniform Response Criteria 
(IMWG-URC) and modified European Group for Blood and Marrow Transplantation 
(EBMT) criteria 
 To evaluate safety and tolerability 
2.2 
SECONDARY OBJECTIVES 
 To evaluate PK of Oprozomib Tablets and Oprozomib ER Tablets 
 To estimate clinical benefit rate (CBR), defined as ORR plus MR, as defined by the 
EBMT criteria 
 To estimate the duration of response (DOR) 
 To estimate progression-free survival (PFS) 
 To estimate time to progression (TTP) 
2.3 
EXPLORATORY OBJECTIVES 
 To evaluate PDn and proteomic biomarkers 
 To evaluate genomic biomarkers that may predict for response and resistance 
following treatment with proteasome inhibitors 
3. 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This study is an open-label, Phase 1b/2, multicenter study in which subjects will receive 
oprozomib administered orally once daily in combination with dexamethasone on 2 different 
treatment schedules.  Subjects will receive oprozomib on Days 1 to 5 of a 14-day treatment 
cycle in combination with 20 mg dexamethasone on Days 1, 2, 8, and 9; or oprozomib on 


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Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone on 
Days 1, 2, 8, and 9 (Figure 1).  Both the Phase 1b and the Phase 2 portions of this study will be 
open to patients with relapsed and/or refractory multiple myeloma.  Primary refractory patients 
are allowed in the Phase 1b portion of the study only. 
Figure 1 
Dosing Regimens 
 
OPZ = oprozomib; Dex = dexamethasone. 
Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, 
or study treatment discontinuation for any reason (see Section 8). 
Disease response assessments will be performed every 4 weeks for the first year through 
Cycle 26 and then every 8 weeks thereafter according to the IMWG-URC.  In addition, nCR and 
MR will be assessed per the modified EBMT criteria. 
3.1.1 
PHASE 1B PORTION 
Subjects will be evaluated for DLTs according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.  Subjects with stable 
disease (SD) or better may continue treatment.  Intrasubject dose escalation to the 
recommended Phase 2 dose may be permitted once that dose has been determined and after 


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discussion between the treating physician and the Sponsor study medical monitor. 
The purpose of the Phase 1b portion of the study is to determine the MTD, RP2D, safety, and 
PK/PDn of oprozomib administered orally once daily in combination with dexamethasone, in 
subjects with relapsed and/or refractory multiple myeloma, using a 3 + 3 dose-escalation 
scheme with and without step-up dosing.  The maximum tolerated dose is defined as the highest 
dose level at which fewer than 33% of subjects have a DLT. 
For each of the 2 schedules being studied, groups of 3 to 6 subjects will be enrolled into 
dose-escalation cohorts.  As long as fewer than 33% of subjects experience a DLT in a given 
cohort, escalation will continue by 30 mg increments of oprozomib onto the next designated 
cohort(s).  A minimum of 6 subjects must be treated at the MTD to establish the dose as the 
MTD with and without step-up dosing. 
Assessment of DLTs will occur during the first 14 days of treatment with continuous dosing 
(Cycle 1) or during the first 14 days of treatment at the step-up dose to be studied (Cycle 2), 
considered the assessment period.  Any subject who develops a DLT during the assessment 
period after receiving at least 1 dose of oprozomib in the assessment period will be considered 
evaluable.  Any subject who does not develop a DLT during the assessment period, but has not 
received all planned doses of oprozomib and dexamethasone, will be considered unevaluable 
and will be replaced. 
3.1.2 
DOSE-ESCALATION PLAN 
Oprozomib Tablets 
Prior to Amendment 3, oprozomib doses were escalated in sequential groups of 3 subjects with 
expansion up to 6 subjects, if a DLT was observed using Oprozomib Tablets.  The initial 
cohorts of the study will be entered at a dose level of 210 mg for both schedules.  All 
subsequent cohorts will be escalated by 30 mg until the MTD is determined. 
In the event that the initial cohort that received the 210 mg dose is found to exceed the MTD 
(the highest dose at which a DLT is observed in fewer than 2 of 6 subjects), dosing will proceed 
at 180 mg or lower, as agreed with the Cohort Safety Review Committee. 


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Oprozomib ER Tablets 
The introduction of Oprozomib ER Tablets into the study and determination of MTD of this 
formulation for the 5/14 and 2/7 schedules are described below: 
5/14 Schedule 
For the 5/14 once-daily dosing schedule, Oprozomib ER Tablets will be introduced with step-up 
dosing as described below.  Determination of the MTD for step-up dosing will proceed in the 
following manner: 
 The first cohort will enroll 6 subjects using step-up dosing.  Subjects will receive 
1 cycle at the 150 mg dose and then step-up to the 180 mg dose for subsequent cycles 
(150/180 mg).  The DLT period will begin in Cycle 2 (the first cycle of dosing at the 
step-up dose level). 
 For the next cohort, 6 subjects will be dosed with continuous dosing of 180 mg (Table 4, 
Cohort 502) of Oprozomib ER Tablets and assessed for DLTs to determine safety of this 
dose level. 
 Further escalation will be based on the following: 
o If < 2 DLTs are observed in the continuous dosing cohort of 180 mg in Cycle 1, dose 
escalation may continue but will revert to step-up dosing (i.e., 150/210 mg, 
150/240 mg, etc.) unless an alternate RP2D has been determined by the CSRC and 
sponsor. 
o If > 2 DLTs are observed, further escalation will not be conducted. 
2/7 Schedule 
For the 2/7 once daily dosing schedule, Oprozomib ER Tablets will be introduced into 
subsequent cohorts where no subjects have been enrolled unless the MTD for continuous dosing 
for Oprozomib Tablets has been previously determined prior to the introduction of the new 
tablets.  One of the following 2 scenarios will be utilized to introduce Oprozomib ER Tablets 
into the dose escalation schema: 
 If the MTD for continuous dosing has not been established for Oprozomib Tablets, 
Oprozomib ER Tablets will be introduced at the next new dose level specified by the 
preexisting dose-escalation plan (Table 3).  Dose escalation will continue in 30 mg 
increments until the MTD for continuous dosing for Oprozomib ER Tablets is established as 
determined by the CSRC and sponsor. 


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 If the MTD for continuous dosing has been established with Oprozomib Tablets, Oprozomib 
ER Tablets will be introduced at the MTD in a cohort of 6 subjects (Table 5, Cohort 601).  
Escalation beyond this dose can only occur using step-up dosing as described below if there 
are < 2 DLTs in the 6 subjects in this cohort enrolled with Oprozomib ER Tablets as 
determined by the CSRC and sponsor. 
Once the MTD for continuous dosing for Oprozomib ER Tablets has been established, step-up 
dosing will be introduced into dose escalation.  Subsequent 2/7 cohorts will be dosed at the 
240 mg for 1 cycle then step-up to the dose level to be studied.  The rationale for this initial 
dose is based on safety and tolerability of this dose level in the current study, as no DLTs were 
observed in this cohort of 3 evaluable subjects at this dose level.  The 240 mg dose is 2 dose 
levels below the single agent MTD, which was found to be 300 mg in Study 2011-001.  
Determination of the MTD for step-up dosing will be evaluated in the following manner: 
 The first step-up dosing cohort will start with 1 cycle of 240 mg, and then starting with 
Cycle 2, subjects will step-up to the MTD from continuous dosing for subsequent 
cycles. 
 All subsequent cohorts will also begin dosing at 240 mg for 1 cycle and then will be 
escalated in Cycle 2 to the step-up dose level to be studied, by 30 mg increments until 
the MTD is defined with Oprozomib ER Tablets, unless an alternate R2PD is determined 
by the CSRC and the sponsor.  The DLT period will begin in Cycle 2 (the first cycle of 
dosing at the step-up dose level). 
Additional details regarding dose escalation can be found in the Cohort Management Plan. 
 


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Table 3: 
Dose-Escalation Schemes Using Oprozomib Tablets for 5 Consecutive Days 
Bimonthly and Using Oprozomib Tablets and Oprozomib Extended Release Tablets 
for 2 Consecutive Day Weekly Schedules 
Cohorts 
Oprozomib Daily Dose 
(mg) 
Dexamethasone Dose (mg) 
5 Consecutive Day 
Bimonthly Schedule 
2 Consecutive Day Weekly 
Schedule 
-301a 
-401a 
180 
20 
301 
401 
210 
20 
NA 
402 
240 
20 
NA 
403 
270 
20 
NA 
404 
300 
20 
NA 
403 
330 
20 
NA 
404b 
360 
20 
CSRC = Cohort Safety Review Committee; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; NA = not 
applicable. 
Note:  This table is for illustrative purposes. 
a If DLTs are observed in 2 or more subjects at the first dose level of 210 mg, dosing of Cohort -301 or -401 will proceed at 
180 mg, or a lower dose as agreed with the CSRC and sponsor, and may be expanded up to 6 evaluable subjects. 
b Additionally, subsequent cohorts of 3 subjects will continue to be enrolled with doses escalated by 30 mg until the MTD (the 
highest dose at which a DLT is observed in fewer than 2 of 6 evaluable subjects) is defined. 
Table 4: 
Dose-Escalation Schemes Using Oprozomib Extended Release Tablets:  
5 Consecutive Day Bimonthly Schedule 
5 Consecutive Day 
Bimonthly Schedule 
Oprozomib Daily 
Dose Cycle 1 (mg) 
Oprozomib Daily Dose to be 
Studied Cycles 2+ (mg) 
Dexamethasone 
Dose (mg) 
Step-up dosing with initial 1 cycle of 150 mg 
501a 
150 
180 
20 
Continuous dosing 
502 
180 
180 
20 
Step-up dosing with initial 1 cycle of 150 mg 
503 
150 
210 
20 
504 
150 
240 
20 
505 
150 
270 
20 
a Cohort will be dosed at 150 mg for 1 cycle and then increased to the step-up dose to be studied on Cycle 2 for the 5/14 
once-daily dosing schedule.  This is just an example and not meant to be all encompassing for further dose escalation beyond 
270 mg.  Dose-limiting toxicity period will be 1 cycle (Cycle 1 for continuous dosing or Cycle 2 for step-up dosing). 
 


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Table 5: 
Dose-Escalation Schemes for Oprozomib Extended Release Tablets:  
2 Consecutive Day Weekly Schedule 
2 Consecutive Day 
Weekly Schedule 
Oprozomib Daily 
Dose Cycle 1 (mg) 
Oprozomib Daily Dose to 
be Studied Cycles 2+ (mg) 
Dexamethasone 
Dose (mg) 
Cohort for continuous dosing 
601 Repeat at continuous dosing 
MTDb unless MTD achieved 
with OPZ ER Tablets 
MTD 
MTDb 
20 
Step-up dosing with initial 1 cycle 240 mga 
602 
240 
MTDb 
20 
603 
240 
MTDb + 30 
20 
604 
240 
MTDb + 60 
20 
605 
240 
MTDb + 90 
20 
a Cohorts will be dosed at 240 mg for 1 cycle and then increased to the step-up dose to be studied on Cycle 2 for the 2/7 
once-daily dosing schedule.  Dose-limiting toxicity period will be 1 cycle (Cycle 1 for continuous dosing or Cycle 2 for 
step-up dosing). 
b MTD for continuous dosing is to be determined. 
3.1.3 
PHASE 2 PORTION 
The purpose of the Phase 2 portion of the study is to evaluate the safety, tolerability, and activity 
of oprozomib.  The activity of the recommended Phase 2 dose will be determined for 1 or both 
treatment schedules (Days 1, 2, 8, and 9, and Days 1–5 of 14-day treatment schedules).  In 
addition, the PK, PDn, proteomic biomarkers, and (optionally) genomic biomarkers will also be 
evaluated in this study. 
3.2 
NUMBER OF CENTERS 
Approximately 12 sites in the US and 4 sites in France will be recruited for participation in the 
protocol.  Sites that do not enroll subjects within 6 months of site initiation may be terminated. 
3.3 
NUMBER OF SUBJECTS 
The total number of subjects planned for this study is approximately 140 relapsed and/or 
refractory multiple myeloma subjects. 
3.3.1 
PHASE 1B PORTION 
For the Phase 1b portion of the study, it is estimated that approximately 60 evaluable subjects 
(30 for the 2/7 once-daily dosing schedule and 30 for the 5/14 once-daily dosing treatment 


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schedule) will be required to determine the recommended Phase 2 dose for each treatment 
schedule.  This is based on an estimate that approximately 5 cohorts will be enrolled per 
treatment schedule, with up to 6 evaluable subjects per cohort. 
3.3.2 
PHASE 2 PORTION 
Approximately 40 subjects will be enrolled per schedule in the Phase 2 portion of the study. 
3.4 
ESTIMATED STUDY DURATION 
The total study duration is expected to be approximately 36 months.  Approximately 22 to 
26 months may be required to enroll all subjects (4–8 months to enroll Phase 1b subjects with 
the Oprozomib Tablets, 4–8 months to enroll Phase 1b subjects with the Oprozomib ER Tablets, 
and 10–12 months to enroll Phase 2 subjects).  Subjects will be treated in 14-day cycles until 
disease progression, unacceptable toxicity, or study treatment discontinuation for any reason (see 
Section 8); responding subjects (SD or better) may continue on treatment. 
Subjects who continue on treatment and whose disease has not progressed 6 months after 
starting study treatment will reduce the frequency of their visits (on Day 1 of their next 
scheduled cycle) to every 4 weeks instead of every 2 weeks, with adequate drug supply for 
2 cycles of treatment starting with Cycle 13.  Disease response will be assessed every 8 weeks 
(4 cycles) after 1 year (26 cycles) on therapy. 
Subjects must complete a visit approximately 4 weeks after the last cycle of treatment to allow 
for safety follow-up within 30 days after the last dose of oprozomib. 
For subjects who discontinue treatment for reasons other than progression, disease assessments 
will no longer be required under protocol amendment 4. 


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4. 
PATIENT SELECTION 
The study population will consist of multiple myeloma patients requiring therapy who have 
relapsed and/or are refractory to their last therapy and have been treated with at least 1, but not 
more than 5, lines of multiple myeloma therapy.  Prior therapy must have consisted of at least 
1 regimen that included lenalidomide and/or bortezomib.  Patients should be considered to be 
appropriate candidates for a clinical study by their treating physicians. 
 Relapsed patients must have previously achieved ≥ MR on at least 1 line of therapy as 
assessed by the treating physicians. 
 Refractory patients are allowed, but it is not required that patients be refractory to their 
last therapy. 
 Primary refractory patients are allowed in the Phase 1b portion of the study only.  
The following definitions will be used to classify multiple myeloma disease state: 
 Refractory multiple myeloma:  Disease that is nonresponsive while on primary or salvage 
therapy or progresses within 60 days of last therapy.  Nonresponsive disease is defined 
as either failure to achieve minimal response (MR) or development of progressive disease 
(PD) while on therapy. 
 Relapsed and refractory myeloma:  Disease that is nonresponsive while on salvage 
therapy, or progresses within 60 days of last therapy in patients who have achieved MR or 
better at some point previously before progressing in their disease course. 
 Primary refractory myeloma:  Disease that is nonresponsive in patients who have never 
achieved an MR or better with any therapy.  It includes patients who never achieve MR or 
better in whom there is no significant change in M-protein and no evidence of clinical 
progression, as well as primary refractory PD where patients meet criteria for true PD. 
 Relapsed multiple myeloma:  Previously treated myeloma that progresses and requires 
the initiation of salvage therapy but does not meet the criteria for either “primary 
refractory myeloma” or “relapsed-and-refractory myeloma.” 
4.1 
INCLUSION CRITERIA 
1. Diagnosis of multiple myeloma with measureable disease as indicated by 1 or more of 
the following: 
a. Serum M-protein ≥ 500 mg/dL 
b. Urine M-protein ≥ 200 mg/24 hour 
c. Only for subjects without measurable serum and urine M-protein, serum free light 
chain:  Involved free light chain (FLC) level ≥ 10 mg/dL, provided serum FLC 
ratio is abnormal 
2. Patients requiring therapy who have relapsed and/or are refractory to their last therapy 
and have been treated with at least 1, but not more than 5, lines of multiple myeloma 


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therapy.  Prior therapy must consist of at least 1 regimen that included lenalidomide 
and/or bortezomib.  Patients should be considered to be appropriate candidates for a 
clinical study by their treating physicians.  Relapsed patients must have previously 
achieved ≥ MR on at least 1 line of therapy as assessed by the treating physician.  
Refractory patients are allowed, but it is not required that patients be refractory to their 
last therapy.  Primary refractory patients are allowed in the Phase 1b portion of the 
study only. 
3. Males and females ≥ 18 years of age 
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2 
5. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal (ULN) 
in the absence of Gilbert’s disease or hemolysis, aspartate aminotransferase (AST) 
≤ 3 times ULN, and alanine aminotransferase (ALT) ≤ 3 times ULN 
6. Absolute neutrophil count (ANC) ≥ 1000 cells/mcL, hemoglobin ≥ 7.0 g/dL, and 
platelet count ≥ 30,000 cells/mcL: 
a. Patients must not have received platelet transfusions for at least 1 week prior to 
Screening. 
b. Screening ANC must be independent of granulocyte colony-stimulating factor 
(G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) 
support for at least 1 week and of pegylated G-CSF for ≥ 2 weeks prior to first 
dose. 
c. Patients may receive red blood cell (RBC) transfusions or receive supportive care 
with erythropoietin or darbepoetin in accordance with institutional guidelines. 
7. Calculated or measured creatinine clearance (CrCl) rate of ≥ 30 mL/min calculated 
using the formula of Cockcroft and Gault [(140 − age) × mass (kg) / (72 × serum 
creatinine mg/dL)].  Multiply result by 0.85 if female. 
8. Uric acid, if elevated, must be corrected to within laboratory normal range before 
dosing 
9. Patients must sign written informed consent form (ICF) in accordance with federal, 
local, and institutional guidelines 
10. Female patients of childbearing potential must have a negative serum or urine 
pregnancy test within 3 days prior to receiving the first dose and agree to use effective 
methods of contraception during the study and for 3 months following the last dose of 
study drug.  Postmenopausal females (> 45 years old and without menses for > 1 year) 
and surgically sterilized females are exempt from these requirements.  Male patients 
must use an effective barrier method of contraception during the study and for 
3 months following the last dose if sexually active with a female of childbearing 
potential. 


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11. Prior carfilzomib is not required but is allowed if a patient had at least 2 cycles of 
carfilzomib alone or in combination with a dose of at least 20/27 mg/m2, as long as the 
patient: 
a. Had at least a partial response to prior carfilzomib therapy 
b. Was not removed from carfilzomib therapy due to toxicity, unless approved by the 
medical monitor 
c. Was not removed from carfilzomib therapy for progressive disease nor 
experienced progressive disease within 6 months after any prior carfilzomib 
therapy. 
4.2 
EXCLUSION CRITERIA 
1. Radiation therapy within 2 weeks prior to first dose; localized radiation therapy within 
1 week prior to first dose 
2. Immunotherapy/standard myeloma therapy within 2 weeks prior to first dose (except 
for antibody therapy, where 6 weeks is required, and alkylator therapy, where 
3 weeks is required); prior stem cell transplant (SCT) therapy (autologous SCT within 
the prior 8 weeks; allogeneic SCT within the prior 16 weeks).  Patients with prior 
allogeneic SCT should not have evidence of moderate to severe graft-versus-host 
disease (GvHD), as defined in Filipovich (2005) 
3. Plasmapheresis is not permitted at any time during the Screening period or while the 
subject is receiving study treatment.  If a subject has started screening procedures 
requiring plasmapheresis, or is anticipated to require plasmapheresis during or after the 
Screening period, this patient will be considered ineligible and should not be enrolled. 
4. Glucocorticoid therapy within 14 days prior to enrollment that exceeds a cumulative 
dose of 160 mg of dexamethasone or equivalent 
5. Participation in an investigational therapeutic study within 3 weeks prior to first dose 
6. Prior oprozomib exposure 
7. Known hypersensitivity/toxicity or intolerance to dexamethasone 
8. Major surgery within 3 weeks prior to first dose 
9. Congestive heart failure ([CHF] New York Heart Association Class III to IV), 
symptomatic ischemia, conduction abnormalities uncontrolled by conventional 
intervention, or myocardial infarction within 6 months prior to first dose 
10. Uncontrolled hypertension or uncontrolled diabetes 
11. Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks 
prior to first dose 
12. Known or suspected human immunodeficiency virus (HIV) infection or patients who 
are HIV seropositive 


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13. Active hepatitis A, B, or C infection 
14. History of previous clinically significant GI bleed in the last 6 months prior to first 
dose 
15. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first 
dose 
16. Other malignancy within the past 3 years with the exception of adequately treated basal 
cell carcinoma of the skin, squamous cell skin cancer, thyroid cancer, carcinoma in situ 
of the cervix, carcinoma in situ of the breast, prostate cancer of Gleason Score 6 or less 
with stable prostate specific antigen levels, or cancer considered cured by surgical 
resection 
17. Plasma cell leukemia 
18. Female patients who are pregnant or nursing 
19. Inability to swallow medication, inability or unwillingness to comply with the drug 
administration requirements, or GI condition that could interfere with the oral 
absorption or tolerance of treatment 
20. Any contraindication to oral hydration (e.g., significant preexisting comorbidity or 
fluid restriction) 
21. Any clinically significant psychiatric or medical condition that, in the opinion of the 
investigator, could increase patient risk or interfere with protocol adherence or a 
patient’s ability to give informed consent 
5. 
SUBJECT ENROLLMENT 
The Screening period for a particular subject commences after the subject signs the ICF.  The 
ICF must be signed before any study-specific tests may be performed.  Every subject who signs 
an ICF will be assigned a study number. 
After a subject has been screened and has successfully fulfilled all eligibility criteria, the site 
representative will submit the completed Inclusion/Exclusion Checklist to the Sponsor.  Please 
see the Study Reference Manual for contact information. 
Each subject will be assigned a study- and site-specific sequential number by the site staff.  
This number will be used to identify each subject throughout the clinical study and will be used 
on all study documentation related to that subject. 
Documentation must include start and stop dates for prior treatment.  Disease progression must 
be documented with appropriate disease assessment parameters.  Copies of all Screening 


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laboratory results are required. 
Subjects who initially fail Screening but subsequently become eligible may still be enrolled in 
the study. 
Sites that do not enroll a single subject within the first 6 months of initiating the study may be 
terminated at the discretion of the sponsor. 
6. 
TREATMENT PROCEDURES 
6.1 
DRUG ADMINISTRATION 
Oprozomib Tablets will be supplied containing 60, 90, or 120 mg of oprozomib.  Oprozomib 
ER Tablets will be supplied containing 150, 180, 210, 240, or 270 mg of oprozomib.  Both types 
of tablets will be administered in single daily doses (Table 3, Table 4, and Table 5).  Refer to the 
Pharmacy Manual for handling, administration, and storage instructions. 
Oprozomib will be administered orally, once daily, on either the 5 consecutive day bimonthly 
schedule or the 2 consecutive day weekly schedule for each 14-day treatment cycle (Figure 1), 
either at the single-dose level (i.e., continuous dosing) or step-up dose level, and the treatments 
will be repeated until disease progression, unacceptable toxicity, or study treatment 
discontinuation for any reason (see Section 8).  Oprozomib will be administered in combination 
with dexamethasone at 20 mg orally (or intravenously, if tablets are unavailable or subject 
cannot tolerate tablets) on Days 1, 2, 8, and 9 for both treatment schedules.  On oprozomib 
dosing days (i.e., on Days 1 and 2 for both schedules and Days 8 and 9 for the 2 consecutive day 
weekly schedule), dexamethasone must be taken at least 30 minutes prior to oprozomib.  On 
days in which PK sampling is taken after a dose, oprozomib must be taken in the fasted state (at 
least 2 hours after a meal and fasting for at least 2 hours after dosing).  On all other days, 
including non-PK days and days in which only a predose PK sample is taken, it is recommended 
that oprozomib is administered with food (i.e., within approximately 30 minutes after eating). 
Subjects may be premedicated pro re nata (as needed [PRN]) with a 5-hydroxytryptamine type-3 
(5-HT3) inhibitor, such as ondansetron or granisetron, before administration of the first dose of 
oprozomib each day and around the clock.  Procedures for dose reductions and adjustments are 
summarized in Section 6.4. 


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In the Phase 1b portion, subjects will be dosed in treatment cohorts in escalating order (see 
Section 3.1.2: Table 3, Table 4, and Table 5 for doses/cohorts, and see Section 6.2 for methods 
of dose escalation to the MTD), as determined by the CSRC and sponsor, only after the safety of 
the previous dose level has been established or until an MTD has been determined. 
In the Phase 2 portion, subjects will be dosed at the recommended Phase 2 dose, as defined in 
the Phase 1b portion of the study (see Section 3.1.2: Table 3, Table 4, and Table 5 for 
doses/cohorts, and see Section 6.2 for methods of dose escalation to the MTD). 
6.1.1 
SWITCHING TO OPROZOMIB ER TABLETS FROM OPROZOMIB 
TABLETS 
When subjects on Oprozomib Tablets switch to the Oprozomib ER Tablets, additional PK 
assessment will be obtained before and after changing formulations (Section 7.4.1). 
6.2 
PHASE 1B 
6.2.1 
SAFETY CONSIDERATIONS FOR PHASE 1B 
Treatment cohorts will be dosed in escalating order (see Section 3.1.2: Table 3, Table 4, and 
Table 5) as determined by the CSRC and sponsor, only after the safety of the previous dose 
level has been established or until an MTD has been determined; de-escalation may be 
performed after the MTD is exceeded and for individual subjects based on tolerability. 
Subsequent cohorts may initiate treatment at the starting dose (of 150 mg for 5/14 or 240 mg for 
2/7) but will not be dosed at the step-up dose to be studied until safety data are obtained from at 
least 3 evaluable subjects in the previous cohort at the step-up dose for Cycle 2.  Rules for dose 
escalation are presented in Section 6.2.2.  Safety will be evaluated based on the incidence, 
relatedness, and severity of AEs, clinical laboratory test results, electrocardiograms (ECGs), and 
other relevant clinical findings as provided by the investigators.  A review of safety data for each 
cohort will be conducted by the CSRC and sponsor when all of the above data are available. 
The CSRC, which comprisesthe Sponsor’s medical monitor,the Sponsor’s drug safety 
representative, and the investigators, will review all clinical and laboratory data and must agree 
whether dose escalation to the next cohort is appropriate.  As PK data from each treatment 
cohort become available, they may also be reviewed by the CSRC.  All available clinical data 


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will be considered for dose-escalation decisions. 
6.2.2 
DOSE-ESCALATION RULES 
The planned and contingent dose levels are provided in Section 3.1.2 (Table 3, Table 4, and 
Table 5), and dose escalation rules are provided in Table 6.  Additional details can be found 
in the Cohort Management Plan. 
Table 6: 
Dose-Escalation Rules 
No. of Evaluable Subjects with 
Treatment-related DLT at a 
Given Dose Level 
Dose Escalation Rules 
0 of 3 
Next cohort of 3 subjects treated at the next planned higher dose level. 
1 of 3 
Up to 3 more subjects are treated at that same dose level. 
≥ 2 of 3 
Dose escalation stops.  Three more subjects will be added to the next lower dose 
level, unless 6 subjects have already been treated at that dose level. 
1 of 6 
Next cohort of 3 subjects treated at the next planned higher dose level. 
≥ 2 of 6 
Dose escalation stops.  Additional subjects may be treated at the next lower dose 
level, for a minimum of 6 subjects treated at that dose level. 
Highest dose with < 2 of 6 
Maximum tolerated dose 
Source:  Modified from Simon 1997.  
DLT = Dose-limiting toxicity. 
Intrasubject dose escalation to the recommended Phase 2 dose may be permitted once that dose 
has been determined and after discussion between the treating physician and the Sponsor 
medical monitor. 
6.3 
DOSE-LIMITING TOXICITY 
Subjects will be evaluated for DLT according to the NCI-CTCAE (Version 4.03).  Subjects with 
SD or better may continue treatment. 
During the Phase 1b portion, assessment of DLTs will occur during the first 14 days of 
treatment with continuous dosing (Cycle 1) or during the first 14 days of treatment with the 
step-up dose to be studied during the 2-week assessment period (Cycle 2).  Any subject who 
develops a DLT during the assessment period after receiving at least 1 dose of oprozomib in the 


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assessment period will be considered evaluable.  Any subject who does not develop a DLT, but 
has not received all planned doses of oprozomib and dexamethasone, will be considered 
unevaluable and will be replaced. 
Guidelines for withholding study treatment, including treatment delays, reintroduction, and 
discontinuation, are described in Section 6.4.1.  “Study drug-related” is defined as a reasonable 
likelihood of clinical causality based on time of event, biology, and dechallenge improvement, 
and that the AE was not likely explained by the subject’s clinical state, underlying disease, 
concomitant medication, or study/nonstudy procedure.  For the purposes of this study, a DLT is 
defined as any of the following treatment-related events occurring in the first 14 days of 
treatment, with treatment at the dose to be studied (i.e., Cycle 1 for continuous dosing or 
Cycle 2 for step-up dosing): 
Any ≥ Grade 3 nonhematologic AE, with the following exceptions or qualifications: 
 ≥ Grade 4 abnormalities in serum creatinine or electrolytes will be considered a DLT. 
 ≥ Grade 3 acute kidney injury, defined as serum creatinine > 3 × baseline or 
> 4.0 mg/dL of any duration will be considered a DLT. 
 Grade 3 nausea, vomiting, diarrhea, or constipation will be considered a DLT only if lasting 
for > 7 days despite optimal supportive care, including (at a minimum) a 5-HT3 antagonist 
and aprepitant or fosaprepitant for nausea and vomiting, and loperamide (e.g., Imodium), and 
diphenoxylate/atropine (e.g., Lomotil) for diarrhea. 
 Grade 3 fatigue lasting > 14 days will be considered a DLT. 
 Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours will not be considered 
a DLT. 
 ≥ Grade 3 dexamethasone-related toxicities will not be considered DLTs. 
Any of the following hematologic AEs will be considered a DLT: 
 Grade 4 neutropenia:  ANC < 500 cells/mcL lasting ≥ 7 days 
 Febrile neutropenia:  Any single temperature ≥ 38.3°C or a sustained temperature of 
≥ 38.0°C for over 1 hour with ≥ Grade 3 neutropenia (ANC < 1000 cells/mcL) 
 Grade 3/4 thrombocytopenia 
o Grade 3 thrombocytopenia of any duration with Grade 2 bleeding or requiring platelet 
transfusion 
o Grade 4 lasting ≥ 7 days 


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o Grade 4 lasting < 7 days with Grade 2 bleeding, or if platelet counts are lower than 
10,000 cells/mcL, requiring a platelet transfusion 
Note:  The following will not be considered a DLT: 
 Grade 4 anemia 
 Grade 4 thrombocytopenia lasting < 7 days with platelet counts above 10,000 cells/mcL 
without clinically significant bleeding and with or without transfusion 
6.4 
DOSE REDUCTIONS/ADJUSTMENTS 
6.4.1 
OPROZOMIB DOSING DELAYS, MODIFICATIONS, AND 
REINTRODUCTION 
The dose of oprozomib should be held and/or reduced according to the guidelines described 
below.  Dose reduction should be continued until resolution of toxicity (per Table 6 and 
Table 7).  Subjects having severe toxicity will be allowed 3 dose reductions in 30 mg increments 
to a maximum reduction of 90 mg with a minimum dose of 150 mg.  A final dose reduction will 
be managed by reducing dose intensity by schedule, if fewer than 3 dose reductions have 
occurred and subjects are currently dosed at 150 mg. 
 Subjects on the 5/14 schedule who have had fewer than 3 reductions down to a dose of 
150 mg may reduce the intensity on the next reduction by changing from 5 to 3 consecutive 
days for every 14-day cycle. 
 Subjects on the 2/7 schedule who have had fewer than 3 reductions down to a dose of 
150 mg may reduce the intensity on the next reduction by changing from 2 consecutive 
doses to 1 day weekly for every 14-day cycle. 
 Exceptions to the dose modification guidelines are permitted after written approval from the 
Sponsor study medical monitor. 
6.4.1.1 
Dose Modification for Hematologic Toxicities 
Table 7 summarizes hematologic toxicities and oprozomib dosing actions that should occur in 
the event of toxicities. 


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Table 7: 
Guidelines for Dose Modification for Hematologic Toxicities 
Toxicity 
Oprozomib Dosing Action 
ANC ≥ 500 cells/mcL 
Continue at full dose 
ANC < 500 cells/mcL for less than 7 days 
Hold dose.  When ANC ≥ 500 cells/mcL, resume at 
full dose. 
ANC < 500 cells/mcL for 7 days or longer 
Hold dose.  When ANC > 500 cells/mcL, resume at 
1 dose decrement. 
Grade 3 febrile neutropenia 
Hold dose.  When ANC ≥ 1000 cells/mcL and fever has 
resolved, resume at 1 dose decrement. 
Platelet count < 50,000 cells/mcL and ≥ 25,000 
cells/mcL without evidence of bleeding 
Continue at full dose 
Platelet count < 50,000 cells/mcL and ≥ 25,000 
cells/mcL with evidence of bleeding 
Hold dose.  When platelet count returns to > 50,000 
cells/mcL and bleeding stops, resume at 1 dose decrement. 
Platelet count < 25,000 cells/mcL for < 7 days 
without evidence of bleeding 
Hold dose.  When platelet count ≥ 25,000 cells/mcL, 
resume at full dose. 
Platelet count < 25,000 cells/mcL for ≥ 7 days with 
or without evidence of bleeding 
Hold dose.  When platelet count ≥ 25,000 cells/mcL, 
resume at 1 dose decrement. 
ANC = absolute neutrophil count. 
Additional guidance regarding hematologic toxicities and dosing actions is as follows: 
 Non-treatment-related events:  If the toxicity resolves to ≤ Grade 1 or baseline and the 
toxicity is not treatment related, oprozomib may be restarted at the same dose level. 
 If required by continued or recurrent toxicity, a second or third dose reduction may be 
permitted down to a minimum dose of 150 mg after discussion with the Sponsor medical 
monitor.  If the subject has not had 3 reductions but is at a dose level of 150 mg, an 
additional reduction may occur via reducing dose intensity (see Section 6.4.1).  No more than 
3 dose reductions will be permitted in an individual subject on study; if toxicity continues, 
the subject should be removed from the study. 
 If the subject tolerates the reduced dose for 1 cycle, the subject’s dose may be escalated to 
the dose prior to the dose reduction. 
 If there is no resolution of toxicity after 2 weeks of withholding treatment (up to 3 weeks if 
an infection is being treated), the subject will be discontinued from the study. 
6.4.1.2 
Dose Reduction for Nonhematologic Toxicities 
Table 8 summarizes nonhematologic toxicities and oprozomib dosing actions that should 
occur in the event of toxicities. 


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Table 8: 
Guidelines for Dose Modification for Nonhematologic Toxicities 
Toxicity 
Oprozomib Dosing Action 
Tumor Lysis Syndrome, defined as abnormalities in at 
least 3 of the following 4 categories: 
(1) Increase in creatinine, uric acid, phosphate 
of ≥ 50% 
(2) Increase in potassium of ≥ 30% 
(3) Decrease in calcium of ≥ 20%, or 
(4) Increase in LDH ≥ 2-fold from baseline 
Hold oprozomib until all abnormalities in serum 
chemistries have resolved to baseline, then resume 
at full doses. 
Grade 3 nonhematologic toxicity 
Hold dose until toxicity resolved to ≤ Grade 1 or has 
returned to baseline.  Resume study drug at 1 dose 
decrement. 
Grade 4 nonhematologic toxicity 
Discontinue dosing. 
Grade 2 neuropathy with pain or 
≥ Grade 3 neuropathy 
Hold dose until toxicity resolved to ≤ Grade 1 or has 
returned to baseline.  Resume study drug at 1 dose 
decrement. 
Grade 3 nausea, vomiting, diarrhea and/or constipation 
without optimal supportive care 
Continue dosing, but administer optimal 
supportive care. 
Grade 3 nausea, vomiting, diarrhea and/or 
constipation with optimal supportive care 
Hold dose until toxicity resolved to ≤ Grade 1 or has 
returned to baseline.  Resume study drug at 1 dose 
decrement. 
Grade 3 fatigue lasting < 14 days 
Continue dosing. 
Grade 3 fatigue lasting ≥ 14 days 
Hold dose until toxicity has resolved to ≤ Grade 1 or has 
returned to baseline.  Resume study drug at 1 dose 
decrement. 
Grade 1 or 2 GI hemorrhage 
DELAY until Grade 0 
DECREASE one dose level for Grade 2 
Grades 3 or 4 GI hemorrhage 
Discontinue dosing 
GI = gastrointestinal; LDH = lactate dehydrogenase. 
Additional guidance regarding nonhematologic toxicities and dosing actions is as follows: 
 Non-treatment-related events:  If the toxicity resolves to ≤ Grade 1 or baseline and the 
toxicity is not treatment-related, oprozomib may be restarted at the same dose level. 
 If required by continued or recurrent toxicity, a second or third dose reduction down to a 
minimum of 150 mg may be permitted after discussion with the Sponsor medical 
monitor.  If the subject has not had 3 reductions but is at a dose level of 150 mg, an 
additional reduction may occur via reducing dose intensity (see Section 6.4.1).  No 
more than 3 dose reductions will be permitted in an individual subject on study; if 
toxicity continues, the subject should be removed from the study. 
 If the subject tolerates the reduced dose for 1 cycle, the subject’s dose may be escalated 


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to the dose prior to the dose reduction. 
 If there is no resolution of toxicity after 2 weeks of withholding treatment (up to 3 weeks 
for infection treatment), the subject will be discontinued from the study. 
 Subjects with Grade 3 or 4 GI hemorrhage should not be rechallenged.  Oprozomib 
should be permanently discontinued.  Endoscopy should be considered for all subjects 
who develop GI hemorrhage. 
6.4.1.3 
Infections 
Subjects with active systemic infections of any kind should have dosing withheld until the 
infection has resolved.  After the infection has resolved, treatment may continue at the original 
dose.  If there is no resolution of infection after 3 weeks, the subject will be discontinued from 
the study. 
6.4.1.4 
Congestive Heart Failure 
Acute development or exacerbation of CHF or new onset of decreased left ventricular ejection 
fraction in a subject (as defined by an increase of NCI-CTCAE ≥ 1 grade from baseline), 
whether or not drug related, requires withholding of the dose until resolution.  After the CHF has 
resolved or returned to baseline, treatment may continue at a dose reduced by 30 mg, with the 
approval of the Sponsor medical monitor, or the subject may be discontinued from the study.  If 
there is no resolution of CHF after 2 weeks, the subject will be discontinued from the study. 
6.4.1.5 
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Oprozomib does not need to 
be held or dose reduced in the following cases: 
 Grade 3 nausea, vomiting, constipation, or diarrhea (unless persisting despite optimal 
treatment with antiemetics or antidiarrheals) 
 Grade 3 fatigue (unless persisting for > 14 days) 
 Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours 
6.4.1.6 
Dosing Delays 
Dosing delays are not permitted in the DLT assessment period.  If the timing of later cycles must 
be adjusted for reasons unrelated to toxicity (e.g., holidays or subject requests), the cycle must 
be started no sooner than 1 day before or no later than 14 days after the originally scheduled 


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next cycle, unless permission is granted by the medical monitor.  If subjects miss more than 
4 weeks of oprozomib, they will be restarted at 150 mg for the 5/14 schedule or 240 mg for the 
2/7 schedule using the step-up dose scheme with 1 cycle at the dose level described for each 
schedule, and then step-up to their last dose level prior to the therapy hold.  Schedule 
adjustments may be made only at the beginning of each cycle; and adjustments may not be 
made mid-cycle.  If possible, future cycles should revert back to the original day of dosing for 
the schedule. 
6.4.2 
DEXAMETHASONE:  DOSING DELAYS, MODIFICATIONS, AND 
REINTRODUCTION 
Guidelines for dexamethasone dose modifications are summarized in Table 9.  In the event 
oprozomib is permanently discontinued, dexamethasone should also be discontinued (refer to 
Section 8). 
 


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Table 9: 
Treatment Guidelines for Dexamethasone-related Toxicity 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
Grades 1 and 2 (requiring 
medical management) 
Continue dexamethasone at same dose and treat with 
therapeutic doses of H2 blockers or proton pump inhibitor.  
May consider adding sucralfate or other anti-ulcer 
treatment as clinically indicated.  If symptoms persist 
despite above measures, decrease dexamethasone dose by 
1 dose level. 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
≥ Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement along with 
concurrent therapy with H2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite above measures, 
discontinue dexamethasone permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
General 
disorders 
Edema ≥ Grade 3 (≥ 30% 
limb discrepancy in volume; 
gross deviation from normal 
anatomic contour; limiting 
self-care ADL) 
Hold dexamethasone until symptoms return to baseline.  
Give diuretics as needed, and restart dexamethasone at 
1 dose decrement; if edema persists despite above 
measures, decrease dose another level.  Discontinue 
dexamethasone permanently if symptoms persist despite 
second reduction. 
Psychiatric 
Disorders 
Confusion or mood alteration 
≥ Grade 2 (interfering with 
function ± interfering with 
ADL) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement.  If symptoms 
persist despite above measures, reduce by another dose 
decrement. 
Musculoskeletal 
Muscle weakness ≥ Grade 2 
(symptomatic and interfering 
with function ± interfering 
with ADL) 
Hold dexamethasone until symptoms return to baseline.  
Restart dexamethasone at 1 dose decrement.  If weakness 
persists, decrease dose by 1 more dose level.  Discontinue 
dexamethasone permanently if symptoms persist. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ Grade 3 
(fasting glucose > 250 mg/dL) 
Hold dexamethasone until glucose is ≤ Grade 2 
(< 250 mg/dL) and treat with insulin or other hypoglycemic 
agents as needed.  If uncontrolled despite above measures, 
decrease dose by 1 dose level until ≤ Grade 2 (< 250 mg/dL) 
All Other 
Other nonhematologic 
toxicity ≥ Grade 3 considered 
related to dexamethasone 
Hold dexamethasone dose.  Resume at 1 dose decrement 
when toxicity has resolved to Grade 2 or less or to 
baseline.  If toxicity recurs, hold dexamethasone dose 
until toxicity has resolved to Grade 2 or less or to baseline, 
and resume dexamethasone dose by 1 more dose 
decrement.  If toxicity recurs despite 2 dose decrements, 
discontinue dexamethasone permanently. 
ADL = activities of daily living. 
Two dose-reduction levels are defined for dexamethasone, as illustrated in Table 10. 
Table 10: 
Dose Decrements for Dexamethasone 
Nominal Dose 
Reduced Dexamethasone Doses 
Dose -1 
Dose -2 
20 mg 
12 mg 
8 mg 


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Dexamethasone will be permanently discontinued after 2 dose reductions in the event of an 
additional dexamethasone-related DLT.  At the investigator’s discretion, dexamethasone 
dosing may be tapered prior to complete discontinuation, according to institutional practice.  If 
the dexamethasone dose is reduced during the previous cycle, the lower dose level will be 
continued on Day 1 of the new cycle.  If the reduced dose level is well tolerated for a complete 
cycle, the subject may, at the investigator’s discretion, be rechallenged at the start of the next 
cycle with the dose level given prior to the reduction.  If myeloma treatment doses of 
dexamethasone as noted in Table 9 are discontinued, antiemetic doses of dexamethasone, 
generally considered to be 4 mg on the days of dosing, may be continued if tolerable per 
investigator discretion. 
6.4.3 
MISSED DOSES 
Subjects must receive all planned doses in the DLT assessment period in order to be assessed for 
DLT in Phase 1.  Planned doses that are missed can be made up if they are received within the 
same calendar day of scheduled administration.  If a subject misses more than 2 consecutive 
cycles after completing the DLT assessment period for reasons other than toxicity, the subject 
will be discontinued unless it is determined that the subject was benefiting from therapy and that 
the medical monitor permits the subject to resume therapy.  See Section 6.4.1.6 for information 
on cycle delays. 
6.5 
SAFETY GUIDANCE FOR INVESTIGATORS 
Based on the experience in nonclinical studies of oprozomib and available Phase 1 clinical data 
in subjects with solid tumors and hematologic malignancies, the following guidance is 
recommended but not mandated to investigators unless otherwise noted in the dose reduction 
guidelines: 
 Subjects with active systemic infections of any kind should not be dosed with oprozomib 
until infection has resolved.  Subjects with neutrophil counts related to their infection of 
ANC < 500 cells/mcL should not be treated until the neutrophil count has recovered to 
> 1500 cells/mcL. 
 For platelet counts < 25,000 cells/mcL, oprozomib dosing should be held until platelet count 
is ≥ 25,000 cells/mcL independent of platelet transfusions for 1 week.  Consideration of 
dose reduction of oprozomib should be given if it is thought that oprozomib may have 
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 Subjects should have anemia corrected in accordance with the institutional guidelines, which 
can include transfusions or support with erythropoietin or darbepoetin. 
 Based on the high incidence of nausea and vomiting that has been observed to date, it is 
recommended that subjects treated with oprozomib receive prophylactic antiemetics that 
would typically be utilized to prevent nausea and vomiting prior to moderately to highly 
emetogenic therapies. 
 Prophylactic treatment for diarrhea is not recommended; however, subjects who experience 
diarrhea should be treated with antidiarrheals and may be given prophylaxis once they are 
known to have diarrhea related to administration of oprozomib. 
 Hypophosphatemia has been observed in a few subjects treated with oprozomib.  Severe 
hypophosphatemia has also been observed in subjects treated with other proteasome 
inhibitors, including carfilzomib (data on file), bortezomib (Messinger 2010), and MLN 
9708 (Richardson 2012).  This typically has been transient and not associated with clinical 
symptoms.  Subjects should be monitored carefully for electrolyte abnormalities, and 
electrolytes should be replaced as needed. 
 Cases of TLS have been observed with proteasome inhibitors, including oprozomib.  It is 
recommended that all subjects begin vigorous oral hydration (1.5–2.0 liters/day) the day 
before and on days of oprozomib dosing until instructed that the risk of TLS has abated.  
Allopurinol prophylaxis and close monitoring of fluid and electrolyte balance are 
recommended for subjects with renal functional impairment and for those with a high tumor 
burden.  For specific recommendations, see Section 6.6.1. 
 Gastrointestinal hemorrhage has been reported in subjects treated with oprozomib, including 
fatalities.  Subjects with Grades 3 and 4 GI hemorrhage should not be rechallenged with 
oprozomib and should be permanently discontinued.  Endoscopy should be considered for 
any subject developing GI hemorrhage. 
See Section 6.4.1 for additional information and recommendations for dose adjustments 
required for specific hematologic and nonhematologic toxicities. 
6.6 
CONCOMITANT MEDICATIONS 
Concomitant medications are defined as any prescription or over-the-counter preparations, 
including vitamins and supplements.  All concomitant medications taken by the subject from 
30 days before Day 1 until 30 days after the subject’s last dose of study drug must be recorded 
on the electronic case report form (eCRF). 
In vitro tests indicate that the time-dependent inhibitory effect of oprozomib on human 
cytochrome P450 3A (CYP3A) is weak (Kinact to KI was only 1.4 mL/min/mcmol).  However, as 
a precaution, concomitant use of drugs that are CYP3A substrates with narrow therapeutic range 
should be avoided within 2 weeks of Day 1 of Cycle 1 and during treatment with oprozomib.  


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Cytochrome P450 3A substrates with narrow therapeutic range refer to drugs whose exposure 
response indicates that increases in their exposure levels by the concomitant use of CYP3A 
inhibitors may lead to serious safety concerns.  Examples of sensitive CYP3A substrates with 
narrow therapeutic range can be found in Appendix G.  Investigators should consider switching 
to an alternative drug or be alert to the need for dose adjustment. 
Plasmapheresis is not permitted at any time during the Screening period or while the subject is 
receiving study treatment.  If a subject who has started screening procedures requires 
plasmapheresis or is anticipated to require plasmapheresis during or after the screening period, 
this patient will be considered a screen failure.  Subjects requiring plasmapheresis while on 
study treatment will discontinue study treatment and will enter Long-Term Follow-up for 
survival.  Subjects requiring plasmapheresis must have 2 serum samples (for serum protein 
electrophoresis [SPEP] and immunofixation) and at least one 24-hour urine sample (for urine 
protein electrophoresis [UPEP] and immunofixation) obtained prior to the procedure. 
6.6.1 
REQUIRED/RECOMMENDED CONCOMITANT 
MEDICATIONS/TREATMENTS 
Contraception 
Female subjects of childbearing potential must agree to use effective methods of contraception 
during the study and for 3 months following the last dose of drug.  Postmenopausal females 
(> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt.  
Male subjects must use an effective barrier method of contraception unless surgically sterile 
during the study and for 3 months following the last dose if sexually active with a female of 
childbearing potential. 
Nausea 
Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, 
prior to administration of the first dose of oprozomib each day and around the clock during the 
days of dosing, with additional doses throughout the cycle as needed to prevent and treat nausea.  
Additional antiemetics may be used if needed. 


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Shingles 
Valacyclovir or an equivalent antiviral is recommended for the duration of treatment to prevent 
herpes zoster (additional prophylaxis is at the investigator’s discretion). 
Acid-related Disorders 
Lansoprazole or other oral proton-pump inhibitor is required unless a subject has 
hypersensitivity or intolerance to proton-pump inhibitors for the duration of treatment to prevent 
peptic disease or other acid related GI toxicities. 
Tumor Lysis Syndrome 
Monitoring and Prophylaxis Guidelines:  Oral hydration of 1.5 to 2 liters per 24 hours should 
be instituted in all subjects 24 through 48 hours prior to initiation of therapy in every cycle and 
continued throughout days of oprozomib dosing.  Premedication with allopurinol or other 
approved uric acid-lowering agents is highly recommended for subjects with high tumor burden 
(i.e., for multiple myeloma:  International Staging System Stage II/III or rapidly increasing 
M-protein or light chains) or compromised renal function (CrCl < 50 cc/min).  These subjects 
may be at elevated risk for TLS and should be closely monitored.  Uric acid levels should be 
normalized prior to initiation of treatment, if appropriate. 
Subjects with laboratory abnormalities prior to dosing that are consistent with lysis of tumor 
cells should not receive the scheduled dose prior to institution of the aforementioned 
preventative measures.  Laboratory abnormalities include increases in serum creatinine 
> 50% over baseline, 2-fold increases of lactate dehydrogenase (LDH) above the ULN, uric acid 
increase above the ULN, phosphate > 50% increase about the ULN, potassium > 30% above the 
ULN, or decreases in serum calcium from baseline.  Subjects with such abnormalities should be 
re-evaluated as clinically indicated, and the medical monitor should be consulted if there are 
anticipated delays in treatment. 
Treatment Guidelines for TLS 
If TLS occurs, serial monitoring of cardiac rhythm, hydration status of the subject, and 


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laboratory assessments should be instituted.  Correction of electrolyte abnormalities, 
monitoring of renal function and fluid balance, and administration of therapeutic and supportive 
care, including dialysis, should be done as clinically indicated.  In the setting of TLS, 
oprozomib treatment will be interrupted until resolution of all clinical and laboratory therapeutic 
abnormalities consistent with TLS. 
All cases of TLS must be reported to the Sponsor as an SAE as outlined in the protocol. 
Orthostatic Hypotension 
Orthostatic hypotension has been reported in subjects taking oprozomib.  The following 
guidelines should be employed in the management of subjects exhibiting orthostatic 
hypotension.  Etiology should be sought, whether neurogenic, non-neurogenic or iatrogenic.  
Dose modifications should be taken in accordance with Table 5 and Table 6. 
 For those subjects with orthostatic hypotension who are taking antihypertensive 
medications, the subject’s dosage and use of antihypertensive agents should be 
evaluated and reassessed on an ongoing basis while on study. 
 Fluid intake should be assessed to confirm the subject is getting appropriate hydration 
in accordance with protocol requirements of six to eight, 8-ounce glasses of fluids in 
the 24 to 48 hours prior to dosing and on all days of oprozomib dosing. 
 Fluid status should be repleted to normal levels in subjects with orthostatic 
hypotension. 
 If protocol requirements for oral intake of fluids are already being met, additional 
measures should be taken to increase blood pressure as per investigator discretion, 
such as increased oral intake, fludrocortisone (Fluorinef) or midodrine or others 
depending on the etiology.  Holding the dose during toxicity and dose reduction upon 
resolution may be a consideration (see Table 7). 
 Ongoing monitoring of fluid status is warranted and should be managed per 
investigator discretion. 
 In addition, vital signs monitoring may be extended beyond the time periods specified 
in the Schedules of Assessments (Appendix A, Appendix B, Appendix C, and 
Appendix D). 
6.6.2 
ALLOWED CONCOMITANT MEDICATIONS 
Subjects may receive RBC or platelet transfusions, if clinically indicated, per institutional 
guidelines.  Subjects who require repeated platelet transfusion support should be discussed with 
the Sponsor medical monitor. 


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Subjects may receive erythropoietin or darbepoetin therapy, if clinically indicated, per 
institutional guidelines. 
Subjects may receive antiemetics, antidiarrheals, and/or laxatives as necessary. 
Colony-stimulating factors (e.g., G-CSF, GM-CSF) may be used if neutropenia occurs but 
should not be given prophylactically and should be administered only after the DLT assessment 
period in Phase 1b but anytime during the Phase 2 portion of the study. 
Palliative radiation therapy is permitted, if clinically indicated, in consultation with the Sponsor 
medical monitor. 
6.6.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with an approved or investigative anticancer therapeutic is not allowed. 
Glucocorticoid therapy that exceeds a cumulative dose of 160 mg of dexamethasone is not 
permitted within 14 days prior to enrollment.  During the study, glucocorticoid therapy (in 
addition to dexamethasone) is permitted only at the discretion of the medical monitor to treat a 
concurrent medical condition (e.g., asthma, inflammatory bowel disease, or as an antiemetic, 
etc.). 
7. 
STUDY TESTS AND OBSERVATIONS 
The Schedule of Assessments for subjects treated on Days 1 to 5 of a 14-day cycle is 
provided in Appendix A and Appendix B, and that for subjects treated on Days 1, 2, 8, and 
9 of a 14-day cycle is provided in Appendix C and Appendix D.  
For subjects with SD or better after at least 12 cycles of therapy who are on a steady dose for 
≥ 2 cycles and are tolerating oprozomib, study assessments may be performed every 4 cycles, 
and 4 cycles of study medication may be dispensed from the study site at a time starting with 
Cycle 13. 
7.1 
VITAL SIGNS ASSESSMENTS 
Vital sign measurements include orthostatic blood pressure, pulse rate, respiration rate, and 
temperature.  Subjects should lie down for approximately 5 minutes and then have blood 


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pressure and pulse rate measured consistently in 1 arm or the other.  This should be followed 
by having the subject stand and the blood pressure and pulse rate measurements should be 
repeated at 1 and 3 minutes.  Any drop of 20 mm/Hg systolic 10 mm/Hg diastolic, or 
lightheadedness/dizziness between supine and standing blood pressure measurements would 
indicate orthostatic hypotension.  Usually an increase in pulse rate of 10 beats/min is also 
associated with, but not required for, diagnosis of orthostatic hypotension.  If the subject has 
orthostatic hypotension, please see Section 6.6.1. 
7.2 
CENTRAL ECG ASSESSMENTS 
For the Phase 2 portion, assessment of QT/QTc interval will be done via central ECGs on 
10 subjects on each schedule. 
 12-lead ECGs will be serially recorded digitally and read centrally 
 On Cycle 1, Day 1, 12-lead ECG will be recorded in a supine position after 
5−10 minutes of rest at the following time points: 
o Within 15 minutes prior to oprozomib dose 
o 30 minutes after oprozomib dose 
o 1 hour, 2 hours, 4 hours, and 6 hours after oprozomib dose 
o Note that ECG data collection will occur within 5 minutes prior to the 
corresponding PK time points where appropriate. 
 The R to R interval (the interval from the beginning of one R wave to the beginning of 
the next; [RR]), PR, and the interval from the beginning of the Q wave to the beginning 
of the T wave (QT) intervals and beginning of the Q wave to the termination of the 
S wave, representing the time for ventricular depolarization (QRS) duration will be 
analyzed and QTc will be calculated using standard methods, including Fridericia’s 
formulas. 
Note:  If 1 schedule does not proceed to Phase 2, central ECGs should be performed on 
20 subjects assessed in the chosen schedule. 
7.3 
NEUROLOGIC ASSESSMENTS 
For neurologic assessments, the Brief Peripheral Neuropathy Screen (BPNS), which is included 
in Appendix J should be performed, and neurologic events should be evaluated according to the 
NCI-CTCAE grading (Version 4.03). 


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7.4 
PHARMACOKINETIC, PHARMACODYNAMIC, AND PROTEOMIC 
STUDIES 
Pharmacokinetic sampling time points are listed below for each treatment schedule and study 
phase.  See Appendix I for time points, and refer to the Laboratory Manual for collection 
volumes, processing, and shipping of PK samples.  At a minimum, the following PK parameters 
will be calculated:  Cmax, time to maximum plasma concentration (Tmax), and AUC. 
Pharmacodynamic and proteomic sampling time points are listed below for each treatment 
schedule and study phase.  See Appendix I for time points, and refer to the Laboratory Manual 
for collection volumes and processing and shipping of PDn and proteomic samples.  A 
fluorogenic substrate assay or enzyme-linked immunosorbent assay (ELISA) will be used to 
measure proteasome activity in whole blood and peripheral blood mononuclear cells (PBMCs).  
Global proteomic profiling using mass spectrometry will be conducted on plasma sample and 
isolated PBMCs taken prior to and after oprozomib administration and analyzed for changes in 
specific protein levels (e.g., cytokines). 
7.4.1 
PHASE 1B:  PHARMACOKINETIC STUDIES 
For the Phase 1b portion, PK samples will be collected at the following time points for both 
treatment schedules: 
Continuous Dosing Subjects: 
Cycles 1 and 2, Day 1 
 Predose 
 15 minutes postdose 
 30 minutes postdose 
 1 hour postdose 
 2 hours postdose 
 4 hours postdose 
 6 hours postdose 
 8 hours postdose 


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Cycle 1, Day 2 
 Predose 
Step-up Dosing Subjects: 
Cycles 1 and 2, Day 1 
 Predose 
 15 minutes postdose 
 30 minutes postdose 
 1 hour postdose 
 2 hours postdose 
 4 hours postdose 
 6 hours postdose 
 7 hours postdose 
Cycles 1 and 2, Day 2 
 Predose 
Samples must be taken within 5 minutes of intended collection times for 15- and 30-minute and 
1- and 2-hour time points and within 15 minutes thereafter.  Note:  Oprozomib must be taken in 
the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days 
in which PK sampling is taken after a dose.  On all other days including non-PK days and days 
in which only a predose PK sample is taken, it is recommended that oprozomib is administered 
with food (i.e., within approximately 30 minutes after eating).  Pharmacokinetic time points are 
also summarized in Appendix I, and blood volumes are detailed in the Laboratory Manual. 
Switching from Oprozomib Tablets to Oprozomib ER Tablets 
When subjects switch from Oprozomib Tablets to Oprozomib ER Tablets, intensive PK 
sampling should be obtained on Day 1 in the cycle prior to switching and on Day 1 of the 
following cycle (i.e., first day with Oprozomib ER Tablet) at the scheduled time points 
described above for step-up dosing subjects on Cycle 1, Day 1.  The time between the 2 days 
of PK collection for switching to the Oprozomib ER tablet will be 1 cycle or 14 days. 


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7.4.2 
PHASE 1B:  PHARMACODYNAMIC AND PROTEOMIC STUDIES  
Blood samples for PDn analyses will be drawn as described above, but no samples for 
proteomic analyses will be collected.  Samples must be taken within 15 minutes of intended 
collection time points between 4 and 8 hours postdose.  Pharmacodynamic and proteomic time 
points are also summarized in Appendix I, and blood volumes are detailed in the Laboratory 
Manual. 
 
Continuous Dosing Subjects: 
Cycles 1 and 2, Day 1 
 Predose 
 4 hours postdose 
 8 hours postdose 
Cycle 1, Day 2 
 Predose 
Step-up Dosing Subjects: 
Cycles 1 and 2, Day 1 
 Predose 
 4 hours postdose 
 6 hours postdose 
Cycles 1 and 2, Day 2 
 Predose 
7.4.3 
PHASE 2:  PHARMACOKINETIC STUDIES 
For the Phase 2 portion of the study, PK blood samples will be drawn from all subjects from the 
5 consecutive day bimonthly and 2 consecutive day weekly schedules at the following time 
points unless collection is discontinued at the sponsor’s discretion: 


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Cycles 1 and 2, Day 1 
 Predose 
 15 minutes postdose 
 30 minutes postdose 
 1 hour postdose 
 2 hours postdose 
 4 hours postdose 
 6 hours postdose 
 7 hours postdose 
Cycles 1 and 2, Day 2 
 Predose 
Samples on Cycle 1, Day 1 and Cycle 2, Day 1 must be taken within 5 minutes of intended 
collection time for 15-and 30-minute and 1- and 2-hour time points and within 15 minutes 
thereafter.  Note:  Oprozomib must be taken in the fasted state (at least 2 hours after a meal and 
fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On 
all other days including non-PK days and days in which only a predose PK sample is taken, it is 
recommended that oprozomib is administered with food (i.e., within approximately 30 minutes 
after eating).  Pharmacokinetic time points are detailed in Appendix I, and blood volumes are 
detailed in the Laboratory Manual.  Samples may also be used for biomarker assessment. 
7.4.4 
PHASE 2:  PHARMACODYNAMIC AND PROTEOMIC STUDIES 
For the Phase 2 portion of the study, PDn and proteomic samples will be collected from all 
subjects from the 5 consecutive day bimonthly and 2 consecutive day weekly schedules at the 
following time points unless collection is discontinued at the sponsor’s discretion: 
Oprozomib Administered Once Daily on the 5 consecutive day bimonthly schedule 
Cycles 1 and 2, Day 1 
 Predose 
 4 hours postdose 


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 6 hours postdose 
Cycles 1 and 2, Day 2 
 Predose 
Oprozomib Administered Once Daily on the 2 consecutive day weekly schedule 
Cycles 1 and 2, Day 1 
 Predose 
 4 hours postdose 
 6 hours postdose 
Cycles 1 and 2, Day 2 
 Predose 
Samples must be taken within 15 minutes of the intended collection time for 4- and 6-hour 
time points.  Pharmacodynamic and proteomic time points are also summarized in 
Appendix I and blood volumes are detailed in the Laboratory Manual. 
7.4.5 
GENOMIC EVALUATIONS 
Analysis of genetic and gene expression biomarkers that may potentially predict for response 
and resistance following treatment with proteasome inhibitors will be conducted on all subjects 
who consent to optional genomic biomarker analysis.  These analyses will be performed on 
baseline bone marrow aspirate (a portion of the bone marrow aspirate sample obtained at 
baseline will be used; no additional sample is required), blood, and saliva, as well as bone 
marrow aspirate at the time of progression. 
The schedule for genomic sampling is outlined in Appendix A for subjects treated on Days 1 to 
5 of the 14-day cycle and in Appendix B for subjects treated on Days 1, 2, 8, and 9 of the 14-day 
cycle. 
7.5 
LABORATORY EVALUATIONS FOR SAFETY 
The schedule for laboratory evaluations for safety is outlined in Appendix A and Appendix B 
for subjects treated on the Days 1–5 of the 14-day cycle treated and in Appendix C and 


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Appendix D for subjects treated on Days 1, 2, 8, and 9 of the 14-day cycle.  The laboratory 
tests included in the full chemistry panel are listed in Table 11. 
Table 11: 
Full Chemistry Panels 
Full Chemistry Panel 
Sodium 
Potassium 
Calcium 
Alkaline phosphatase 
Blood urea nitrogen 
Uric acid 
Lactate dehydrogenase 
Creatinine 
Chloride 
Bicarbonate 
Glucose 
Total protein 
Albumin 
Total bilirubin 
Alanine aminotransferase 
Aspartate aminotransferase 
Phosphorous 
Magnesium 
Calculate or measure creatinine clearance rate 
Source:  Appendix A, Appendix B, Appendix C, and Appendix D. 
The complete blood count (CBC) with differential includes the following:  hemoglobin, 
hematocrit, white blood cell (WBC) count with complete manual or automated differential (total 
neutrophils, lymphocytes, monocytes, eosinophils, basophils; absolute or percentage will be 
acceptable), RBC count, and platelet count. 
Coagulation tests include the following:  prothrombin time, activated partial thromboplastin 
time, and international normalized ratio. 
The pregnancy test can be performed using urine or serum and must be done within 3 days prior 
to first dose for females of childbearing potential. 


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7.6 
DISEASE RESPONSE ASSESSMENTS 
The schedules of disease assessments for subjects treated on either treatment schedule are 
provided in Appendix E.  Beginning with Cycle 3, assessments are to be completed every 
4 weeks for the first year while on study drug and then changed to every 8 weeks (4 cycles) after 
Cycle 26.  Subjects enrolled in the Phase 2 portion of the study will be evaluated for disease 
response following the IMWG-URC; evaluations will also include MR and nCR from EBMT 
criteria (Appendix F). 
Disease response will be assessed by the investigator. 
7.7 
ASSESSMENTS AT END OF STUDY TREATMENT OR EARLY 
DISCONTINUATION 
Early discontinuation and End-of-Study assessments must be performed any time within 30 days 
following the subject’s last administration of study drug and prior to initiation of any other 
treatment. 
For subjects who discontinue treatment for reasons other than progression, disease assessments 
will no longer be required under protocol Amendment 4. 
8. 
STUDY TREATMENT DISCONTINUATION 
Subjects may discontinue from the study at any time.  Subjects who discontinue from study 
treatment will be monitored for AEs for 30 days after the last dose of oprozomib.  In the 
Phase 1b portion of the study, additional subjects may be enrolled to replace discontinued 
subjects to reach the target population of MTD-evaluable subjects for each cohort. 
For the purposes of estimation of response rate, subjects who discontinue from study treatment 
before completing a full 14-day cycle (Cycle 1) at the dose or step-up dose to be studied 
(Cycle 2), do not receive all scheduled doses without a DLT, do not have evaluable disease at 
Screening, or do not complete a response assessment will be considered unevaluable. 
The Sponsor may elect to discontinue the study or either schedule at any time. 


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The investigator may remove a subject from study treatment for the following reasons: 
 Subject with disease progression 
 Subject with unacceptable toxicity 
 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 
 Female subject who becomes pregnant, in which case treatment must be immediately 
discontinued 
The Sponsor or designee must be notified within 24 hours if a subject is discontinued from 
study treatment. 
If the reason for discontinuation is the occurrence of an AE, the subject will be followed by the 
investigator until such event(s) resolve and/or stabilize, and according to the investigator’s 
judgment, there is no need for further follow-up.  The reason for discontinuation from study 
treatment will be documented on the eCRF. 
Additional subjects may be enrolled to account for subjects who have not had adequate safety 
or efficacy evaluations. 
9. 
ADVERSE EVENTS 
9.1 
ADVERSE EVENTS DEFINITIONS 
An AE is any untoward medical occurrence in a study subject administered an investigational 
product(s), regardless of the causal relationship with treatment. 
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 preexisting 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.  All reported AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA). 


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Laboratory findings should not be recorded as AEs unless corrective action is required (e.g., 
transfusions, initiation of antibiotics or treatment regimens, hydration) or the event is deemed 
clinically significant by the treating physician. 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be preexisting in nature and part of the 
subject’s medical history. 
An unexpected AE is any AE, the specificity or severity of which is not consistent with the 
current Investigator’s Brochure (IB) or prescribing information for a marketed compound; or 
that adds significant information on specificity or severity of a known, already-documented AE.  
For example, an event more specific or more severe than described in the Investigator’s 
Brochure would be considered “unexpected.” 
Whenever possible, the NCI-CTCAE (Version 4.03) should be used to describe the event and 
for assessing the severity of AEs (National Cancer Institute 2010).  The National Cancer 
Institute Common Terminology Criteria for Adverse Events does not use to the term 
“intermittent” and this term must not be used to describe AEs.  Any AEs representing a 
change in the NCI-CTCAE grade need to be reported on the AE eCRF.  For AEs not adequately 
addressed in the NCI-CTCAE, the table below (Table 12) may be used. 
Table 12: 
Adverse Event Severity Grades 
Severity 
Description 
GRADE 1 - Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
GRADE 2 - Moderate 
Minimal, local or noninvasive intervention indicated; limiting age- 
appropriate instrumental ADL 
GRADE 3 - Severe 
Medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
GRADE 4 - Life-threatening 
Life-threatening consequences; urgent intervention indicated 
GRADE 5 - Fatal 
Death related to AE 
ADL = activities of daily living; AE = adverse event. 


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9.2 
CAUSALITY 
The relationship of the AE to the study drug should be assessed using the following criteria: 
 Yes:  The event is suspected to be related if: 
o There is a clinically plausible time sequence between onset of the AE and 
administration of study treatment; and/or 
o There is a biologically plausible mechanism for the study treatment to cause or 
contribute to the AE; and/or 
o The event responds to withdrawal of the study medication (dechallenge) and/or 
recurs with rechallenge (when clinically feasible); and/or 
o The AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, 
or procedures 
 No:  The event is not suspected to be related if: 
o The AE is more likely to be explained by the subject’s clinical state, underlying 
disease, concomitant medication, study or non-study procedure; and/or 
o The time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
o The event is unlikely to be related to the investigational product(s) 
9.3 
ADVERSE EVENTS REPORTING PROCEDURES 
9.3.1 
GENERAL PROCEDURES 
All AEs (e.g., any new event or worsening in severity or frequency of a preexisting condition or 
laboratory finding) with an onset date after the subject signs consent for study participation must 
be promptly documented on the AE eCRF.  Details of the event must include severity, 
relationship to study drug, duration, action taken, and outcome.  Whenever possible, reporting 
specific diagnosis is preferred rather than individual signs or symptoms.  Serious adverse events 
will be recorded on the AE eCRF and on the SAE reporting form (see Section 9.5, Serious 
Adverse Event Reporting and Documentation Requirements). 
All AEs occurring from the time that the subject signs the ICF and through 30 days after the last 
administered dose of study drug will be reported, regardless of whether new chemotherapy 
regimens are initiated.  In addition, the investigator should report any AE that may occur after 
this time period that is believed to have a reasonable possibility of being associated with study 
drug.  If a subject discontinues the study prior to receiving any study drug, AEs must be 


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captured until it is documented that the subject fails to enroll in the study. 
All AEs that are considered related to study drug and all SAEs regardless of relationship to 
study drug must be followed to resolution or stabilization if improvement is not expected.  
Adverse events that completely resolve and then recur should be recorded as new AEs.  For 
subjects who complete the End-of-Study Assessment 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.  Adverse events continuing at 30 days after the last 
dose of study drug should have a comment in the source file by the investigator that the event 
has stabilized or is not expected to improve. 
The investigator is responsible for evaluating all AEs, obtaining supporting documents, and 
determining that documentation of the event is adequate.  The investigator may delegate these 
duties to subinvestigators and must ensure that these subinvestigators are qualified to perform 
these duties under the supervision of the investigator and that they are listed on the 
FDA Form 1572. 
9.3.2 
DISEASE PROGRESSION 
Signs and symptoms associated with disease progression will be reported as SAEs if the sign or 
symptom meets the seriousness criteria (e.g., death, hospitalization).  Signs and symptoms 
clearly associated with disease progression will be reported as AEs only if the event is 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 eCRF as an AE. 
All deaths that occur from the time that ICF is signed until 30 days after the last dose of study 
drug is administered are to be reported as SAEs (see Section 9.4).  Death due to disease 
progression in the absence of signs and symptoms should be reported as the primary 
tumor type (eg, metastatic, pancreatic cancer).  Note:  The term “disease progression” 
should not be used to describe the disease related event or adverse event.  Additional 
details of the event (such as the primary and contributory causes of death) should be reported on 
the Death eCRF. 


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Discontinuation of treatment due to either disease progression or deterioration of myeloma 
malignancy should be recorded on the Treatment Discontinuation eCRF as “Disease 
Progression.” 
9.4 
SERIOUS ADVERSE EVENTS DEFINITIONS 
An SAE is an event that meets 1 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; i.e., 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 any nonacute, 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 
 Is an important medical event 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 
9.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
Amgen Global Patient Safety must be notified within 24 hours of the investigator, designee, or 
site personnel knowledge of the event.  To report an SAE to Amgen Global Patient Safety, 
please refer to the SAE reporting guidelines below. 
The primary mechanism for reporting serious adverse events will be the electronic data 
capture system (EDC) via the Safety Report Form.  If the EDC system is unavailable for 
more than 24 hours, then the site will report the information to Amgen using an electronic 
Serious Adverse Contintency Report Form (see Appendix K) within 24 hours of the 
investigator’s knowledge of the event.  The site will enter the serious adverse event data 
into the electronic system as soon as it becomes available. 
After the study is completed at a given site, the EDC system will be taken offline to prevent 
the entry of new data or changes to existing data. 


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If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
offline, then the site can report this information on a paper Serious Adverse Event Report 
Form (see Appendix K). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
New or updated information will be recorded in the originally completed Event CRF. 
The investigator will submit any updated serious adverse even data to Amgen Global 
Patient Safety within 24 hours of receipt of the information. 
The investigator is responsible for notifying the Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) in accordance with local regulations, of all SAEs.  The sponsor may 
request additional source documentation pertaining to the SAE.  If a subject is permanently 
discontinued from the study because of an SAE, this information must be included in the initial 
or follow-up SAE report form as well as the Study Discontinuation eCRF. 
All SAEs occurring from the time that the subject signs consent for study participation and 
through 30 days after the last administered dose of study drug will be reported, regardless of 
whether new chemotherapy regimens are initiated (see Section 9.2 for additional information).  
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 
If a subject or spouse or partner of a subject becomes pregnant during treatment or up to 
30 days following administration of study treatment, Amgen Global Patient Safety and the 
medical monitor must be notified within 24 hours of the investigator, designee, or site 
personnel learning of the pregnancy.  On notification to Amgen, the investigator must obtain 
a separate information release and authorization form for the use and disclosure of health 
information of the pregnant spouse or partner of a patient.  If the patient becomes 
pregnant while taking oprozomib, oprozomib must be immediately discontinued.  Patients, 


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spouses, or partners will be followed through the outcome of the pregnancy.  The 
investigator will be required to complete an Amgen Pregnancy Notification Worksheet and 
report the information as specified below.  To report a pregnancy to Amgen Global Patient 
Safety, please refer to the pregnancy reporting guidelines below. 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 30 days after stopping 
oprozomib. 
 Information will be recorded on the Pregnancy Notification Worksheet (Appendix L).  
The worksheet must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws. 
 After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 30 days after 
stopping oprozomib.  This information will be forwarded to Amgen Global Patient 
Safety.  Generally, infant follow-up will be conducted up to 12 months after the birth 
of the child (if applicable). 
 Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
 While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or developmental 
delay, fetal death, or suspected adverse reactions in the neonate will be reported as an 
adverse event or serious adverse event.  Note that an elective termination with no 
information on fetal congenital malformation or maternal complication is generally not 
considered an adverse event, but still must be reported to Amgen as a pregnancy 
exposure case. 
 If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, 
or neonatal death or there is a fetal or neonatal congenital anomaly) the investigator 
will report the event as a serious adverse event. 
 Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator will be 
reported to Amgen Global Patient Safety as described in Section 9.5.  While the 


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investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting. 
 Any female subject who becomes pregnant while participating will discontinue study 
treatment. 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 In the event a male subject fathers a child during treatment, and for an additional 
90 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet (Appendix L).  The worksheet must 
be submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  Note:  Sites are not required to provide any information on the 
Pregnancy Notification Worksheet that violates the country or regions local privacy 
laws. 
 The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires.  This information will be forwarded to Amgen Global Patient Safety. 
 Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
 Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days after stopping oprozomib. 
 Information will be recorded on the Lactation Notification Worksheet (Appendix M) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 Study treatment will be discontinued if female subject breastfeeds during the study as 
described in exclusion criterion 16. 
 With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 30 days after discontinuing 
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10. 
STATISTICAL CONSIDERATIONS 
This section describes the statistical analysis that will be employed for assessing each of the 
safety and efficacy endpoints considered in the study.  Specifics of the analyses will be provided 
in the Statistical Analysis Plan (SAP).  Any other changes made to the planned analyses after 
the protocol and SAP have been finalized, along with an explanation as to when and why they 
occurred, will be described in the clinical study report, in which any post hoc exploratory 
analyses also will be clearly identified. 
10.1 
STUDY ENDPOINTS 
Primary Endpoints 
Phase 1b 
 Dose-limiting toxicities identified to determine the MTD and RP2D, defined as the 
highest dose at which < 33% of subjects experience DLTs after 1 cycle (14 days 
Cycle 1 for continuous dosing and Cycle 2 for step-up dosing) of treatment. 
 Safety and tolerability 
Phase 2 
 Overall response status, to determine whether a subject has a best response of sCR, CR, 
VGPR, or PR, as defined by IMWG-URC, and MR or nCR per EBMT criteria 
(Appendix H) 
 Safety and tolerability 
Secondary Endpoints 
Phase 1b/2 
 Pharmacokinetics of Oprozomib Tablets and Oprozomib ER Tablets 
Phase 2 
 Clinical benefit response status, to determine whether a subject has a best response of 
sCR, CR, VGPR, or PR, as defined by IMWG-URC, and MR or nCR per EBMT 
criteria (Appendix H) 
 Duration of response, defined as the time from first evidence of PR or better to 
confirmation of disease progression or death due to any cause 
 Progression-free survival, defined as the time from the start of treatment to disease 


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progression or death due to any cause 
 Time to progression, defined as the time from first dose to disease progression 
 Time to response, defined as time from the start of study treatment until the start of the 
first confirmed response (PR or better). 
Exploratory Endpoints 
Phase 1b/2 
 Pharmacodynamics and proteomic biomarkers 
 Genomic biomarkers that may potentially predict for response and resistance following 
treatment with proteasome inhibitors 
10.2 
SAMPLE SIZE CONSIDERATIONS 
For the Phase 1b portion of the study, it is estimated that approximately 60 subjects 
(approximately 30 subjects per treatment schedule) will be required to determine the 
recommended Phase 2 dose for each treatment schedule.  This is based on an estimate that up to 
5 cohorts will be enrolled per treatment schedule, with up to 6 evaluable subjects per cohort. 
For the recommended dose group (dose-escalation cohort plus Phase 2 cohort), the null (H0) and 
the alternative (HA) hypotheses are as follows: 
H0:  ORRCd ≤ 15% HA:  ORRCd > 15% 
With a sample size of 46 subjects (6 evaluable dose-escalation subjects + 40 Phase 2 subjects 
enrolled at the recommended dose) per schedule, a 1-sample exact binomial test with a 1-sided 
significance level of 5% will have 77% power at an ORR of 30%.  If at least 12 of the 
46 subjects have a best overall response of PR or better, then the null hypothesis will be rejected 
and it will be inferred that the ORR is > 15%. 
The total study sample size will depend on the number of dose levels required to establish the 
recommended dose for each schedule and the number of schedules initiated in the Phase 2 
portion of the study.  The study will enroll approximately 140 subjects. 


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10.3 
STATISTICAL ANALYSIS 
10.3.1 
ANALYSIS POPULATIONS 
All subjects who receive at least 1 dose of study treatment will be considered evaluable for both 
the efficacy and safety analyses (Safety Population).  Additional efficacy analyses will be 
performed using the Response-evaluable Population, defined as subjects who are included in the 
safety evaluable population and have a baseline disease assessment and at least 1 postbaseline 
disease assessment, or who dropped out due to AE prior to first postbaseline disease assessment. 
10.3.2 
EFFICACY ANALYSIS 
An estimate of the ORR and its 1-sided 95% exact binomial confidence interval for the 
recommended Phase 2 dose group(s) will be determined.  Additionally, the ORR and CBR 
along with the associated 2-sided 95% exact binomial confidence intervals will be determined 
for each dose cohort (within each schedule), including the recommended Phase 2 dose group 
(dose-escalation cohort + Phase 2 cohort).  Responses will be defined using the IMWG-URC 
for sCR, CR, VGPR, or PR, and the EBMT for MR and nCR. 
Analysis for time-to-events endpoints (PFS, DOR, and TTP) will be performed using the 
Kaplan-Meier method.  Medians and other quartiles for each time-to-event endpoints will be 
estimated with the corresponding 2-sided 95% confidence intervals. 
For purposes of calculating PFS, the start date for PD is the date at which progression is first 
observed.  For such subjects, the primary analysis of PFS and DOR will be right-censored 
according to the conventions described in Table 13.  The same censoring rules, except for death, 
as in analysis of PFS will be applied in calculation of TTP.  Subjects who die prior to 
progressive disease will be censored at the date of last evaluable response assessment. 


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Table 13: 
Date of Progression or Censoring for Duration of Response 
and Progression Free Survival 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first dose 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to start of 
new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease assessment 
visit 
Date of last disease assessment visit without 
documentation of PD that is before the first 
missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
Death or PD between planned disease 
assessments 
Date of death or first disease assessment showing 
PD, whichever occurs first 
Progressed 
Death before first disease assessment 
Date of death 
Progressed 
PD = progressive disease. 
The mean, standard deviation, median, minimum, and maximum will be calculated for time 
to response (TTR). 
10.3.3 
SAFETY ANALYSIS 
Safety and tolerability assessments will include extent of exposure to study treatment, AEs 
(including the DLT assessment period DLTs and SAEs), laboratory values, vital sign results, 
and ECGs.  Safety data will be examined on an ongoing basis to ensure subject safety. 
Extent of exposure to the study treatment will be summarized using descriptive statistics 
(n, mean, standard deviation, median, and range).  Percent of subjects and number of cycles 
with dose holds and reductions will be calculated by treatment group. 
Adverse events will be coded using MedDRA.  Treatment-emergent AEs are defined as AEs 
occurring from the first dose of study treatment through 30 days after the last dose of study 
treatment.  An AE that is present before the first administration of study treatment and 
subsequently worsens in severity between the first dose of study treatment and 30 days after the 
last dose of study treatment is also considered to be treatment emergent.  Adverse events will 
be summarized by MedDRA system organ class and preferred term for the number and 
percentage of subjects who experienced the event.  A subject reporting the same AE more than 
once will be counted only once when calculating (1) within a given system organ class and (2) 
within a given system organ class and preferred term combination.  For such cases, the 


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maximum NCI-CTCAE toxicity grade and strongest causal relationship to study treatment for 
the event will be used in the incidence calculations.  Treatment-emergent AEs will be tabulated 
to examine their frequency, severity, and relationship to study treatment.  Additional summaries 
will be provided for SAEs and events resulting in the permanent discontinuation of treatment.  
All AEs will also be included in individual subject listings. 
A listing of subjects who experience a DLT during the DLT assessment period of the 
dose- escalation portion will be generated along with the results associated with the PK/PDn 
parameters considered. 
Laboratory parameters will be summarized using descriptive statistics and by postdose shifts 
relative to baseline.  Vital sign results will also be summarized descriptively for each scheduled 
protocol time point.  Changes will be calculated relative to the values collected at baseline, 
defined as the last assessment taken prior to the first dose of study drug on Day 1 of Cycle 1. 
The analysis of the locally performed ECGs will involve descriptive statistics. 
10.4 
PHARMACOKINETIC, PHARMACODYNAMIC, AND PROTEOMIC 
ANALYSES 
10.4.1 
PHARMACOKINETIC ANALYSES 
Blood samples will be collected to measure plasma concentration of oprozomib and potential 
metabolite(s), as detailed in Section 7.2 and Appendix I. 
The following PK parameter estimates will be determined when possible for Oprozomib Tablets 
and Oprozomib ER Tablets and/or metabolite(s): 
 Cmax (observed) 
 Tmax (observed) 
 Area under the curve at the last measurable time point (AUC0-τ) 
 Area under the curve extrapolated to infinity (AUC0-inf) 
Unless otherwise specified, the PK parameters will be estimated based on noncompartmental 
methods.  These estimates will be summarized descriptively by dose cohort and formulation.  
Dose proportionality across dose levels will be analyzed.  Exploratory analyses may be 
performed to evaluate the relationship between the estimated PK parameters and selected safety, 


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biomarker, or clinical effect endpoints.  Individual plasma PK samples may also be used to 
assess the changes in endogenous markers of hepatic CYP3A activity upon oprozomib dosing. 
10.4.2 
PHARMACODYNAMIC AND PROTEOMIC ANALYSES 
Blood samples will be collected for PDn and proteomic analyses from subjects in all portions of 
the study as detailed in Section 7.2 and Appendix I. 
The extent of inactivation of proteasome activity after oprozomib dosing in RBCs and PBMCs 
will be monitored as a PDn parameter.  Proteasome activity will be measured in RBCs and 
PBMCs isolated from the blood samples.  A fluorogenic substrate assay will be used to measure 
proteasome activity in samples, and a site-specific ELISA that quantitates drug binding to the 
active sites of the proteasome may also be performed to further characterize target binding.  The 
extent of proteasome inactivation will be determined by comparing the activity of the postdose 
oprozomib samples with the samples taken before dosing.  Exploratory analyses may be 
performed to evaluate the relationship between the RBC or PBMC PDn and selected safety, 
biomarker, PK, or clinical effect endpoints. 
In the Phase 2 portion, blood samples for PDn and proteomics will be taken prior to and after 
oprozomib administration.  The plasma samples and the PBMCs will be analyzed for changes 
in specific protein levels.  The plasma samples for proteomics will be drawn and processed in 
the same manner as the PK samples. 
10.4.3 
GENOMIC ANALYSES 
Whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome 
sequencing will be conducted on isolated tumor (CD138+) cells from bone marrow samples 
taken at baseline and disease progression.  In addition, WGS or WES will be performed on a 
normal tissue sample (e.g., saliva or CD3+ T cells isolated from PBMCs) to distinguish germ line 
mutations from somatic mutations in tumor cell samples.  Data will be analyzed to examine 
whether drug response is related to alterations in genes regulated by or involved in activation of 
nuclear factor kappa light chain enhancer of activated B cells (NF-κB) transcription factors, as 
well as genes involved in immunoglobulin production and plasma cell protein homeostasis.  
Immunoglobulin levels in tumor cells will be quantified by ELISA or other protein 


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quantification methods.  These data will also be used to derive new hypotheses about 
mechanisms of drug response, resistance, and safety. 
11. 
INVESTIGATIONAL PRODUCT 
11.1 
OPROZOMIB DRUG PRODUCT 
11.1.1 
DESCRIPTION 
Oprozomib is a synthetic small molecule peptide bearing the chemical name N-((S)-3-methoxy-
1-((S)-3-methoxy-1-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-ylamino)-1-
oxopropan-2-ylamino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide.  The molecular 
formula is C25H32N4O7S and the molecular weight is 532.61.  It specifically functions as an 
inhibitor of the chymotrypsin-like activity of the 20S proteasome, which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis. 
11.1.2 
FORMULATION 
Oprozomib will be provided as a tablet containing 60, 90, or 120 mg of oprozomib drug 
substance for oral administration, or as an extended release (ER) tablet containing 150, 180, 
210, 240, or 270 mg of oprozomib.  Both Oprozomib Tablets and Oprozomib ER Tablets are 
intended to release greater than or equal to 75% (quantity) of the total dose of oprozomib over 
approximately 8 hours. 
Oprozomib Tablets are white to off-white, film-coated, round, biconvex tablets manufactured at 
3 dosage strengths: 
 Oprozomib 60 mg Tablets are debossed with “1” on one side and contain 60 mg of 
oprozomib. 
 Oprozomib 90 mg Tablets are debossed with “3” on one side and contain 90 mg of 
oprozomib. 
 Oprozomib 120 mg Tablets are debossed with “5” on one side and contain 120 mg of 
oprozomib. 


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Oprozomib ER Tablets are white to off-white, oval-shaped tablets manufactured at 5 dosage 
strengths: 
 Oprozomib 150 mg ER Tablets are debossed with “H” on one side and contain 150 mg 
of oprozomib 
 Oprozomib 180 mg ER Tablets are debossed with “I” on one side and contain 180 mg of 
oprozomib 
 Oprozomib 210 mg ER Tablets are debossed with “J” on one side and contain 210 mg 
of oprozomib 
 Oprozomib 240 mg ER Tablets are debossed with “K” on one side and contain 240 mg 
of oprozomib 
 Oprozomib 270 mg ER Tablets are debossed with “L” on one side and contain 270 mg of 
oprozomib 
The excipients for the drug product are lactose monohydrate, microcrystalline cellulose, sodium 
lauryl sulfate, magnesium stearate, hydroxy propyl methyl cellulose, and Opadry II White.  
The drug substance-to-excipient ratio is the same in all 8 dosage strengths. 
No changes in drug product, dosage, or treatment regimen occurred in this protocol 
amendment from the previous version. 
11.1.3 
HOW SUPPLIED 
Oprozomib Tablets will be supplied containing 60, 90, or 120 mg of oprozomib.  Oprozomib 
ER Tablets will be supplied containing 150, 180, 210, 240, and 270 mg of oprozomib.  Details 
may be found in the Pharmacy Manual. 
11.1.4 
STORAGE CONDITIONS 
Oprozomib must be stored at room temperature (15°C–30°C; 59°F–86°F) in a securely locked 
area to which access is limited to appropriate study personnel. 
11.2 
ACCOUNTABILITY 
The Sponsor and the investigator will maintain records of each shipment of investigational 
product.  The records will document shipment dates, method of shipment, batch numbers, and 
number of bottles contained in the shipment.  On receipt of the investigational product, the 
designated recipient at the study site will inspect the shipment, verify the number and condition 


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of the drug product, and prepare an inventory or drug accountability record.  Drug accountability 
records must be readily available for inspection by representatives of the Sponsor and by 
regulatory authorities.  Further instructions are provided in the Pharmacy Manual. 
Instructions for the destruction and return of unused drug supply are also provided in the 
Pharmacy Manual. 
11.3 
DEXAMETHASONE DRUG PRODUCT 
11.3.1 
DESCRIPTION 
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, 
crystalline powder (Roxanne Laboratories, Inc. 2007). 
11.3.2 
HOW SUPPLIED 
Dexamethasone is a commercially available drug, available both as tablets for oral 
administration and as various sterile formulations for parenteral administration 
(Roxanne Laboratories, Inc. 2007). 
11.3.3 
STORAGE CONDITIONS 
Dexamethasone is to be stored at controlled room temperature 20°C to 25°C (68°F to 77°F).  
Consult the package insert of the respective product for additional storage and usage instructions 
(Roxanne Laboratories, Inc. 2007). 
11.3.4 
ACCOUNTABILITY 
Sites will be required to record and document subject compliance regarding dexamethasone 
dosing. 


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12. 
REGULATORY OBLIGATIONS 
12.1 
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 or its designated representative will provide the investigator with a sample ICF.  Local 
and/or institutional requirements may require disclosure of additional information in the ICF.  
Any changes to the ICF must be submitted to the sponsor or its designated representative for 
approval, prior to submission to the IRB/IEC.  The IRB/IEC will review the ICF for approval.  
A copy of the approved form must be submitted to the sponsor or its designated representative 
prior to initiation of the study. 
Before any study procedure is implemented, informed consent shall be documented by the use 
of a written ICF 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 ICF will be given 
to the subject or subject’s legally authorized representative.  The original signed ICF must be 
maintained by the investigator and available for inspection by Onyx, its designated 
representative, or regulatory authority at any time. 
12.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with FDA and International Council for 
Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, 
any applicable local health authority, and IRB or IEC requirements. 
This study must have the approval of a properly constituted IRB/IEC.  Before the 
investigational drug is shipped to the investigator, the investigator or designee will provide the 


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Sponsor with a copy of the IRB/IEC approval letter stating that the study protocol and any 
subsequent amendments and ICFs have been reviewed and approved. 
The investigator or designee will be responsible for obtaining annual IRB/IEC 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 the Sponsor or 
designee. 
The investigator is also responsible for notifying his or her IRB/IEC of any significant AEs that 
are serious and/or unexpected. 
The Sponsor or its designated representatives will provide study sites with any Investigational 
New Drug (IND) safety reports generated, changes to the Investigator’s Brochure, and any 
safety updates.  The investigator is responsible for immediately notifying their IRB/IEC of any 
such updates. 
The Sponsor 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 ICF, if 
applicable.  Written documentation of IRB/IEC approval must be received before the 
amendment is implemented.  On completion of the study, the investigator must provide the 
IRB/IEC with a summary of the study’s outcome. 
12.3 
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. 
The investigator/institution will permit direct access to source data and documents for Onyx, its 
designee, the FDA, and other applicable regulatory authorities.  The access may consist of 
study-related monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority inspections. 
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 Regulations (CFR) 164.508, 


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and, if and to the extent applicable, the principles set out in Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to 
the processing of personal data and on the free movement of such data, and national legislation 
with regard to data privacy. 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
All protocol amendments will be implemented by Onyx 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/IEC, along 
with the revised ICF, to Onyx or its designated representatives. 
Both Onyx 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 or it designated 
representatives. 
13.2 
STUDY DOCUMENTATION AND ARCHIVES 
13.2.1 
SOURCE DOCUMENTS 
Source records are original documents, data, and records (e.g., medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated instruments, 
laboratory data) that are relevant to the clinical study.  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 study.  Source 
records must be adequate to reconstruct all data transcribed onto the eCRFs. 
13.2.2 
CASE REPORT FORM COMPLETION 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol.  The investigator agrees to maintain accurate eCRFs and source documentation aspart 
of the case histories.  These source documents may include subject diaries, laboratory reports, 
etc.  Onyx will supply the eCRF, which will be completed in English. 


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The investigators or designee must enter all results collected during the clinical study into 
eCRFs.  Guidelines for completion of eCRFs will be reviewed with study site personnel at the 
site initiation visits.  Investigators are responsible for approval of the entered/corrected data; 
however, they can authorize subinvestigators listed on the FDA Form 1572 to sign/approve the 
data.  More detailed instructions may be found in the Study Reference Manual. 
13.2.3 
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 or applicable regulatory 
authorities are notified. 
The investigator must retain protocols, amendments, IRB approvals, copies of the FDA 
Form 1572, signed and dated ICFs, medical records, eCRFs, drug accountability records, all 
correspondence, and any other documents pertaining to the conduct of the study. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
Following prequalification and initiation of the study site, periodic monitoring visits will be 
made by  the Sponsorand/or its designated representative.  The investigator must provide 
sufficient space and allocate sufficient time for the monitor to inspect subject source records, 
eCRFs, drug accountability records, and regulatory documents. 
The purpose of clinical study 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 study 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 after each study site visit or 
study- related communication.  Reports shall include a summary of what the monitor 
reviewed and significant findings, deviations and deficiencies, conclusions, and actions 
taken or to be taken to ensure site compliance. 


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The investigator must also permit study-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 
 eCRF review against source documents 
 Data management quality control checks 
 Sponsor medical review 
The sponsor or its designee will be responsible for the design and distribution of the eCRFs and 
for data management.  The sponsor or its designee will be responsible for the monitoring of the 
eCRFs.  The clinical research organization, and/or the Sponsor 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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14. 
REFERENCES 
Badros AZ, Vij R, Martin T, et al. Phase II study of carfilzomib in patients with 
relapsed/refractory multiple myeloma and renal insufficiency. J Clin Oncol. 2010;28(15_suppl). 
ASCO Annual Meeting 2010. Abstract 8128. 
Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in 
patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
transplantation. European Group for Blood and Marrow Transplant. Myeloma Subcommittee of 
the EBMT. Br J Haematol. 1998;102(5):1115–1123. 
Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007;67(13):6383–6391. 
Dispenzieri A. Bortezomib for myeloma—much ado about something. N Engl J Med. 
2005;352(24):2546–2548. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple 
myeloma. Leukemia. 2006;20(9):1467−73. Errata in: Leukemia 2006;20(12):2220 & Leukemia 
2007;21(5):1134. 
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and staging working group report. Biol Blood Marrow Transplant. 
2005;11(12):945-956. 
Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, 
induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer 
Res. 2001;61(7):3071–3076. 
Jagannath S, Richardson RG, Barlogie B, et al. Bortezomib in combination with dexamethasone 
for the treatment of patients with relapsed and/or refractory multiple myeloma with less than 
optimal response to bortezomib alone. Haematologica. 2006;91(7):929–934. 
Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible 
inhibitor of the ubiquitin proteasome pathway, against preclinical models of multiple myeloma. 
Blood. 2007;110(9):3281–3290. 
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia. 2009;23(1):3–9. 
Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with 
chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a 
report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood 
Cancer. 2010;55(2):254–259. 


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Mikhael JR, Belch AR, Prince HM, et al. High response rate to bortezomib with or without 
dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global 
phase 3b expanded access program. Br J Haematol. 2009;144(2):169–75. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
May 29, 2009 (v4.03 June 14, 2010). NCI, NIH, DHHS. NIH publication # 09-7473. 
O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and 
pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with 
hematologic malignancies. Clin Cancer Res. 2009;15(22):7085–91. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55. 
Onyx Pharmaceuticals. Kyprolis (carfilzomib) for injection full prescribing information. 2012. 
Papadopoulos KP, Mendelson DS, Tolcher AW, et al. A phase I, open-label, dose-escalation 
study of the novel oral proteasome inhibitor (PI) ONX 0912 in patients with advanced refractory 
or recurrent solid tumors. J Clin Oncol. 2011;29(15_suppl). ASCO Annual Meeting 2011. 
Abstract 3075. 
Rajkumar SV, Harousseau J-L, Durie BG, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011;117(18):4691–95. 
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, 
refractory myeloma. N Engl J Med. 2003;348(26):2609–17. 
Richardson PG, Baz R, Wang L, et al. Investigational agent MLN9708, an oral proteasome 
inhibitor, in patients (Pts) with relapsed and/or refractory multiple myeloma (MM): results from 
the expansion cohorts of a phase 1 dose-escalation study. Blood. 2012;120(21). ASH Annual 
Meeting. Abstract 301. 
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for 
relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98. 
Roxanne Laboratories, Inc. Dexamethasone full prescribing information. 2007. 
Simon R, Freidlin B, Rubinstein L, et al. Accelerated titration designs for phase I clinical trials 
in oncology. J Natl Cancer Inst. 1997;89(15):1138–47. 
Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib resistant 
adenocarcinoma cells. PLoS ONE, 2011;6(12):e27996. 
Zhou HJ, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and 
selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem. 
2009;52(9):3028-38. 


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Appendix A SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON THE 5 CONSECUTIVE DAY 
BIMONTHLY SCHEDULE (DAYS 1 TO 5 OF EACH 14-DAY TREATMENT CYCLE), PHASE 1B 
5/14 Phase 1b, Continuous Dosing Subjects 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 Cycle 3+r 
End of Study/ 
Early Discontinuations 
D -14 to -1 
D 1 
D 2 
D 3, 4 
D 5 
D 1 
D 2 
D 5 
D 1 
Medical History 
X 
Previous Treatment History 
X 
Targeted 
Physical Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE grading) 
X 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
Serum Chemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and Plateletsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testi 
X 
Blood for PKj,k 
X 
X 
X 
Blood for PDn Assayl 
X 
X 
X 
Administer Antiemeticsm 
X 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingn,o 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


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Footnotes to Appendix A, 5/14 Phase 1b, Continuous Dosing Subjects 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; 
CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; Diff = differential; ECG = electrocardiogram; EOS = End of 
Study; PDn = pharmacodynamics; PK = pharmacokinetics. 
a A physical examination can be performed every 4 cycles after subjects have been on study for more than 2 months, if clinically indicated (i.e., starting at Cycle 5, Day 1, then at 
Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1. 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment under 
Amendment 4 will have this assessment performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dose and at 30 ± 5 min, 1 hour (± 15 min), 
and 2 hours (± 15 min) after each dose (Cycle 1, Days 1–5; and Cycle 2, Days 1, 2, and 5).  Measure once at Screening and at EOS.  Subjects should lie down for 5 minutes 
and then and have blood pressure and pulse measured.  This should be followed by having the subject stand and the blood pressure and pulse should be repeated at 1 and 
3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic or lightheadedness/dizziness would indicate orthostatic hypotension (usually an increase in pulse rate of 
10 beats/min is associated but not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above.  
Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate are required within 1 hour prior to first dose and within 30−60 minutes after 
first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by having the subject stand 
and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these assessments performed only if 
clinically indicated and at EOS. 
e Perform local ECGs at Screening, within 6 hours postdose on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 of 
every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.). 
f Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
g Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total 
protein, albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active 
treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCL.  Screening results may be used for Cycle 1, 
Day 1 if obtained within 72 hours of Cycle 1, Day 1. 
h Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
i A serum or urine pregnancy test is to be done within 3 days prior to first dose in females of childbearing potential only. 
j Blood sampling for PK for continuous dosing subjects in the Phase 1b portion:  Blood samples to measure oprozomib and its metabolite(s) will be collected on Cycle 1, Days 1 
and 2 and Cycle 2, Day 1 for subjects given oprozomib at a single dose level.  Samples on Cycles 1 and 2, Day 1 must be taken within 5 minutes of intended collection times for 
15- and 30-minute and 1- and 2-hour time points and within 15 minutes for 4-, 6-, and 8-hour time points.  Oprozomib must be taken in the fasted state (at least 2 hours after a 
meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days including non-PK days and days in which only a 
predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes after eating).  Sampling times and volumes are 
provided in the Laboratory Manual. 
k When subjects switch from Oprozomib Tablets to Oprozomib ER Tablets, intensive PK sampling should be obtained on Day 1 in the cycle prior to switching and on Day 1 of 
the following cycle (i.e., first day with Oprozomib ER Tablet) at the scheduled time points described for the step-up dosing subjects in Phase 1b. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 100 of 154 
 
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Footnotes to Appendix A, 5/14 Phase 1b, Continuous Dosing Subjects 
l Blood sampling for PDn for continuous dosing subjects in the Phase 1b portion:  Blood samples for determination of proteasome inhibition by oprozomib will be drawn on 
Cycle 1, Days 1 and 2 and Cycle 2, Day 1 for subjects given oprozomib at a single dose level.  Samples must be taken within 15 minutes of intended collection time for all 
postdose time points.  Sampling times and volumes are provided in the Laboratory Manual.  Subjects may be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron 
or granisetron, before administration of the first dose of oprozomib each day and throughout the day as needed. 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on the 5 consecutive day bimonthly schedule will be provided with oprozomib dose for Days 1–5 of the 14-day cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 and continue until 
30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


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5/14 Phase 1b, Step-up Dosing Subjects 
 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 Cycle 3+r 
End of Study/ 
Early Discontinuations 
D -14 to -1 
D 1 
D 2 
D 3,4 
D 5 
D 1 
D 2 
D 5 
D 1 
Medical History 
X 
Previous Treatment 
History 
X 
Targeted Physical 
Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE 
grading) 
X 
 
 
 
 
 
 
 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
Serum Chemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testi 
X 
Blood for PKj,k 
X 
X 
X 
X 
Blood for PDn Assay and 
Proteomic Analysesl 
X 
X 
X 
X 
Administer Antiemeticsm 
X 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingn,o 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


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Oprozomib Tablets 
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CONFIDENTIAL 
 
 
 
Footnotes to Appendix A, 5/14 Phase 1b, Step-up Dosing Subjects 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; CRF = case 
report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; ECG = electrocardiogram; Diff = differential; EOS = End of Study; 
PDn = pharmacodynamics; PK = pharmacokinetics. 
a A physical examination may be performed every 4 cycles after subjects have been on study for more than 2 months if clinically indicated.  (i.e., starting at Cycle 5, Day 1, then 
at Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1. 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment 
under Amendment 4 will have this assessment performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dose and at 30 ± 5 min, 1 hour 
(± 15 min), and 2 hours (± 15 min) after each dose (Cycle 1, Days 1–5; and Cycle 2, Days 1, 2, and 5).  Measure once at Screening and at EOS.  Subjects should lie down for 
5 minutes and then and have blood pressure and pulse measured.  This should be followed by having the subject stand, and the blood pressure and pulse should be repeated 
at 1 and 3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic or lightheadedness/dizziness would indicate orthostatic hypotension (usually an increase in pulse 
rate of 10 beats/min is associated, but it is not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified 
above.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate are required within 1 hour prior to first dose and within 30−60 minutes after 
first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by having the subject stand 
and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these assessments performed only if 
clinically indicated and at EOS. 
e Perform local ECGs at Screening, within 6 hourspostdose on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 of 
every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.).  Patients on active treatment under Amendment 4 will have these assessments 
performed only if clinically indicated and at EOS. 
f Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
g Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total 
protein, albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active 
treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCL.  Screening results may be used for 
Cycle 1, Day 1 if obtained within 72 hours of Cycle 1, Day 1. 
h Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
i A serum or urine pregnancy test is to be done within 3 days prior to first dose in females of childbearing potential only. 
j Blood sampling for PK for step-up dosing subjects in the Phase 1b portion:  Blood samples to measure oprozomib and its metabolite(s) will be collected on Cycle 1, Days 1 and 2 
and Cycle 2, Days 1 and 2 for subjects given oprozomib using step-up dosing.  Samples on Cycles 1 and 2, Day 1 must be taken within  5 minutes of intended collection times 
for 15- and 30-minute and 1- and 2-hour time points and within 15 minutes for 4-, 6-, and 7-hour time points.  Oprozomib must be taken in the fasted state (at least 2 hours after a 
meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days, including non-PK days and days in which only a predose 
PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes after eating).  Sampling times and volumes are provided 
in the Laboratory Manual. 
k When subjects switch from Oprozomib Tablets to Oprozomib ER Tabletsintensive PK sampling should be obtained on Day 1 in the cycle prior to switching and on Day 1 of 
the following cycle (i.e., first day with Oprozomib ER Tablet) at the scheduled time points described for the step-up dosing subjects in Phase 1b. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 103 of 154 
 
CONFIDENTIAL 
 
l Blood sampling for PDn for step-up dosing subjects in the Phase 1b portion:  Blood samples for determination of proteasome inhibition by oprozomib will be drawn on Cycle 1, 
Days 1 and 2 and Cycle 2, Days 1 and 2 for subjects given oprozomib using step-up dosing.  Samples must be taken within 15 minutes of the intended collection time for all 
postdose time points.  Sampling times and volumes are provided in the Laboratory Manual. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 104 of 154 
 
CONFIDENTIAL 
 
 
 
Footnotes to Appendix A, 5/14 Phase 1b, Step-up Dosing Subjects 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on the 5-consecutive-days bimonthly schedule will be provided with oprozomib dose for Days 1–5 of 14-day cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 and continue until 
30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 105 of 154 
 
CONFIDENTIAL 
 
 
Appendix B SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON THE 5 CONSECUTIVE DAY 
BIMONTHLY SCHEDULE (DAYS 1-5 OF EACH 14-DAY TREATMENT CYCLE), PHASE 2 
5/14 Phase 2 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 Cycle 3+r 
End of Study/ 
Early Discontinuations 
D -14 to -1 
D 1 
D 2 
D 3,4 
D 5 
D 1 
D 2 
D 5 
D 1 
Medical History 
X 
Previous Treatment History 
X 
Targeted Physical 
Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE 
grading) 
X 
 
 
 
 
 
 
 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
ECG Central Labf 
X 
Urinalysisg 
X 
X 
Serum Chemistryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and Plateletsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testj 
X 
Blood for PKk 
X 
X 
X 
X 
Blood for PDn Assay and 
Proteomic Analysesl 
X 
X 
X 
X 
Administer Antiemeticsm 
X 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingn,o 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 106 of 154 
 
CONFIDENTIAL 
 
 
Footnotes to Appendix B, 5/14 Phase 2 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; 
CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; ECG = electrocardiogram; Diff = differential; EOS = End 
of Study; PDn = pharmacodynamics; PK = pharmacokinetics; QT = the interval from the beginning of the Q wave to the beginning of the T wave; QTc = the interval between 
the start of the Q wave and the end of the T wave. 
a A physical examination may be performed every other month after subjects have been on study for more than 2 months if clinically indicated (i.e., starting at Cycle 5, Day 1, 
then at Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1. 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment 
under Amendment 4 will have this assessment performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dose and at 30 minutes (± 5 min), 1 hour 
(± 15 min), and 2 hours (± 15 min) after each dose (Cycle 1, Days 1–5; and Cycle2, Days 1, 2, and 5).  Measure once at Screening and at EOS.  Subjects should lie down for 
5 minutes and then have blood pressure and pulse measured.  This should be followed by having the subject stand, and the blood pressure and pulse should be repeated at 1 
and 3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic or lightheadedness/dizziness would indicate orthostatic hypotension (usually an increase in pulse rate of 
10 beats/min is associated, but it is not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above.  
Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate are required within 1 hour prior to first dose and within 30−60 minutes after 
first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by having the subject stand, 
and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these assessments performed only if 
clinically indicated. 
e Perform local ECGs at Screening, within 6 hours postdose on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 of 
every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.).  Patients on active treatment under Amendment 4 will have these assessments performed 
only if clinically indicated and at EOS. 
f Electrocardiograms Central Lab:  Outside the requirements for local ECGs, assessment of QT/QTc interval will done via central ECGs on10 subjects on each schedule.  
Twelve-lead ECGs including QT/QTc interval will be performed in triplicate using an ECG machine provided by a central laboratory at the following time points during 
Cycle 1, Day 1:  within 15 minutes prior to oprozomib dosing and at 30 minutes, 1, 2, 4 and 6 hours after oprozomib dosing. 
g Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
h Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total 
protein, albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active 
treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCl.  Screening results may be used for Cycle 1, 
Day 1 if obtained within 72 hours of Cycle 1, Day 1. 
i Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
j A serum or urine pregnancy test is to be done within 3 days prior to first dose in females of childbearing potential only. 


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Footnotes to Appendix B, 5/14 Phase 2 
k Blood sampling for PK for subjects in the Phase 2 portion:  Blood samples for determination of plasma concentrations of oprozomib and its metabolite(s) will be drawn on 
Cycle 1, Days 1 and 2 and Cycle 2, Days 1and 2 for all subjects on the 5 consecutive day bimonthly schedule.  Samples on Cycles 1 and 2, Day 1 must be taken within 5 
minutes of intended collection time for 15-and 30-minute and 1- and 2-hour time points and within 15 minutes for 4-, 6-, and 7-hour  time points.  Oprozomib must be taken in 
the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days, including non-
PK days and days in which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes after eating).  
Sampling times and volumes are provided in the Laboratory Manual.  Blood samples will be obtained for all subjects unless collection is discontinued at the sponsor’s discretion.  
Samples may also be used for biomarker assessment. 
l Blood sampling for PDn and proteomic analyses for subjects in the Phase 2 Portion:  Blood samples for determination of proteasome inhibition by oprozomib and proteomic 
analyses will be drawn on Cycle 1, Days 1 and 2 and Cycle 2, Days 1 and 2 for all subjects on the 5 consecutive day bimonthly schedule. 
Samples must be taken within 15 minutes of intended collection time for 4- and 6-hour time points.  Sampling times and volumes are provided in the Laboratory Manual. 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on the 5-consecutive-days bimonthly schedule will be provided with oprozomib doses for Days 1–5 of each 14-day cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 and continue until 
30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


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Appendix C SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON THE 2 CONSECUTIVE DAY WEEKLY 
SCHEDULE (DAYS 1, 2, 8, AND 9 OF EACH 14-DAY TREATMENT CYCLE), PHASE 1B 
2/7 Phase 1b, Continuous Dosing Subjects 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 3+r 
End of Study/ 
Early Discontinuations 
D -14 to -1 
D 1 
D 2 
D 8 
D 9 
D 1 
D 2, 9 
D 1 
Medical History 
X 
Previous Treatment History 
X 
Targeted Physical 
Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE grading) 
X 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
Serum Chemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and Plateletsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testi 
X 
Blood for PKj,k 
X 
X 
X 
Blood for PDn Assay and 
Proteomic Analysesl 
X 
X 
X 
Administer Antiemeticsm 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingn,o 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


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Footnotes to Appendix C, 2/7 Phase 1b, Continuous Dosing Subjects 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; 
CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; ECG = electrocardiogram; Diff = differential; EOS = End 
of Study; PDn = pharmacodynamics; PK = pharmacokinetics. 
a A physical examination may be performed every 4 cycles after subjects have been on study for more than 2 months if clinically indicated (i.e., starting at Cycle 5, Day 1, then at 
Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1. 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment 
under Amendment 4 will have this assessments performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dosing and at 30 minutes (± 5 min), 1 hour 
(± 15 min) and 2 hours (± 15 min) after each dose (Cycle 1, Days 1, 2, 8 and 9; and Cycle 2, Days 1, 2, and 9).  Measure once at Screening and at EOS.  Subjects should lie 
down for 5 minutes and then have blood pressure and pulse measured.  This should be followed by having the subject stand, and the blood pressure and pulse should be 
repeated at 1 and 3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic, or lightheadedness/dizziness would indicate orthostatic hypotension (usually an increase in 
pulse rate of 10 beats/min is associated, but it is not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods 
specified above.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate are required within 1 hour prior to first dose and within 30– 60 minutes after 
first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by having the subject stand, 
and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these assessments performed only if 
clinically indicated. 
e Perform local ECGs at Screening, within 6 hours after dosing, on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 
of every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.).  Patients on active treatment under Amendment 4 will have these assessments 
performed only if clinically indicated and at EOS. 
f Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
g Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, 
albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) is to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active treatment under 
Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCl.  Screening results may be used for Cycle 1, Day 1 if obtained 
within 72 hours of Cycle 1, Day 1. 
h Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
i A serum or urine pregnancy test is to be done within 3 days prior to first dose in females of childbearing potential only. 
j Blood sampling for PK for continuous dosing subjects in the Phase 1b portion:  Blood samples to measure oprozomib and its metabolite(s) will be collected on Cycle 1, Days 1 
and 2 and Cycle 2, Day 1 for subjects given oprozomib at a single dose level.  Samples on Cycles 1 and 2, Day 1 must be taken within 5 minutes of intended collection times for 
15- and 30-minute and 1- and 2-hour time points and within 15 minutes for 4-, 6-, and 8-hour time points.  Oprozomib must be taken in the fasted state (at least 2 hours after a 
meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days, including non-PK days and days in which only a predose 
PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes after eating).  Sampling times and volumes are provided 
in the Laboratory Manual. 
k When subjects switch from Oprozomib Tablets to Oprozomib ER Tablets, intensive PK sampling should be obtained on Day 1 in the cycle prior to switching and on Day 1 of 
the following cycle (i.e., first day with Oprozomib ER Tablet) at the scheduled time points described for step-up dosing subjects in Phase 1b. 


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Oprozomib Tablets 
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l Blood sampling for PDn for continuous dosing subjects in the Phase 1b portion:  Blood samples for determination of proteasome inhibition by oprozomib will be drawn on 
Cycle 1, Days 1 and 2 and Cycle 2, Day 1 for subjects given oprozomib at a single dose level.  Samples must be taken within 15 minutes of the intended collection time for all 
postdose time points on Cycles 1 and 2, Day 1.  Sampling times and volumes are provided in the Laboratory Manual. 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 


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Footnotes to Appendix C, 2/7 Phase 1b, Continuous Dosing Subjects 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on 2 consecutive day weekly schedule will be provided with oprozomib dose for Days 1, 2, 8, and 9 of 14-day cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from the time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 and continue until 
30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


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2/7 Phase 1b, Step-up Dosing Subjects 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 
Cycle 3+r 
End of Study/Early 
Discontinuations 
D -14 to -1 
D 1 
D 2 
D 8 
D 9 
D 1 
D 2 
D  9 
D 1 
Medical History 
X 
Previous Treatment 
History 
X 
Targeted Physical 
Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE 
grading) 
X 
 
 
 
 
 
 
 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
Serum Chemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testi 
X 
Blood for PKj,k 
X 
X 
X 
X 
Blood for PDn Assay and 
Proteomic Analysesl 
X 
X 
X 
X 
Administer Antiemeticsm 
X 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingn,o 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


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Oprozomib Tablets 
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CONFIDENTIAL 
 
 
 
Footnotes to Appendix C, 2/7 Phase 1b, Step-up Dosing Subjects 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; CRF = case 
report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; ECG = electrocardiogram; Diff = differential; EOS = End of Study; 
PDn = pharmacodynamics; PK = pharmacokinetics. 
a A physical examination can be performed every 4 cycles after subjects have been on study for more than 2 months if clinically indicated (i.e., starting at Cycle 5, Day 1, then at 
Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1. 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment 
under Amendment 4 will have this assessment performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dosing and at 30 minutes (± 5 min), 1 hour (± 15 
min) and 2 hours (± 15 min) after each dose (Cycle 1, Days 1, 2, 8 and 9; and Cycle 2, Days 1, 2, and 9).  Measure once at Screening and at EOS.  Subjects should lie down for 5 
minutes and then have blood pressure and pulse measured.  This should be followed by having the subject stand, and the blood pressure and pulse measurements should be repeated 
at 1 and 3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic, or lightheadedness/dizziness would indicate orthostatic hypotension (usually an increase in pulse of 
10 beats/min is associated, but it is not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above.  Patients 
on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate measurements are required within 1 hour prior to first dose and within 
30-60 minutes after first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by 
having the subject stand and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these 
assessments performed only if clinically indicated. 
e Perform local ECGs at Screening, within 6 hours after dosing on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 
of every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.).  Patients on active treatment under Amendment 4 will have these assessments 
performed only if clinically indicated and at EOS. 
f Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
g Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total 
protein, albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active 
treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCl.  Screening results may be used for 
Cycle 1, Day 1 if obtained within 72 hours of Cycle 1, Day 1. 
h Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
i A serum or urine pregnancy test is to be done within 3 days prior to first dose in females of childbearing potential only. 
j Blood sampling for PK for step-up dosing subjects in the Phase 1b portion:  Blood samples to measure oprozomib and its metabolite(s) will be collected  on Cycle 1, Days 1 
and 2 and Cycle 2, Days 1 and 2 for subjects given oprozomib using step-up dosing.  Samples on Cycles 1 and 2, Day 1 must be taken within 5 minutes of intended collection 
times for 15- and 30-minute and 1- and 2-hour time points and within 15 minutes for 4-, 6-, and 7-hour time points.  Oprozomib must be taken in the fasted state (at least 
2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days, including non-PK days and days in 
which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes after eating).  Sampling times 
and volumes are provided in the Laboratory Manual. 
k When subjects switch from Oprozomib Tablets to Oprozomib ER Tablets, PK samples should be obtained on Day 1 in the cycle prior to switching and on Day 1 of the 
following cycle (i.e., first day with Oprozomib ER Tablet) at the scheduled time points described for the step-up dosing subjects in Phase 1b. 


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Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
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CONFIDENTIAL 
 
l Blood sampling for PDn for step-up dosing subjects in the Phase 1b portion:  Blood samples for determination of proteasome inhibition by oprozomib will be drawn on 
Cycle 1, Days 1 and 2 and Cycle 2, Days 1 and 2 for subjects given oprozomib using step-up dosing.  Samples must be taken within 15 minutes of intended collection time 
for all postdose time points on Cycles 1 and 2, Day 1.  Sampling times and volumes are provided in the Laboratory Manual. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 115 of 154 
 
CONFIDENTIAL 
 
 
 
Footnotes to Appendix C, 2/7 Phase 1b, Step-up Dosing Subjects 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on the 2 consecutive day weekly schedule will be provided with oprozomib dose for Days 1, 2, 8, and 9 of each 14-day cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from the time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 and continue 
until 30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 4 
Oprozomib Tablets 
Page 116 of 154 
 
CONFIDENTIAL 
 
 
Appendix D SCHEDULE OF STUDY ASSESSMENTS:  SUBJECTS TREATED ON THE 2 CONSECUTIVE DAY WEEKLY 
SCHEDULE (DAYS 1, 2, 8, AND 9 OF EACH 14-DAY TREATMENT CYCLE), PHASE 2 
2/7 Phase 2 
 
Visit 
Screening 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 
Cycle 3+r 
End of Study/ 
Early Discontinuations 
D -14 to -1 
D 1 
D 2 
D 8 
D 9 
D 1 
D 2 
D 9 
D 1 
Medical History 
X 
Previous Treatment 
History 
X 
Targeted Physical 
Examinationa 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and CTCAE 
grading) 
X 
 
 
 
 
 
 
 
Xb 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
12–lead ECG (Local)e 
X 
X 
X 
X 
X 
X 
ECG Central Labf 
X 
Urinalysisg 
X 
X 
Serum Chemistryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests 
X 
Pregnancy Testj 
X 
Blood for PKk 
X 
X 
X 
X 
Blood for PDn Assay and 
Proteomic Analysesl 
X 
X 
X 
X 
Administer Antiemetics m 
X 
X 
X 
X 
X 
X 
X 
X 
Oprozomib Dosingno 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingp 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsq 


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Oprozomib Tablets 
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CONFIDENTIAL 
 
Footnotes to Appendix D, 2/7 Phase 2 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; 
CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; CrCL = creatinine clearance; ECG = electrocardiogram; Diff = differential; EOS = End 
of Study; PDn = pharmacodynamics; PK = pharmacokinetics; QT = the interval from the beginning of the Q wave to the beginning of the T wave; QTc = the interval between 
the start of the Q wave and the end of the T wave. 
a A physical examination can be performed every other month after subjects have been on study for more than 2 months, if clinically indicated (i.e., starting at Cycle 5, Day 1, 
then at Cycle 9, Day 1, etc.).  The screening exam may be used for Cycle 1, Day 1 if obtained within 7 days of Cycle 1, Day 1 
b Neurological assessments (BPNS and CTCAE grading) will be performed at Screening, every 4 cycles starting from Cycle 5, Day 1, and at EOS.  Patients on active treatment 
under Amendment 4 will have this assessment performed only if clinically indicated and at EOS. 
c Measure blood pressure, pulse rate, orthostatic blood pressure and pulse rate, respiration rate, and temperature within 1 hour prior to dosing and at 30 minutes (± 5 min), 1 hour 
(± 15 min) and 2 hours (± 15 min) after each dose (Cycle 1, Days 1, 2, 8 and 9; and Cycle 2, Days 1, 2, and 9).  Measure once at Screening and at EOS.  Subjects should lie 
down for 5 minutes and then have blood pressure and pulse measured.  This should be followed by having the subject stand, and the blood pressure and pulse measurements 
should be repeated at 1 and 3 minutes.  Any drop of 20 mm/Hg systolic, 10 mm/Hg diastolic, or lightheadedness/dizziness would indicate orthostatic hypotension (usually an 
increase in pulse rate of 10 beats/min is associated, but it is not required).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time 
periods specified above.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated. 
d During Cycles 3 and higher, respiration rate, temperature, orthostatic blood pressure and pulse rate measurements are required within 1 hour prior to the first dose and within 
30-60 minutes after first dose administration.  Subjects should lie down for 5 minutes and then and have blood pressure and pulse measured.  This should be followed by having 
the subject stand, and the blood pressure and pulse should be repeated at 1 and 3 minutes.  Patients on active treatment under Amendment 4 will have these assessments 
performed only if clinically indicated. 
e Perform local ECGs at Screening, within 6 hours after dosing on specified days with oprozomib dosing, and at EOS.  Starting from Cycle 5, ECGs will be performed on Day 1 
of every fourth cycle (i.e., starting at Cycle 5, Day 1, then at Cycle 9, Day 1, etc.).  Patients on active treatment under Amendment 4 will have these assessments 
performed only if clinically indicated and at EOS. 
f Electrocardiograms Central Lab:  Outside the requirements for local ECGs, assessment of QT/QTc interval will done via central ECGs on 10 subjects on each schedule.  
Twelve-lead ECGs including QT/QTc interval will be performed in triplicate using an ECG machine provided by a central laboratory at the following time points during 
Cycle 1, Day 1:  15 minutes prior to oprozomib dosing and at 30 minutes, 1, 2, 4 and 6 hours after oprozomib dosing. 
g Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein. 
h Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total 
protein, albumin, total bilirubin, ALT, AST, phosphorous, and magnesium) to be done at Screening, within 4 hours prior to dosing on specified days.  Patients on active 
treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS.  Calculate CrCL.  Screening results may be used for 
Cycle 1, Day 1 if obtained within 72 hours of Cycle 1, Day 1. 
i Hemoglobin, hematocrit, WBC count with differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils, absolute or percentage will be acceptable), RBC 
count, and platelet count.  Patients on active treatment under Amendment 4 will have these assessments performed only if clinically indicated and at EOS. 
j A serum or urine pregnancy test is to be done within 3 days prior to the first dose in females of childbearing potential only. 
k Blood sampling for PK for subjects in the Phase 2 portion:  Blood samples for determination of plasma concentrations of oprozomib and its metabolite(s) will be drawn on 
Cycle 1, Days 1 and 2, and Cycle 2, Days 1 and 2 for all subjects administered with a 2 consecutive day weekly schedule.  Samples on Cycles 1 and 2, Day 1 must be taken 
within 5 minutes of intended collection time for 15-and 30-minute and 1- and 2-hour time points and within 15 minutes for the 4-, 6-, and 7-hour time points.  Oprozomib must 
be taken in the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all other days, 
including non-PK days and days in which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 
30 minutes after eating).  Sampling times and volumes are provided in the Laboratory Manual.  Blood samples will be obtained for all subjects unless collection is 
discontinued at the sponsor’s discretion.  Samples may also be used for biomarker assessment. 


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Footnotes to Appendix D, 2/7 Phase 2 
l Blood sampling for PDn and proteomic analyses for subjects in the Phase 2 portion:   Blood samples for determination of proteasome inhibition by oprozomib and proteomic 
analyses will be drawn on Cycle 1, Days 1 and 2 and Cycle 2, Days 1 and 2, for all subjects on the 2 consecutive day weekly schedule.  Samples must be taken within 15 minutes 
of intended collection time for 4- and 6-hour time points.  Sampling times and volumes are provided in the Laboratory Manual. 
m Subjects will be premedicated PRN with a 5-HT3 inhibitor, such as ondansetron or granisetron, before administration of the first dose of oprozomib each day and throughout 
the day as needed. 
n Treatment will be administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. 
o Subjects on the 2 consecutive day weekly schedule will be provided with oprozomib dose for Days 1, 2, 8, and 9 of each 14-day treatment cycle. 
p Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, and 9 of each 14-day treatment cycle.  Dexamethasone must be taken at least 30 minutes prior to oprozomib. 
q Record all AEs from the time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to 
Day 1 and continue until 30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the 
CRF. 
r For patients with ≥ SD for at least 6 months (12 cycles), who are on a steady dose for ≥ 2 cycles, and are tolerating oprozomib, study assessments may be reduced to every 
4 cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, etc.) and 4 cycles of study medication can be provided at clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at every cycle. 
s All End-of-Study Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other treatment. 


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Appendix E SCHEDULE OF STUDY ASSESSMENTS:  DISEASE RESPONSE EVALUATIONS 
 
Assessment 
Screening 
Cycle 2 
Every 2 
Cycles 
EOS/ 
WDa 
At 
Progression 
LTFU for 
subjects 
without PD 
-14 to -1 
Day 1 
Days 10–14 
Disease response assessment labs 
Every 8 weeks 
SPEPb 
X 
X 
X 
X 
Serum immunofixation 
X 
X 
X 
X 
SFLCb 
X 
Xc 
X 
X 
X 
24-hr Urine sample:  UPEPb,d urine 
immunofixation 
X 
X 
X 
X 
β2 microglobulin 
X 
Skeletal surveye 
X 
Xf 
Xe 
Plasmacytoma evaluationg 
X 
Xf 
Xg 
Bone marrow aspirate and biopsy, cytogenetics, 
and FISH analysesh 
X 
Xf 
Optional Genomic Biomarker samplesi 
X 
X 
CT = computed tomography, lab = laboratory, EOS = End of Study, FISH = fluorescence in situ hybridization, LFTU = long-term follow-up; SFLC = serum free 
light chain; SPEP = serum protein electrophoresis, UPEP = urine protein electrophoresis, WD = withdrawal (from study), WM = Waldenström 
macroglobulinemia. 
Footnotes apply to Phase 1b and Phase 2. 
a All End of Study Treatment Assessments must be performed within 30 days following the subject’s last administration of study drug and before initiation of any other treatment.  
For subjects who discontinue treatment for reasons other than progression, disease assessments will no longer be required under Amendment 4. 
b After screening, disease response assessments should be done every 2 cycles after all study drug (oprozomib and dexamethasone) doses have been taken in that cycle (e.g., 
Cycle 2, Days 10–14) OR on Day 1 of the next scheduled cycle (e.g., Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1).  However, the time of assessment(s) should precede the 
Day 1 dose.  The times of assessments and study drug dose must be recorded in the source documents.  All subjects are required to complete SFLC assessments at each time 
point noted above.  For subjects with ≥ SD after being on study for 26 cycles, Days 10−14 OR predose on Cycle 27, Day 1 (the next assessment would be on Cycle 30, Days 
10–14 OR Cycle 31, Day 1). 
c For Cycle 2 only, SFLC specifically should be performed on Day 1.  After this assessment, SFLC can be performed with the other assessments. 
d UPEP (on a 24-hour collection) is required; no substitute method is acceptable. 
e All patients are required to have a skeletal survey at Screening.  Skeletal survey does not need to be repeated if previously done within 30 (± 15) days of consent.  Skeletal survey 
includes lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri.  Repeat skeletal survey 
as clinically indicated and to confirm CR or document PD.  Skeletal survey for EOS does not need to be repeated if done within the prior 30 days to prevent unnecessary 


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radiation exposure. 
f Also if clinically indicated to confirm response or PD within 30 days of laboratory assessment.  Cytogenetic analysis (Phase 1b only) and FISH from bone marrow samples will 
not be repeated after the Screening assessment.  Bone marrow assessments and FISH analyses are to be performed at a central laboratory. 
g Extramedullary plasmacytoma evaluation at baseline only required for patients with known or suspected plasmacytoma.  Historical evaluation performed as part of standard of 
care may be used as long as it is within 30 days of C1D1 dosing.  Extramedullary plasmacytoma evaluation to be repeated during treatment only to confirm a response of PR or 
better or to confirm PD, or as clinically indicated.  The same technique (which may include clinical evaluation by palpation, ultrasound, x-ray, CT scan, MRI or PET) should be 
employed for each measurement as clinically appropriate. 
h For the bone marrow aspirate or biopsy, quantitate percent plasma cell involvement at Screening and repeat when appropriate to confirm sCR, CR, or PD.  Obtain bone marrow 
sample for cytogenetic analysis and FISH studies at Screening only.  Screening bone marrow assessment does not need to be repeated if previously completed within 30 (± 15) 
days of the patient’s providing consent and assuming that FISH and cytogenetics were obtained.  Bone marrow assessments and FISH analyses are to be performed at a central 
laboratory. 
i For subjects who consent to participate, bone marrow aspirate (obtained from the bone marrow aspirate for FISH analysis; no new sample is required), blood, and saliva samples 
will be collected at baseline, as well as bone marrow aspirate at the time of progression (may be at time of treatment discontinuation or during long term follow-up). 


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Appendix F EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Grade 
ECOG 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Death 
Source:  Oken 1982. 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 


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Appendix G CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES WITH NARROW 
THERAPEUTIC RANGE 
CYP3A4 substrates with narrow therapeutic range refers to drugs whose exposure-response 
indicates that increases in their exposure levels by the concomitant use of CYP3A4 inhibitors 
may lead to serious concerns.  Investigators should seriously consider switching to an alternative 
agent whenever possible, or exercise caution and be alert for signs requiring dose modification.  
The following list provides examples of CYP3A4 substrates with narrow therapeutic range 
(note that this is not an exhaustive list): 
 
Alfentanil 
Diergotamine 
Quinidine 
Astemizolea 
Ergotamine 
Sirolimus 
Cisapridea Cyclosporine 
Fentanyl Pimozide 
Tacrolimus Terfenadinea 
a Not available in the United States. 


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Appendix H RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) 
Response 
Subcategorya 
Response Criteria 
sCRb 
 Negative immunofixation on the serum and urine and 
 Disappearance of any soft tissue plasmacytomas and 
 < 5% plasma cells in bone marrow and 
 Normal SFLC ratio and 
 Absence of clonal cells in bone marrowc 
CRb 
 Negative immunofixation on the serum and urine and 
 Disappearance of any soft tissue plasmacytomas and 
 < 5% plasma cells in bone marrow 
VGPRb, d 
 Serum and urine M-protein detectable by immunofixation, but not on electrophoresis 
or 
 ≥ 90% reduction in serum M-component with urine M-component < 100 mg per 
24 hours 
PRb, d 
 ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 
≥ 90% or to < 200 mg per 24 hours 
 If the serum and urine M-protein are not measurable, a decrease ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria. 
 If the serum and urine M-protein are not measurable, a decrease ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria. 
 If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is 
also requiredd, e 
Stable disease 
 Not meeting criteria for CR, VGPR, PR, or PD 
Page 1 of 2 
Footnoted defined on next page 


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Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) (cont’d) 
 
Response 
Subcategorya 
 
Response Criteria 
PDe 
Any one or more of the following increase of ≥ 25% from lowest response value in: 
 
Serum M-component (absolute increase must be ≥ 0.5 g/dL) and/or 
 
Urine M-component (absolute increase must be ≥ 200 mg per 24 hours) and/or 
 
Only in subjects without measurable serum and urine M-protein levels: 
the difference between involved and uninvolved FLC levels (absolute increase must 
be > 10 mg/dL) 
 
Only in subjects without measurable serum and urine M-protein levels and without 
measurable disease by FLC levels, bone marrow PC percentage (absolute percentage 
must be ≥ 10%) 
 
Bone marrow plasma cell percentages (absolute % must be ≥ 10%) 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
size of existing bone lesions or soft tissue plasmacytomasf, g, h 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) 
attributed solely to the plasma cell proliferative disorder 
Page 2 of 2 
Sources:  Durie 2006; Rajkumar 2011. 
CR = complete response; sCR = stringent complete response; FLC = serum free light chain; PD = progressive disease; 
PR = partial response; SFLC = serum free light chain; VGPR = very good partial response. 
a Subjects with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to meet response 
criteria in both UPEP and SPEP in order to qualify for a PR or better.  Conversely, it should be noted that criteria for PD 
only need to be met and confirmed in 1 parameter. 
b All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before the 
institution of any new therapy, as well as no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response requirements.  Bone marrow assessments 
are not required to be confirmed by repeat testing, but these should be done within 30 days of the confirmatory assessment 
if appropriate for the response category. 
c 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. 
d Response criteria for all categories and subcategories of response except CR and VGPR are applicable only to subjects that 
have “measurable” disease defined by at least one of SPEP ≥ 1.0 g/dL) or UPEP ≥ 200 mg per 24 hours; except for 
assessment of sCR, CR, or VGPR, subjects with measurable disease restricted to SPEP will need to be followed only by 
SPEP.  Correspondingly, subjects with measurable disease restricted to UPEP will need to be followed only by UPEP. 
e Determination of PD based on M-protein, hypercalcemia, or FLC while on study requires 2 consecutive assessments made 
at any time before classification of PD and/or the institution of new therapy.  Serum M-component increases of ≥ 1 g/dL are 
sufficient to define progression if starting M-component is ≥ 5 g/dL. 
f Plasmacytomas: A definite increase in the size is defined as a ≥ 50% increase as measured serially by the sum of the 
products of the cross-diameters of the measurable lesion.  A plasmacytoma is considered measurable if the longest 
diameter is at least 1 cm and the product of the cross diameters is at least 1 cm2.  Plasmacytomas of lesser size will be 
considered nonmeasurable. 
g The requirement for bi-directional measurements will only be applied to plasmacytomas. 
h The plasmacytoma specifications for PD are based on the sponsor’s interpretation of the IMWG-URC and practical 
considerations for study execution. 


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Definition of Minimal Response and Near-Complete Response per EBMT Criteria 
 
Response 
Subcategory 
Response Criteria 
MRa 
≥ 25 but < 49% reduction in serum M-protein and a 50-89% reduction in 24-hour urinary 
M-protein, which still exceeds 200 mg per 24 h 
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. 
25-49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination) 
No increase in size or number of lytic bone lesions (development of compression fracture 
does not exclude response) 
nCRa 
Immunofixation-positive response.  Absence of M-protein on electrophoresis, independent 
of the immunofixation test status, stable bone disease, and a normal serum calcium 
concentration, 
Sources:  Bladé 1998, Kyle 2009, Richardson 2003. 
EBMT = European Group for Blood and Marrow Transplantation; MR = minimal response; nCR = near- complete response. 
a Response categories (MR and nCR) require 2 consecutive assessments made at any time before the institution of any new 
therapy, as well as no known evidence of progressive or new bone lesions if radiographic studies were performed.  Radiographic 
studies are not required to satisfy these response requirements.  Bone marrow assessments are not required to be confirmed by 
repeat testing. 


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Appendix I 
BLOOD SAMPLES FOR PHARMACOKINETIC AND PHARMACODYNAMIC/PROTEOMIC ANALYSES:  
SAMPLING TIMES 
Phase 1b Sampling Time Points (continuous dosing subjects only) 
Time Point 
Cycle 
Day 
Predose 
15 min 
Postdose 
30 min 
Postdose 
1 hour 
Postdose 
2 hours 
Postdose 
4 hours 
Postdose 
6 hours 
Postdose 
8 hours 
Postdose 
Schedule:  5 Consecutive Days Bimonthly (Days 1–5 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PK 
PDn 
1 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PK 
PDn 
Schedule:  2 Consecutive Days Weekly (Days 1, 2, 8, and 9 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PK 
PDn 
1 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PK 
PDn 
PK = blood draw for pharmacokinetic analysis; PDn = blood draw for pharmacodynamic analyses; — indicates that no blood sample is obtained. 
Note:  Oprozomib must be taken in the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all 
other days including non-PK days and days in which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 
30 minutes after eating).  Subjects switching from Oprozomib Tablet to Oprozomib ER Tablet should follow Day 1 PK sampling as described for step-up dosing (predose to 7 hours 
postdose) on Day 1 of the cycle prior and Day 1 of the cycle subsequent to the switch. 


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Phase 1b Sampling Time Points (step-up dosing subjects only) 
Time Point 
Cycle 
Day 
Predose 
15 min 
Postdose 
30 min 
Postdose 
1 hour 
Postdose 
2 hours 
Postdose 
4 hours 
Postdose 
6 hours 
Postdose 
7 hours 
Postdose 
Schedule:  5 Consecutive Days Bimonthly (Days 1–5 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PDn 
PK 
1 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PDn 
PK 
2 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
Schedule:  2 Consecutive Days Weekly (Days 1, 2, 8, and 9 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PDn 
PK 
1 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn 
PK 
PK 
PK 
PK 
PK 
PDn 
PK 
PDn 
PK 
2 
2 
PK 
PDn 
— 
— 
— 
— 
— 
— 
— 
PK = blood draw for pharmacokinetic analysis; PDn = blood draw for pharmacodynamic analyses; — indicates that no blood sample is obtained. 
Note:  Oprozomib must be taken in the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all 
other days including non-PK days and days in which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 30 minutes 
after eating). 


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Phase 2 Sampling Time Points 
 
Time Point 
Cycle 
Day 
Predose 
15 min 
Postdose 
30 min 
Postdose 
1 hour 
Postdose 
2 hours 
Postdose 
4 hours 
Postdose 
6 hours 
Postdose 
7 hours 
Postdose 
Schedule:  5 Consecutive Days Bimonthly (Days 1–5 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn/P 
PK 
PK 
PK 
PK 
PK 
PDn/P 
PK 
PDn/P 
PK 
1 
2 
PK 
PDn/P 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn/P 
PK 
PK 
PK 
PK 
PK 
PDn/P 
PK 
PDn/P 
PK 
2 
2 
PK 
PDn/P 
— 
— 
— 
— 
— 
— 
— 
Schedule:  2 Consecutive Days Weekly (Days 1, 2, 8, and 9 of Each 14-day Treatment Cycle) 
1 
1 
PK 
PDn/P 
PK 
PK 
PK 
PK 
PK 
PDn/P 
PK 
PDn/P 
PK 
1 
2 
PK 
PDn/P 
— 
— 
— 
— 
— 
— 
— 
2 
1 
PK 
PDn/P 
PK 
PK 
PK 
PK 
PK 
PDn/P 
PK 
PDn/P 
PK 
2 
2 
PK 
PDn/P 
— 
— 
— 
— 
— 
— 
PK = blood draw for pharmacokinetic analysis; PDn/P = blood draw for pharmacodynamic and proteomic analyses; — indicates that no blood sample is obtained. 
Note:  Oprozomib must be taken in the fasted state (at least 2 hours after a meal and fasting for at least 2 hours after dosing) on days in which PK sampling is taken after a dose.  On all 
other days including non-PK days and days in which only a predose PK sample is taken, it is recommended that oprozomib is administered with food (i.e., within approximately 
30 minutes after eating). 


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Appendix J 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 
1. Elicit Subjective Symptoms 
Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) 
to 10 (most severe) for right and left feet and legs.  Enter the score for each symptom in the 
columns marked R (right lower limb) and L (left lower limb).  If a symptom has been present in 
the past, but not since the last visit, enter "00 - Currently Absent."  If the symptom has never 
been present, enter "11 - Always Been Normal." 
 
Always Been Normal 
Currently Absent 
Mild ←→ Severe 
11 
00 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
Symptoms 
R 
L 
a. Pain, aching, or burning in feet, legs 
b. "Pins and needles" in feet, legs 
c. Numbness (lack of feeling) in feet, legs 
 
2. Grade Subjective Symptoms 
Use the single highest severity score from Question 1 above to obtain a subjective sensory 
neuropathy score.  If all severity scores are "00" or "11," the subjective sensory neuropathy score 
will equal "0." 
Subjective Sensory Neuropathy Score (based on highest severity rating) 
 01‒03 = grade of 1 
 04‒06 = grade of 2 
 07‒10 = grade of 3 
 11 or 00 = grade of 0 
 
R 
L 


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3. Evaluate Perception of Vibration 
Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch.  Place the 
vibrating tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she 
can recognize the vibration or "buzzing" quality of the tuning fork.  Again, compress the ends of 
the tuning fork just hard enough that the sides touch.  Immediately place the vibrating tuning 
fork gently but firmly on the top of the distal interphalangeal (DIP) joint of one great toe and 
begin counting the seconds.  Instruct the subject to tell you when the "buzzing" stops.  Repeat 
for the other great toe. 
Vibration perception 
 a. Great toe DIP joint perception of vibration in seconds 
 b. Vibration perception score 
 0 = felt > 10 seconds (normal) 
 1 = felt 6−10 seconds (mild loss) 
 2 = felt < 5 seconds (moderate loss) 
 3 = not felt (severe loss) 
 8 = unable to or did not assess 
 
4. 
 
Evaluate Deep Tendon Reflexes 
With the subject seated, the examiner uses one hand to press upward on the ball of the foot, 
dorsiflexing the subject's ankle to 90 degrees.  Using a reflex hammer, the examiner then 
strikes the Achilles tendon.  The tendon reflex is felt by the examiner's hand as a plantar flexion 
of the foot, appearing after a slight delay from the time the Achilles tendon is struck.  Use 
reinforcement by having the subject clench his/her fist before classifying the reflex as absent. 
Ankle Reflexes Score 
 0 = absent 
 1 = hypoactive 
 2 = normal deep tendon reflexes 
 3 = hyperactive 
 4 = clonus 
 8 = unable to or did not assess 
 
R 
L 
 
Source:  NIAID Adult AIDS Clinical Trials Group:  From Peripheral Neuropathy, Primary Care of Veterans 
with HIV, Office of Clinical Public Health Programs, Veterans Health Administration, 2009 
R 
L 


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Appendix K EXAMPLE ELECTRONIC SERIOUS ADVERSE EVENT 
CONTINGENCY REPORT FORM 
 


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Appendix L EXAMPLE AMGEN PREGNANCY NOTIFICATION WORKSHEET 
 
 


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Appendix M EXAMPLE AMGEN LACTATION NOTIFICATION WORKSHEET 
 
 
 


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Appendix N SUMMARY OF CHANGES IN PROTOCOL 2012-001 AMENDMENT 4 
Study 2012-001 was amended due to the following 
 Study visits are less frequent with data collection (eg labs, vitals, ECGs), and are being 
pared down to instances of clinical need for subjects on active treatment.  This 
amendment is based on the completion of the primary analysis of the study and 
abbreviated clinical study report. 
In addition, administrative updates, editorial changes, and style and formatting revisions have 
been made to improve clarity and consistency throughout the document.  Significant changes 
are described in the table below. 


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SUMMARY OF CHANGES 
Deletions of text are presented in strikethrough format.  Added text is presented in bold format. 
Section(s) 
Changed from 
Changed to 
Rationale 
Global 
International Conference on Harmonisation 
(ICH) 
International Council for Harmonisation (ICH) 
Change in regulatory 
body name 
Global 
Onyx 
The Sponsor 
New sponsor protocol 
SOP 
Global 
Onyx Drug Safety 
Sponsor Global Patient Safety 
New sponsor protocol 
SOP 
Title page 
New text added 
NCT Number:  NCT01832727 
New protocol SOP 
Title page 
Onyx Therapeutics 
249 East Grand Avenue 
South San Francisco, CA 94080 USA 
Phone:  (650) 266-0000 
Onyx Therapeutics 
One Amgen Center Drive 
Thousand Oaks, CA shou91320 USA 
(805) 447-1000 
Change in sponsor title 
and contact information 
Title page 
Medical monitor:  
, MD 
Medical Director, Clinical Development 
Onyx Pharmaceuticals 
249 East Grand Avenue 
South San Francisco, CA 94080  USA 
Phone:  
 
Email:  
 
Medical monitor:  
, MD 
Medical Director, Clinical Development 
1120 Veterans Blvd 
South San Francisco, CA 94080 USA 
Phone:  
 
Email:  
 
Change in responsibilities 
Title page 
New text added 
Amendment 4 / 08 February 2018 
New amendment 
identifiers 
Clinical Study 
Protocol Approval 
Signature Page 
Protocol Approval Signature Page 
[Approval section removed] 
New sponsor protocol 
SOP 
Protocol Acceptance 
Page 
Amendment 3 / 26 June 2014 
Amendment 4 / 08 February 2018 
New amendment 
identifiers 
Synopsis  
(Study Design) 
New text added 
The 240 mg dose is 2 dose levels below the single agent 
MTD, which was found to be 300 mg in Study 2011-001.  
Subjects on active treatment will continue with 
Oprozomib ER Tablets under protocol Amendment 4.  
No changes in drug product, dosage, or treatment 
Provide clarity for 
patients remaining 
on-study regarding study 
drug 


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regimen occurred in this protocol amendment from the 
previous version. 
Synopsis  
(Duration of 
study/treatment 
periods) 
Note:  For subjects who discontinue 
treatment for reasons other than progression 
in either study phase, disease assessments 
must be performed every 8 weeks until 
progression or until a new multiple myeloma 
therapy is started. 
Note:  For subjects who discontinue treatment for reasons 
other than progression in either study phase, disease 
assessments will no longer be required under protocol 
Amendment 4. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Section 1 
(Introduction) 
The main purpose of the current amendment 
(Amendment 3) is to: 
1. Introduce the Oprozomib ER tablet 
broadly in the study. 
2. Introduce step-up dosing in the dose 
escalation to determine if tolerability and 
safety are improved.  This approach is 
based on preclinical data suggesting this 
schedule may be better tolerated than 
continuous dosing (see Section 1.3). 
3. Include the use of the results of the safety 
and tolerability of step-up dosing in the 
determination of the recommended Phase 2 
dose. 
4. Provide additional safety guidance and 
exclusion criteria regarding GI hemorrhage 
as toxicities were observed in subjects 
treated with oprozomib on the 5/14 schedule 
(5 consecutive days every 14 days 
bimonthly) at 240 mg. 
The main purpose of the current amendment 
(Amendment 4) is to: 
Pare down data collection for subjects on active 
treatment due to the completion of this study’s analysis 
and abbreviated clinical study report. 
Update text to reflect the 
rationale for 
Amendment 4 
Section 1.5.1 
(Dose Rationale) 
New text added 
Protocol Amendment 4 
No changes in drug product, dosage, or treatment 
regimen occurred in this protocol amendment from the 
previous version. 
Added text to maintain 
continuity within the 
section to explain no 
changes to dose in 
Amendment 4 
Section 3.4 
(Estimated Study 
Duration) 
For subjects who discontinue treatment for 
reasons other than progression, disease 
assessments must be performed every 8 
For subjects who discontinue treatment for reasons other 
than progression, disease assessments will no longer be 
required under protocol amendment 4. 
Provide convenience for 
those on study treatment 


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Section(s) 
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weeks, or until a new multiple myeloma 
therapy is started or disease progresses. 
as study has completed its 
abbreviated report 
Section 7 (Study 
Tests and 
Observations) 
For subjects with SD or better after at least 
12 cycles of therapy who are on a steady 
dose for ≥ 2 cycles and are tolerating 
oprozomib, study assessments may be 
performed every 2 cycles, and 2 cycles of 
study medication may be dispensed from the 
study site at a time starting with Cycle 13 
For subjects with SD or better after at least 12 cycles of 
therapy who are on a steady dose for ≥ 2 cycles and are 
tolerating oprozomib, study assessments may be 
performed every 4 cycles, and 4 cycles of study 
medication may be dispensed from the study site at a time 
starting with Cycle 13 
 
Section 7.7 
(Assessments At 
End Of Study 
Treatment Or Early 
Discontinuation) 
 
For subjects who discontinue treatment for 
reasons other than progression, disease 
assessments will be performed every 8 
weeks or until a new multiple myeloma 
therapy is started or disease progresses.  The 
same methods of disease assessment must be 
used throughout the study.  If disease 
assessments show confirmed disease 
progression, assessments do not need to be 
repeated with End-of-Study Assessments. 
For subjects who discontinue treatment for reasons other 
than progression, disease assessments will no longer be 
required under protocol Amendment 4. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Appendix E 
(Schedule of 
Assessments:  
Disease Response 
Evaluations, 
footnote a) 
For subjects who discontinue treatment for 
reasons other than progression, disease 
assessments must be performed every 8 
weeks or until a new multiple myeloma 
therapy is started or disease progresses.  The 
same methods of disease assessment must be 
used throughout the study.  If disease 
assessments show confirmed disease 
progression, assessments do not need to be 
repeated with End-of-Study Assessments. 
For subjects who discontinue treatment for reasons other 
than progression, disease assessments will no longer be 
required under Amendment 4. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Section 9.1 (Adverse 
Events Definitions) 
New text added 
The National Cancer Institute Common Terminology 
Criteria for Adverse Events does not use to the term 
“intermittent” and this term must not be used to 
describe AEs.   
Update safety reporting 
language with latest 
template. 


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Section 9.2 
(Causality) 
A suspected adverse reaction means any AE 
for which there is a reasonable possibility 
that the study drug caused the AE. 
“Reasonable possibility” means there is 
evidence to suggest a causal relationship 
between the drug and the AE.  An adverse 
reaction means any AE caused by a drug.  
The relationship of the AE to the study drug 
should be assessed using the following 
criteria: 
A suspected adverse reaction means any AE for which 
there is a reasonable possibility that the study drug caused 
the AE. “Reasonable possibility” means there is evidence 
to suggest a causal relationship between the drug and the 
AE.  An adverse reaction means any AE caused by a 
drug.  The relationship of the AE to the study drug should 
be assessed using the following criteria: 
Update safety reporting 
language with latest 
template. 
Section 9.3.2 
(Disease 
Progression) 
All deaths that occur from the time that ICF 
is signed until 30 days after the last dose of 
study drug is administered are to be reported 
as SAEs (see Section 9.4).  Disease 
progression-related deaths must be reported 
on the AE eCRF using 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 eCRF. 
All deaths that occur from the time that ICF is signed until 
30 days after the last dose of study drug is administered 
are to be reported as SAEs (see Section 9.4).  Death due 
to disease progression in the absence of signs and 
symptoms should be reported as the primary tumor 
type (eg, metastatic, pancreatic cancer).  Note:  The 
term “disease progression” should not be used to 
describe the disease related event or adverse event.  
Additional details of the event (such as the primary and 
contributory causes of death) should be reported on the 
Death eCRF. 
Update safety reporting 
language with latest 
template. 
Section 9.5 (Serious 
Adverse Event 
Reporting and 
Documentation 
Requirements) 
Onyx Drug Safety must be notified within 
24 hours of the investigator, designee, or site 
personnel knowledge of the event.  To report 
an SAE to Onyx Drug Safety , please refer to 
the SAE reporting guidelines in the Study 
Reference Manual. 
Follow-up reports must be submitted in a 
timely fashion as additional information 
becomes available. 
Amgen Global Patient Safety must be notified within 24 
hours of the investigator, designee, or site personnel 
knowledge of the event.  To report an SAE to Amgen 
Global Patient Safety, please refer to the SAE reporting 
guidelines below. 
The primary mechanism for reporting serious adverse 
events will be the electronic data capture system (EDC) 
via the Safety Report Form.  If the EDC system is 
unavailable for more than 24 hours, then the site will 
Update safety reporting 
language with latest 
template. 


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The investigator is responsible for notifying 
the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) in 
accordance with local regulations, of all 
SAEs.  The sponsor may request additional 
source documentation pertaining to the SAE.  
If a subject is permanently discontinued 
from the study because of an SAE, this 
information must be included in the initial 
or follow-up SAE report form as well as the 
Study Discontinuation eCRF. 
All SAEs occurring from the time that the 
subject signs consent for study participation 
and through 30 days after the last 
administered dose of study drug will be 
reported, regardless of whether new 
chemotherapy regimens are initiated (see 
Section 9.2 for additional information).  All 
SAEs, regardless of relationship to study 
drug, must be followed to resolution or to 
stabilization if improvement or resolution is 
not expected. 
report the information to Amgen using an electronic 
Serious Adverse Contintency Report Form (see 
Appendix K) within 24 hours of the investigator’s 
knowledge of the event.  The site will enter the serious 
adverse event data into the electronic system as soon as 
it becomes available. 
After the study is completed at a given site, the EDC 
system will be taken offline to prevent the entry of new 
data or changes to existing data. 
If a site receives a report of a new serious adverse event 
from a study subject or receives updated data on a 
previously reported serious adverse event after the 
EDC has been taken offline, then the site can report this 
information on a paper Serious Adverse Event Report 
Form (see Appendix K). 
If a subject is permanently withdrawn from protocol-
required therapies because of a serious adverse event, 
this information must be submitted to Amgen. 
New or updated information will be recorded in the 
originally completed Event CRF. 
The investigator will submit any updated serious 
adverse even data to Amgen Global Patient Safety 
within 24 hours of receipt of the information. 
The investigator is responsible for notifying the 
Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) in accordance with local regulations, of 
all SAEs.  The sponsor may request additional source 
documentation pertaining to the SAE.  If a subject is 
permanently discontinued from the study because of an 
SAE, this information must be included in the initial or 


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follow-up SAE report form as well as the Study 
Discontinuation eCRF. 
All SAEs occurring from the time that the subject signs 
consent for study participation and through 30 days after 
the last administered dose of study drug will be reported, 
regardless of whether new chemotherapy regimens are 
initiated (see Section 9.2 for additional information).  All 
SAEs, regardless of relationship to study drug, must be 
followed to resolution or to stabilization if improvement or 
resolution is not expected. 
Section 9.6 
(Pregnancy) 
Subjects will be instructed to notify the 
investigator as soon as possible after 
becoming pregnant or learning of the 
pregnancy of a partner.  If a subject or 
partner of a subject becomes pregnant 
during treatment or up to 30 days following 
the last study drug administration, the 
investigator will notify Onyx within 24 
hours of learning of the pregnancy. 
 
If the subject becomes pregnant 
while taking an Onyx drug, the 
drug will be immediately 
discontinued.  The investigator will 
discuss the risks and concerns of 
investigational drug exposure to a 
developing fetus and counsel the 
subject and/or pregnant partner (or 
ensure that such counseling is 
provided). 
 
Pregnancies will be followed 
through the outcome of the 
pregnancy. 
If a patient or spouse or partner of a patient becomes 
pregnant during treatment or up to 30 days following 
administration of study treatment, Amgen Global 
Patient Safety and the medical monitor must be notified 
within 24 hours of the investigator, designee, or site 
personnel learning of the pregnancy.  On notification to 
Amgen, the investgator must obtain a separate 
information release and authorization form for the use 
and disclosure of health information of the pregnant 
spouse or partner of a patient.  If the patient becomes 
pregnant while taking oprozomib, oprozomib must be 
immediately discontinued.  Patients, spouses, or 
partners will be followed through the outcome of the 
pregnancy.  The investigator will be required to 
complete an Amgen Pregnancy Notification Worksheet 
and report the information as specified below.  To 
report a pregnancy to Amgen Global Patient Safety, 
please refer to the pregnancy reporting guidelines 
below. 
Update safety reporting 
language with latest 
template. 
 


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 
Newborns should be followed for a 
minimum of 12 weeks. 
The investigator will complete a Pregnancy 
Monitoring Form and report the information 
regarding the pregnancy, outcome, and 
status of the newborn, as appropriate. 
.   
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on 
any female subject who becomes pregnant while 
taking protocol-required therapies through 
30 days after stopping oprozomib. 
 
Information will be recorded on the Pregnancy 
Notification Worksheet (Appendix L).  The 
worksheet must be submitted to Amgen Global 
Patient Safety within 24 hours of learning of a 
subject’s pregnancy.  Note:  Sites are not required 
to provide any information on the Pregnancy 
Notification Worksheet that violates the country or 
regions local privacy laws. 
 
After obtaining the female subject’s signed 
authorization for release of pregnancy and infant 
health information, the investigator will collect 
pregnancy and infant health information and 
complete the pregnancy questionnaire for any 
female subject who becomes pregnant while taking 
protocol-required therapies through 30 days after 
stopping oprozomib.  This information will be 
forwarded to Amgen Global Patient Safety.  
Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if 
applicable). 
 
Any termination of pregnancy will be reported to 
Amgen Global Patient Safety, regardless of fetal 
status (presence or absence of anomalies) or 
indication for procedure. 
 
While pregnancy itself is not considered to be an 
adverse event or serious adverse event, any 


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pregnancy complication or report of a congenital 
anomaly or developmental delay, fetal death, or 
suspected adverse reactions in the neonate will be 
reported as an adverse event or serious adverse 
event.  Note that an elective termination with no 
information on fetal congenital malformation or 
maternal complication is generally not considered 
an adverse event, but still must be reported to 
Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion 
for immediate classification as a serious adverse 
event (eg, female subject experiences a 
spontaneous abortion, stillbirth, or neonatal death 
or there is a fetal or neonatal congenital anomaly) 
the investigator will report the event as a serious 
adverse event. 
 
Any serious adverse event occurring as a result of 
a post-study pregnancy which is considered 
reasonably related to the study treatment by the 
investigator will be reported to Amgen Global 
Patient Safety as described in Section 9.5.  While 
the investigator is not obligated to actively seek 
this information in former study subjects, he or 
she may learn of a serious adverse event through 
spontaneous reporting. 
 
Any female subject who becomes pregnant while 
participating will discontinue study treatment. 
Male Subjects With Partners Who Become Pregnant or 
Were Pregnant at the Time of Enrollment 
 
In the event a male subject fathers a child during 
treatment, and for an additional 90 days after 
discontinuing protocol-required therapies, the 
information will be recorded on the Pregnancy 


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Notification Worksheet (Appendix L).  The 
worksheet must be submitted to Amgen Global 
Patient Safety within 24 hours of the site’s 
awareness of the pregnancy.  Note:  Sites are not 
required to provide any information on the 
Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws. 
 
The investigator will attempt to obtain a signed 
authorization for release of pregnancy and infant 
health information directly from the pregnant 
female partner to obtain additional pregnancy 
information. 
 
After obtaining the female partner’s signed 
authorization for release of pregnancy and infant 
health information, the investigator will collect 
pregnancy outcome and infant health information 
on the pregnant partner and her baby and 
complete the pregnancy questionnaires.  This 
information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if 
applicable). 
 
Any termination of the pregnancy will be reported 
to Amgen Global Patient Safety regardless of fetal 
status (presence or absence of anomalies) or 
indication for procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on 
any female subject who breastfeeds while taking 
protocol-required therapies through 30 days after 
stopping oprozomib. 


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 
Information will be recorded on the Lactation 
Notification Worksheet (Appendix M) and 
submitted to Amgen Global Patient Safety within 
24 hours of the investigator’s knowledge of event. 
 
Study treatment will be discontinued if female 
subject breastfeeds during the study as described 
in exclusion criterion 16. 
With the female subjects signed authorization for 
release of mother and infant health information, the 
investigator will collect mother and infant health 
information and complete the lactation questionnaire 
on any female subject who breastfeeds while taking 
protocol-required therapies through 30 days after 
discontinuing protocol-required therapies. 
Section 11.1.2 
(Formulation) 
New text added 
No changes in drug product, dosage, or treatment 
regimen occurred in this protocol amendment from the 
previous version. 
Added text to maintain 
continuity within the 
section to explain no 
changes to dose in 
Amendment 4 
Section 14 
(References) 
Text deleted 
Kummar S, Gutierrez M, Doroshow JH, et al. Drug 
development in oncology: classical cytotoxics and 
molecularly targeted agents. Br J Clin Pharmacol. 
2006;62(1):15–26. 
 
Reference deleted per 
body of protocol 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, Step-up 
Dosing Subjects, 
footnote a) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, 
New text added 
A physical examination may be performed every 4 cycles 
after subjects have been on study for more than 2 months if 
clinically indicated. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 


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Continuous Dosing 
Subjects, footnote a) 
 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, 
Continuous Dosing 
Subjects, footnote a) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, Step-up 
Dosing Subjects, 
footnote a) 
New text added 
A physical examination can be performed every 4 cycles 
after subjects have been on study for more than 2 months if 
clinically indicated. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Appendix B 
(Schedule of 
Assessments – 5/14 
Phase 2, footnote a) 
 
New text added 
A physical examination may be performed every other 
month after subjects have been on study for more than 2 
months if clinically indicated 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Appendix D 
(Schedule of 
Assessments – 2/7 
Phase 2, footnote a) 
New text added 
A physical examination can be performed every other 
month after subjects have been on study for more than 2 
months if clinically indicated 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, 
Continuous Dosing 
Subjects, footnotes 
b) 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, Step-up 
New text added 
Patients on active treatment under Amendment 4 will 
have this assessment performed only if clinically 
indicated and at EOS. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 


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Dosing Subjects, 
footnotes b, and e) 
Appendix B 
(Schedule of 
Assessments – 5/14 
Phase 2, footnote b) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, 
Continuous Dosing 
Subjects, footnote b) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, Step-up 
Dosing Subjects, 
footnote b 
Appendix D 
(Schedule of 
Assessments – 2/7 
Phase 2, footnote b) 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, 
Continuous Dosing 
Subjects, footnotes d 
an h) Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, Step-up 
Dosing Subjects, 
footnotes d and h) 
 Appendix B 
(Schedule of 
New text added 
Patients on active treatment under Amendment 4 will 
have these assessments performed only if clinically 
indicated and at EOS. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 


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Assessments – 5/14 
Phase 2 footnotes e, 
and i) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, 
Continuous Dosing 
Subjects, footnotes e, 
and h) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, Step-up 
Dosing Subjects, 
footnotes e, and h) 
Appendix D 
(Schedule of 
Assessments – 2/7 
Phase 2, footnotes e 
and i) 
 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, 
Continuous Dosing 
Subjects, footnotes c 
and g) 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, Step-up 
Dosing Subjects, 
footnotes c and g) 
New text added 
Patients on active treatment under Amendment 4 will 
have these assessments performed only if clinically 
indicated 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 


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Appendix B 
(Schedule of 
Assessments – 5/14 
Phase 2, footnotes c, 
d, and h) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, 
Continuous Dosing 
Subjects, footnotes c, 
d, and g) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, Step-up 
Dosing Subjects, 
footnotes c, d, and g) 
Appendix D 
(Schedule of 
Assessments – 2/7 
Phase 2, footnotes c, 
d, and h) 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, 
Continuous Dosing 
Subjects, footnote r) 
Appendix A 
(Schedule of 
Assessments – 5/14 
Phase 1b, Step-up 
Dosing Subjects, 
footnote r) 
For patients with ≥ SD for at least 6 months 
(12 cycles), who are on a steady dose for ≥ 2 
cycles, and are tolerating oprozomib, study 
assessments may be reduced to every 2 
cycles (starting at Cycle 13, Day 1, then 
Cycle 15, Day 1, etc.) and 2 cycles of study 
medication can be provided at clinic visits.  
Subjects who do not meet these criteria 
should continue to have study assessments 
performed at every cycle. 
For patients with ≥ SD for at least 6 months (12 cycles), 
who are on a steady dose for ≥ 2 cycles, and are tolerating 
oprozomib, study assessments may be reduced to every 4 
cycles (starting at Cycle 13, Day 1, then Cycle 15, Day 1, 
etc.) and 4 cycles of study medication can be provided at 
clinic visits.  Subjects who do not meet these criteria 
should continue to have study assessments performed at 
every cycle. 
Provide convenience for 
those on study treatment 
as study has completed its 
abbreviated report 


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Appendix B 
(Schedule of 
Assessments – 5/14 
Phase 2, footnote r) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, 
Continuous Dosing 
Subjects, footnote r) 
Appendix C 
(Schedule of 
Assessments – 2/7 
Phase 1b, Step-up 
Dosing Subjects, 
footnote r) 
Appendix D 
(Schedule of 
Assessments – 2/7 
Phase 2, footnote r) 
Appendix K 
(Example Electronic 
Serious Adverse 
Event Contingency 
Report Form) 
New text added 
 
Provide updated adverse 
event reporting form. 


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Appendix L 
(Example Amgen 
Pregnancy 
Notification 
Worksheet) 
New text added 
 
Provide updated 
pregnancy reporting 
worksheet. 
Appendix M 
(Example Amgen 
Lactation 
Notification 
Worksheet) 
New text added 
 
Provide updated lactation 
reporting worksheet. 
 


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Protocol 2012-001, Amendment 3
Oprozomib Tablets
Page 128 of 197
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APPENDIX K
SUMMARY OF CHANGES IN PROTOCOL 2012-001 
AMENDMENT 3
The key changes in Amendment 3 are listed below: 
1. Addition of the new Oprozomib ER formulation Tablets
2. Addition of the step-up dosing for dose escalation
3. Addition of additional clinic visits for safety assessments
4. Addition of PK and PD assessments based on new dosing and formulation
5. Addition of assessments of orthostatic hypotension and management 
6. Updates to safety and efficacy information from oprozomib studies
7. Updates to Inclusion/Exclusion criteria
8. Updates to phototoxicity risk with oprozomib
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes are 
described in the table below.  Changes in sections of the protocol body were also made in the 
protocol synopsis and elsewhere in the document, as applicable.  Changes in the schedules of 
assessments have been updated to be current with the revised study plan and assessment 
schedule.  Please see body of the protocol and the schedules of assessments for additional 
details.  Added text is presented in bold format.


Onyx Therapeutics, Inc.
Protocol 2012-001, Amendment 2
Oprozomib Tablets
Page 95 of 102
CONFIDENTIAL
APPENDIX I:
SUMMARY OF CHANGES IN 
PROTOCOL 2012-001 AMENDMENT 2
Study 2012-001 was amended to incorporate FDA requested changes/additions, specifically with 
regard to the definition of dose-limiting toxicities as applied to the Phase 1b component of the 
study and the incorporation of specific guidelines for the Prophylaxis and Management of Tumor 
Lysis Syndrome (TLS).  The key changes in Amendment 2 are listed below: 
1. Study Synopsis (Study Design) and Section 6.3 Dose-Limiting Toxicity:  The text was 
edited to classify Grade ≥ 4 abnormalities in serum creatinine or electrolytes as DLTs; 
Grade ≥ 3 acute kidney injury defined as creatinine > 3 × baseline or > 4.0 mg/dL of any 
duration is to be considered a DLT; and occurrence of Grade ≥ 3 nausea, vomiting, 
constipation or diarrhea of > 7 days duration in spite of optimal management, including a 
5-HT3 antagonist and aprepitant for nausea and vomiting, and loperamide (e.g.,
Imodium®) and diphenoxylate/atropine (e.g. Lomotil®) for diarrhea is to be considered a 
DLT.
2. Sections 6.5 and 6.6.1:  Text was added to provide guidance for monitoring/prophylaxis 
and treatment of tumor lysis syndrome.
Administrative updates, editorial changes, and style and formatting revisions have been made to 
improve clarity and consistency throughout the document.  Significant changes are described in 
the table below.  Changes in sections of the protocol body were also made in the protocol 
synopsis and elsewhere in the document, as applicable. Added text is presented in bold format.


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 1 
Oprozomib Tablets 
Page 98 of 114 
 
Confidential   
18 March 2013 
APPENDIX I: 
SUMMARY OF CHANGES IN  
PROTOCOL 2012-001 AMENDMENT 1 
Study 2012-001 was amended to implement a new starting dose for Oprozomib Tablets for both 
dosing schedules based on dose-escalation data from ongoing Study 2011-001.  This and other 
key changes in Amendment 1 are listed below:  
1. Global change:  Starting dose of 150 mg was changed to 210 mg for both oprozomib 
dosing schedules.  This update was made based on dose-escalation data from ongoing 
Study 2011-001 from both tablet and product-in-capsule (PIC) formulations. 
2. Global change:  Changed units for absolute neutrophil count (ANC) and platelet counts 
from [value] ×109/L to standard units, [value] cells/mcL. 
3. Study Synopsis (Test Product, Dose, and Mode of Administration):  Removed specific 
dexamethasone oral tablet strengths (4 mg and 6 mg).  This text did not appear in the 
protocol body.  
4. Section 1.4.1:  Added dose rationale for 210 mg starting dose of Oprozomib Tablets 
based on preliminary safety results from Study 2011-001, PK data demonstrating 
comparable exposures between the tablet and capsule, and rationale for the combination 
of oprozomib with low-dose dexamethasone as a means to reduce gastrointestinal (GI) 
toxicity.  
5. Section 3.4, Appendix A and Appendix B (footnote 1):  Added that subjects continuing 
on study treatment and whose disease has not progressed 1 year after starting study 
treatment will reduce the frequency of their visits (on Day 1 of their next scheduled 
cycle) to every 4 weeks instead of every 2 weeks, with adequate drug supply for 2 cycles 
of treatment.  Also clarified that disease response will be assessed every 8 weeks 
(4 cycles) after 1 year on therapy. 
6. Section 4.1:  Clarified in Inclusion Criterion #5 that bilirubin must be ≤ 1.5 times the 
upper limit of normal (ULN) in the absence of Gilbert’s disease or hemolysis. 
7. Section 4.2:  Clarified in Exclusion Criterion #3 that glucocorticoid therapy within 
14 days prior to randomization that exceeds a cumulative dose of 160 mg of 
dexamethasone or equivalent is not allowed.   
8. Section 4.2:  Added Exclusion Criterion #10, uncontrolled hypertension or uncontrolled 
diabetes. 
9. Section 4.2:  Deleted Exclusion Criteria #14, patients with pleural effusions requiring 
routine thoracentesis, and #15, patients with ascites requiring routine paracentesis. 
10. Section 4.2:  Updated Exclusion Criterion #18 to add “increased patient risk” to the 
criterion. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 1 
Oprozomib Tablets 
Page 99 of 114 
 
Confidential   
18 March 2013 
11. Section 6.1:  Appendices A and B (footnote 23):  Provided clarification that 
dexamethasone must be taken at least 30 minutes prior to oprozomib.    
12. Section 6.1:  Specified that oprozomib will be administered in combination with 
dexamethasone at 20 mg orally (or intraveneously, if tablets are unavailable or subject 
cannot tolerate tablets).  
13. Section 6.2.2:  Added that intrasubject dose escalation to the recommended Phase 2 dose 
may be permitted once that dose has been determined and after discussion between the 
treating physician and Onyx medical monitor. 
14. Section 6.3:  Added note that ≥ Grade 3 dexamethasone-related hyperglycemia is not 
considered a DLT. 
15. Section 6.3:  Added note that Grade 3 fatigue lasting < 14 days is not considered a DLT. 
16. Section 6.6.1:  Added recommended concomitant medications, valacyclovir and 
lansoprazole, for prevention of herpes zoster and peptic disease, respectively.  
17. Sections 7.3.1–7.3.4, Appendix A and Appendix B (footnotes 15-18), and Appendix G:  
Updated protocol body and schedule of assessments to provide clarification and 
flexibility around PK and PDn sampling timepoints.  For Phase 2 subjects, also provided 
clarity that subjects must fast before and after study drug administration on PK sampling 
days. 
18. Section 9.3.1:  Revised the text for how AEs are captured for subjects who do not receive 
any study drug. 
19. Appendix A:  Removed redundant term, cytogenetics, to clarify that FISH is the 
cytogenetic technique that will be used.. 
20. Appendix A:  Added missing Cycle 2, Day 3 and 4 column that includes administration 
of oprozomib, administration of optional antiemetics, and recording of AEs and 
concomitant medications. 
21. Appendices A and B (footnote 9):  Added that serum chemistry and complete blood count 
(CBC) on Cycle 2, Day 5 will be completed for Phase 2 only (if PK or PDn sample is 
being collected). 
22. Appendices A and B (footnote 12):  Added that, if present at Baseline, bone lesions must 
be monitored every 2 cycles throughout the study. 
23. Appendices A and B (footnote 13):  Provided clarification that, in addition to Screening 
and End of Study assessments, subjects with plasmacytoma(s) at Baseline must also be 
monitored every 2 cycles throughout the study per IMWG response criteria. 
24. Appendices A and B (footnote 14):  Add clarification that bone marrow aspirate will also 
be collected at the time of progression (may be at time of treatment discontinuation or 
during long-term follow up) for subjects who have signed the separate consent. 
25. Appendix B:  Added missing timepoint for Cycle 2, Day 1 PDn/Proteomic analyses. 


Onyx Therapeutics, Inc. 
Protocol 2012-001, Amendment 1 
Oprozomib Tablets 
Page 100 of 114 
 
Confidential   
18 March 2013 
26. Appendix F (EBMT criteria):  Updated criteria for minimal response based on Kyle 2009 
article on response assessment in multiple myeloma. 
Minor editorial changes and updates to style and formatting have been made to improve clarity 
and consistency throughout the document. 
Detailed changes are described in the table below.  Changes in sections of the protocol body 
were also made in the protocol synopsis and elsewhere in the document, as applicable.  
Deleted text is presented in strikethrough format.  Revised text is presented in bold format. 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN   
PROTOCOL ONX-2012-001 
Phase 1b/2, Multicenter, Open–label Study of Oprozomib and Dexamethasone in Subjects with 
Relapsed and/or Refractory Multiple Myeloma  
Sponsor: Onyx Pharmaceuticals, an Amgen subsidiary 
One Amgen Center Dr.  
Thousand Oaks, CA 91320 
(805) 447-4897
Date:        OCT 20, 2016 
Version:   1.0 
Confidential Information 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be 
disclosed unless such disclosure is required by applicable laws and regulations. In any event, persons to whom the information is 
disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is indicated as privileged or confidential. 
Date/Time of most recent changes: 10/20/2016 
NCT Number: NCT01832727
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 2
 
Signature Page                           
Prepared by: 
 
 
 
 
 
 
 
  Date:     
 
 
 
 
 
 PhD 
 
 
Senior Manager, Biostatistics 
 
Reviewed by: 
 
 
 
 
 
  Date:    
 
 
  
PhD  
Director, Global Biostatistics 
 
 
 
 
 
 
  Date:    
 
 
  
MD  
Medical Monitor: Oprozomib 
 
 
 
 
 
 
  Date:    
 
 
  
PharmD  
Medical Sciences Director 
 
 


Onyx Pharmaceuticals Inc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol ONX-2012-001 
Signature Page 
 
Date: 
2o OcT20/6 
PhD 
Senior Manager, Biostatistics 
PhD 
Director, Global Biostatistics 
-------------- Date: 
MD 
Medical Monitor: Oprozomib 
~------------~ Date: ~--------
PharmD 
Medical Sciences Director 
page 2 


Onyx Pharmaceuticals Inc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol ONX-2012-001 
Signature Page 
PhD 
Senior Manager, Biostatistics 
PhD 
Director, Global Biostatistics 
MD 
Medical Monitor: Oprozomib 
PharmD 
Medical Sciences Director 
page 2 


Onyx Pharmaceuticals Inc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol ONX-2012-001 
Signature Page 
PhD 
Senior Manager, Biostatistics 
PhD 
Director, Global Biostatistics 
MD 
Medical Monitor: Oprozomib 
page 2 
i 
J 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 3
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
CRF 
case report form 
CBR 
clinical benefit response 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
MM 
multiple myeloma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MTD 
maximum tolerated dose 
N 
number of subjects 
nCR 
near complete response 
ORR  
overall response rate 
PD 
progressive disease 
PDn 
pharmacodynamic 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 4
Abbreviation or Term 
Definition 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
PR 
partial response 
PT 
MedDRA preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
stable disease 
SOC 
MedDRA system organ class 
TEAEs 
Treatment-emergent adverse events 
TTP 
time to progression 
VGPR 
very good partial response  
 
 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 5
TABLE OF CONTENTS 
 
 
1 
INTRODUCTION ............................................................................................ 7 
2 
STUDY OVERVIEW ....................................................................................... 7 
2.1 
Overall Study Design ............................................................................... 7 
2.2 
Study Objectives ...................................................................................... 8 
2.2.1 
Primary Objectives................................................................................... 8 
2.2.2 
Secondary Objectives............................................................................... 9 
2.3 
Sample Size Justification ......................................................................... 9 
3 
STUDY ENDPOINTS ................................................................................... 10 
3.1 
Primary Endpoints ................................................................................. 10 
3.2 
Secondary Endpoints ............................................................................. 10 
4 
ANALYSIS POPULATIONS ........................................................................ 11 
5 
ANALYTIC DEFINITIONS ........................................................................... 11 
5.1 
Study Day 1............................................................................................ 11 
5.2 
Study Day............................................................................................... 11 
5.3 
Baseline .................................................................................................. 12 
6 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ................... 12 
7 
STATISTICAL METHODS ........................................................................... 12 
7.1 
General Considerations .......................................................................... 12 
7.2 
Disposition of Subjects .......................................................................... 13 
7.3 
Demographic and Baseline Characteristics ........................................... 13 
7.3.1 
Demographic and Baseline Characteristics ........................................... 13 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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7.3.2 
Medical History ..................................................................................... 14 
7.3.3 
Disease Characteristics .......................................................................... 14 
7.3.4 
Prior Cancer Therapies .......................................................................... 15 
7.4 
Treatments and Medications .................................................................. 15 
7.4.1 
Study Drug Administration .................................................................... 15 
7.5 
Efficacy Analyses .................................................................................. 16 
7.5.1 
Overall Response Rate ........................................................................... 16 
7.5.2 
Progression Free Survival ...................................................................... 16 
7.5.3 
Time to Progression ............................................................................... 17 
7.5.4 
Duration of Response ............................................................................. 18 
7.5.5 
Duration of Clinical Benefit Response .................................................. 18 
7.6 
Safety Analysis ...................................................................................... 18 
7.6.1 
Adverse Events ...................................................................................... 19 
7.6.2 
Laboratory Data ..................................................................................... 20 
7.6.3 
Vital Signs and Weight .......................................................................... 21 
7.6.4 
12-Lead Electrocardiogram ................................................................... 21 
7.6.5 
Prior and Concomitant Medications ...................................................... 21 
7.6.6 
Protocol Deviations ................................................................................ 22 
8 
STATISTICAL/ANALYTICAL ISSUES ........................................................ 22 
8.1 
Handling of Dropouts or Missing Data .................................................. 22 
8.2 
Interim Analysis and Data Monitoring .................................................. 22 
 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) was prepared for an abbreviated clinical study report 
(aCSR) in accordance with Protocol ONX-2012-001, dated 26June2014 (amendment 3), 
and describes the analyses of data collected within the scope of the study. Any changes 
that are made to the planned analyses after the SAP is finalized, along with an 
explanation as to when and why they occurred, will be noted in the abbreviated clinical 
study report produced for the study.  Any changes made to the planned analyses that are 
in the protocol will be identified and documented in this document. 
 
2 
STUDY OVERVIEW 
2.1 
Overall Study Design  
This study is an open–label, Phase 1b/2, multicenter study in which subjects will receive 
oprozomib (OPZ)  administered orally once daily in combination with dexamethasone 
(DEX) on 2 different treatment schedules.  Subjects will receive OPZ on Days 1–5 of a 
14–day cycle in combination with 20 mg DEX on Days 1, 2, 8, and 9; or OPZ on Days 1, 
2, 8, and 9 of a 14–day cycle in combination with 20 mg dexamethasone on Days 1, 2, 8, 
and 9.  Both the Phase 1b and Phase 2 portions of this trial will be open to subjects with 
relapsed and/or refractory multiple myeloma. 
Treatment will be administered in 14–day cycles until disease progression, unacceptable 
toxicity, or study treatment discontinuation for any reason. 
Disease response assessments will be performed every 4 weeks for the first year through 
Cycle 26 and then every 8 weeks thereafter  according to the IMWG–URC.  In addition, 
nCR and MR will be assessed per the modified EBMT criteria. 
A minimum of 3 subjects will be entered within each dose cohort, to be expanded up to 6 
subjects if DLTs are observed.  Assessment of DLTs will occur during the first 14 days 
of treatment (or Cycle 1) or the first 14 days of treatment with the step-up dose to be 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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studies (Cycle 2).  Any subject who develops a DLT after receiving at least 1 dose of 
OPZ will be considered evaluable.  Any subject who does not develop a DLT, but has not 
received all planned doses of OPZ and DEX will be considered unevaluable for the dose 
escalation decision and will be replaced. 
If none of the first 3 subjects in a cohort experiences a DLT in the first cycle, enrollment 
will commence at the next planned dose level.  If 1 of 3 subjects enrolled in a cohort 
experiences a DLT during the first treatment cycle, the same cohort will be expanded up 
to 6 evaluable subjects.  If 1 of 6 subjects experiences a DLT during the first treatment 
cycle, the next cohort will enroll at the next higher dose level.  If 2 or more subjects in a 
cohort experience a DLT in the first treatment cycle, the MTD will have been exceeded, 
additional enrollment within the cohort will cease, and dose escalation will stop. 
If 2 or more subjects experience a DLT at a given dose, additional subjects will be added 
to the preceding dose group if there are fewer than 6 subjects in that cohort, for a 
minimum of 6 subjects treated at that dose in order to determine the MTD.  The MTD 
will be defined as the highest dose in which a DLT is observed in less than 2 of 6 subjects 
At least 6 subjects must be treated at the MTD for a minimum of 1 cycle to establish this 
dose as tolerated. 
The initial cohort will be entered at a dose level of 210 mg.  All subsequent cohorts will 
be escalated by 30 mg until the MTD is determined.  There will not be a predefined 
maximum dose to be studied.    
2.2 
Study Objectives  
2.2.1 Primary Objectives 
Phase 1b: 
• To determine the MTD and recommended Phase 2 dose (RP2D) of OPZ given 
orally, once daily, on 2 different schedules:  5 consecutive days every 14 days 
(bimonthly; 5/14) or 2 consecutive days every 7 days (weekly; 2/7) for a 14–day 
treatment cycle, both schedules given in combination with DEX. 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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• To evaluate safety and tolerability 
Phase 2: 
• To estimate the overall response rate (ORR), defined as the proportion of subjects 
with the best overall response of stringent complete response (sCR), complete 
response (CR), near complete response (nCR), very good partial response 
(VGPR), and partial response (PR) as defined by the International Myeloma 
Working Group–Uniform Response Criteria (IMWG–URC) and modified 
European Group for Blood and Marrow Transplantation (EBMT) criteria. 
• To evaluate safety and tolerability 
2.2.2 Secondary Objectives 
• To evaluate PK of OPZ tablet and OPZ ER tablet 
• To estimate clinical benefit rate (CBR), defined as ORR plus minimal response 
(MR), as defined by the EBMT criteria 
• To estimate the duration of response (DOR) 
• To estimate progression–free survival (PFS) 
• To estimate time to progression (TTP) 
 
2.3 
Sample Size Justification 
For the Phase 1b portion of the study, it is estimated that up to approximately 60 subjects 
(approximately 30 subjects per treatment schedule) will be required to determine the 
recommended Phase 2 dose for each treatment schedule.  This is based on an estimate 
that up to 5 cohorts will be enrolled per treatment schedule, with up to 6 evaluable 
subjects per cohort. 
For the recommended dose group (dose escalation cohort plus Phase 2 cohort), the null 
(H0) and the alternative (HA) hypotheses are as follows: 
H0:  ORRCd ≤ 15% 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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HA: ORRCd > 15% 
With a sample size of 46 subjects (6 evaluable dose escalation subjects + 40 Phase 2 
subjects enrolled at the recommended dose),  a 1–sample exact binomial test with a 1–
sided significance level of 5% will have 77% power at an ORR of 30%.  If at least 12 of 
the 46 subjects have a best overall response of PR or better, then the null hypothesis will 
be rejected and it will be inferred that the ORR is > 15%.  
The total study sample size will depend on the number of dose levels required to establish 
the recommended dose for each schedule and the number of schedules initiated in the 
Phase 2 portion of the study. The study will enroll approximately 140 subjects. 
 
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoints   
Phase 1b: 
• Dose–limiting toxicities identified to determine the MTD and RP2D, defined as 
the highest dose at which < 33% of subjects experience DLTs after 1 cycle (14 
days) of treatment.  
• Safety and tolerability 
Phase 2: 
• Overall response status, to determine whether a subject has  a best response of 
sCR, CR, nCR, VGPR, or PR, as defined by IMWG–URC and EBMT criteria 
(nCR) 
• Safety and tolerability 
3.2 
Secondary Endpoints   
Phase 1b/2: 
• Pharmacokinetics of OPZ tablet and OPZ ER tablet 
Phase 2: 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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• Clinical benefit response status, to determine whether a subject has a best 
response of sCR, CR, nCR, VGPR, or PR, as defined by IMWG–URC and EBMT 
criteria (MR and nCR) 
• Duration of response  
• Progression–free survival 
• Time to progression 
 
4 
ANALYSIS POPULATIONS    
All subjects who receive at least 1 dose of study treatment will be considered evaluable 
for both the efficacy and safety analyses (Safety Population).  The Safety Population will 
be the primary population for all safety and efficacy data presented (Phase 1 and Phase 
2). 
5 
ANALYTIC DEFINITIONS    
5.1 
Study Day 1  
Study day 1 corresponds to the date of the first dose of study drug. 
5.2 
Study Day   
For events, assessments, and interventions after study day 1, study day represents the 
elapsed number of days from study day 1, inclusive:   
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day 
Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to study day 1.  Study day −1 will be the day 
before study day 1, and in general for assessments prior to study day 1, study day is 
defined as: 
Study Day n = (Date of assessment – Date of Study Day 1)  
For listings (such as for adverse events) that include the derivation of “days since last 
dose,” this is defined as event date – date of last dose. Events that occur on the same day 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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as the last dose of study drug will therefore be described as occurring zero days from the 
last dose of study drug. 
5.3 
Baseline  
Unless otherwise specified, the baseline value is defined as the last assessment prior to 
the first dose of OPZ and DEX.   
6 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES 
There are no formal interim analyses planned for this study.   A Cohort Safety Review 
Committee (CSRC) will review the clinical and laboratory data of each dose cohort 
before escalating the OPZ dose to the next dose cohort.   
7 
STATISTICAL METHODS 
7.1 
General Considerations 
This statistical analysis plan is being generated prior to locking the study database.  It 
specifies the main efficacy and safety analyses to be performed.  
All statistical summaries and analyses will be performed in SAS® version 9.3 or higher 
(SAS Institute Inc., Cary, NC, USA) on a PC platform. 
In general, summaries of all data will be presented by schedule and dose groups, defined 
as initial dose level cohort for phase 1 and recommended dose cohort for phase 2.   In 
addition, some summaries will include the combined recommended dose cohort from 
phase 1 and 2 and total cohorts (all subjects by schedule).   
Summary statistics will be provided for selected endpoints.  For continuous variables, the 
number of subjects with non-missing data (n), mean, standard deviation, median, 
minimum, and maximum will be presented.  For discrete data, the frequency and percent 
distribution will be presented.  Unless otherwise indicated, percentages will be calculated 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 13
based upon the number of subjects in the Safety Population in each dose group as the 
denominator.   
Confidence intervals, when presented, will be constructed at the 95% level. For binomial 
variables, exact distribution methods will be employed. The distribution of time-to-event 
endpoints will be summarized by Kaplan-Meier method. Quartiles including median will 
be estimated by Kaplan-Meier method along with their 95% confidence intervals.  
Individual subject data recorded on the electronic case report forms (eCRFs) and any 
derived data will be presented by dose cohort and subject in data listings. 
7.2 
Disposition of Subjects 
The following subject disposition information will be summarized for all subjects by each 
of the schedule and dose group and for the combined dose groups (total group).   
• number of treated subjects  
• number (%) of subjects who discontinue from the study drug 
• primary reason for study drug discontinuation 
• number (%) who had an End of Study visit 
• reason for no End of Study visit 
7.3 
Demographic and Baseline Characteristics   
7.3.1 Demographic and Baseline Characteristics   
The following demographic and baseline characteristics will be summarized for the 
Safety Population.  
• Age (years) and age categorized (years) as <65, 65 - <75, and ≥ 75 
• Sex 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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• Ethnicity 
• Race 
• Baseline ECOG performance status 
• Baseline fertility status 
• Baseline weight (kg) 
• Baseline height (cm) 
7.3.2 Medical History 
The number (%) of subjects who experienced a prior disease or disorder will be 
summarized by body system for the Safety Population.   
7.3.3 Disease Characteristics 
The following disease characteristics will be summarized for the Safety Population. 
• ISS at initial diagnosis and at Screening 
• Time (years) since initial diagnosis, defined as date of informed consent signed 
minus date of diagnosis 
• Category of multiple myeloma 
• Heavy chain and light chain status 
• Plasma cell involvement (%) as assessed with bone marrow assessment ( < 50%, 
≥ 50%, unknown or missing) 
• FISH (standard risk, high risk, unknown or not done) 
o High risk: with one of the following abnormalities: t(4;14), t(14;16), 
del(17p;13), or 1q21 amplification 
o Standard risk: none of the high risk finding 
• Baseline β2 microglobulin  (mg/L) (< 5.5 mg/L versus ≥ 5.5 mg/L) 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 15
7.3.4 Prior Cancer Therapies 
The following prior cancer therapy data will be summarized for the Safety Population: 
• Number (%) of subjects with at least one prior: 
o Chemotherapy 
o Transplant 
o Radiotherapy 
o No prior therapy 
• Number of regimens of prior treatment (1, 2, etc) for multiple myeloma and 
number of prior drugs 
7.4 
Treatments and Medications 
7.4.1 Study Drug Administration   
The overall extent of study treatment exposure and dose information will be summarized 
for the Safety Population for both OPZ and DEX. 
• Duration of treatment (weeks), defined as (date of last dose – date of first 
dose + 1) divided by 7  for OPZ and DEX 
• Total number of treatment cycles during which one full daily dose of OPZ and 
DEX was taken by the subject.  
• Number (%) of subjects dosed by cycle, where a subject will be considered to 
have been dosed in a cycle if the subject receives at least one full daily dose of 
OPZ and DEX. 
• Total doses received  across all cycles of OPZ and DEX 
• Dose modifications of study drug based on AE action taken data 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
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7.5 
Efficacy Analyses 
All efficacy analyses will be based on the Safety Population.  Disease progression as 
collected at the end of treatment (end of study visit) as determined by the investigator 
will be used for the analysis for PFS, TTP, and DOR.   
7.5.1 Overall Response Rate  
The overall response rate (ORR) is defined as proportion of subjects for whom the best 
overall confirmed response is stringent complete response (sCR), complete response 
(CR), near complete response (nCR), very good partial response (vGPR), or partial 
response (PR) as defined by International Myeloma Working Group Uniform Response 
Criteria (IMWG-URC) and modified European Group for Blood and Marrow 
Transplantation (EBMT) criteria (nCR). An estimate of the ORR and its 1–sided 95% 
exact binomial confidence interval for each of the recommended dose groups will be 
determined.  Additionally, the ORR and CBR along with the associated 2–sided 95% 
exact binomial confidence intervals will be determined including the recommended dose 
group (dose escalation cohort + Phase 2 cohort).   
7.5.2 Progression Free Survival   
Progression free survival (PFS) is defined as number of months (one month = 30.4 days) 
between start of treatment and first evidence of documented disease progression or death 
(due to any cause), whichever occurs first. Disease progression will be determined using 
IMWG-URC and will be determined by the investigator.   
PFS = Earliest date of disease progression, death, or censoring – Date of first 
dose + 1 and expressed in months 
The duration of PFS will be right–censored for subjects who meet 1 of the following 
conditions:  1) starting a new anticancer therapy before documentation of disease 
progression or death; 2) death or disease progression immediately after more than 
1 consecutively missed disease assessment visit or; 3) alive without documentation of 


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                                  Statistical Analysis Plan For Protocol ONX-2012-001 
 
page 17
disease progression before the data cutoff date.  For such subjects, the analysis of PFS 
will be right–censored according to the conventions described in Table 1. 
Table1: Date of Progression or Censoring for PFS and DOR 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first dose 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to start 
of new anticancer therapy 
Censored 
Death or PD immediately after more than 1 
consecutively missed disease assessment 
visit 
Date of last disease assessment visit without 
documentation of PD that is before the first 
missed visit 
Censored 
Alive and without PD documentation  
Date of last disease assessment 
Censored 
Death or PD between planned disease 
assessments 
Date of death or first disease assessment 
showing PD, whichever occurs first 
Progressed
Death before first disease assessment 
Date of death 
Progressed
PD = progressive disease 
 
Kaplan-Meier method will be used to estimate the distribution of PFS and the median and 
other quartiles in addition to the corresponding two-sided 95% confidence intervals.  
Duration of follow-up for PFS will be summarized according to the Kaplan-Meier 
estimate of potential follow-up also termed “reverse Kaplan-Meier” (Schemper 1996).    
7.5.3 Time to Progression 
Time to progression (TTP) is defined as number of months between start of treatment to 
the first documentation of disease progression. Disease progression will be determined 
using IMWG-URC as assessed by the investigator: 
TTP = Earliest date of disease progression or censoring – Date of first dose + 1 
and expressed in months 
The same censoring rules, except for death, as in analysis of PFS will be applied in 
calculation of TTP.  Subjects who die prior to progressive disease will be censored at the 
date of last evaluable response assessment. 


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7.5.4 Duration of Response  
Duration of response (DOR) will be calculated for subjects who achieve a sCR, CR, nCR, 
VGPR, or PR.  For such subjects, the duration of overall response is defined as the time 
from first evidence of PR or better to disease progression or death due to any cause.   
DOR = Earliest date of disease progression, death, or censoring - Date of first 
observation of PR or better before confirmation + 1 and expressed in 
months 
Duration of response will be right–censored for subjects who at least achieve a PR based 
on the censoring conventions defined previously for PFS.  Analysis of DOR will be 
performed using the Kaplan–Meier method.  Medians and other quartiles for DOR will be 
estimated in addition to the corresponding 2–sided 95% confidence intervals. 
7.5.5 Duration of Clinical Benefit Response 
Duration of clinical benefit response (CBR) will be calculated for subjects who achieve a 
MR or better.  For such subjects, the duration of CBR is defined as the time from first 
documentation of MR or better to disease progression or death due to any cause.  Dates 
of progression and censoring will be determined as described for the analysis of PFS.  
Duration of CBR = Earliest date of disease progression, death, or censoring - 
Date of first observation of MR or better before confirmation + 1 and 
expressed in months 
The duration of CBR will be summarized descriptively using the Kaplan-Meier method. 
The quartiles of the Kaplan-Meier distribution will be used to estimate the median 
duration of CBR.   
7.6 
Safety Analysis 
All safety analyses will be based on the Safety population. 


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7.6.1 Adverse Events  
Each reported AE term will be mapped to a preferred term (PT) and a system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent adverse events (TEAEs) are defined as AEs that start on or after the 
first day of study treatment and within 30 days of the last day of study treatment.  An AE 
that is present before the first administration of study treatment and subsequently worsens 
in severity during treatment is also considered to be treatment-emergent.  
Adverse events will be summarized based on the number (%) of subjects experiencing 
events by MedDRA system organ class and preferred term.  The denominator for the 
percentage will be based on the number of subjects at in the Safety Population (i.e., those 
that received at least one dose of study drug).  
A subject reporting the same AE more than once will be counted only once when 
calculating 1) within a given system organ class, and 2) within a given system organ class 
and preferred term combination.  For such cases, the maximum National Cancer Institute 
(NCI; US) - Common Terminology Criteria for Adverse Events toxicity grade and 
strongest causal relationship to study treatment for the event will be used in the incidence 
calculations.  AEs will also be summarized by severity and by relationship to study drug.   
An overall summary of TEAEs will summarize the number (%) of subjects 
• with at least one TEAE 
• with at least one treatment-related TEAE, defined as related to OPZ or DEX 
• with at least one grade 3 or higher TEAE  
• with at least one treatment-related grade 3 or higher TEAE, either OPZ or DEX 
•  with at least one serious AE 
• with TEAE leading to discontinuation of study drug, either OPZ or DEX 
• with TEAE leading to discontinuation of OPZ  


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• who died within 30 days of last dose of study drug 
Summaries of the following TEAEs will be provided by SOC and/ or PT unless otherwise 
noted:  
• all TEAEs 
• all TEAs (PT)  
• TEAEs by maximum severity  
• treatment-related adverse events (OPZ, DEX, and study drug [OPZ/DEX]) 
• serious TEAEs 
• TEAEs that led to permanent discontinuation of study drug (OPZ, DEX and study 
drug [OPZ/DEX]) 
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending order of incidence of system organ class and preferred term within each 
system organ class for the total group.  Summaries of TEAEs, treatment-related AEs will 
also be provided by descending order of incidence of preferred terms in the total group. 
All AEs, including TEAEs, will be included in listings by subject.  
Listings of AEs determined to be DLTs during the first cycle of Phase 1, serious AEs, 
and AEs leading to discontinuation of study drug will be provided. 
A summary of the number of deaths and the cause of death, classified by deaths within 30 
days of last dose of study drug and deaths more than 30 days after the last dose, will be 
provided. 
7.6.2 Laboratory Data 
All available laboratory results will be included in the subject data listings. 


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Selected laboratory test results will be assigned toxicity grades using CTCAE 4.03.  A 
summary of post-baseline grade 3 or higher laboratory toxicities will be provided.  The 
laboratory parameters of interest for these summaries are: 
Hematology (all decrease) 
Serum Chemistry (increase except where noted) 
Hemoglobin  
ALT 
Albumin 
Platelets 
AST 
Uric Acid 
WBC  
Alkaline Phosphatase 
Sodium (increase, decrease) 
Neutrophils (absolute) 
Total Bilirubin 
Phosphorus (decrease) 
Lymphocytes (absolute) 
Creatinine 
Potassium (increase, 
decrease) 
 
Calcium (increase, 
decrease) 
Magnesium (increase, 
decrease) 
 
Glucose (increase, 
decrease) 
 
7.6.3 Vital Signs and Weight 
Vital sign results including blood pressure, pulse, and temperature will be included in the 
subject data listings. 
7.6.4 12-Lead Electrocardiogram  
Maximum post-baseline and maximum increase from baseline categories of corrected QT 
interval results will be summarized.    
7.6.5 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using WHO Drug Dictionary.  
Concomitant medications are defined as medications with start date or end date on or 
after the date of first dose and before the date of the last dose + 30 days or are ongoing at 
the time of first dose.  Prior medications are defined as medications with a stop date 
before the date of first dose. 
Concomitant medications will be summarized by generic name. 


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7.6.6 Protocol Deviations 
Protocol deviations will be included in the subject data listings. Major protocol 
deviations will be either captured on the designated eCRF (e.g., eligibility 
violations) or identified through data review and surveillance.  
8 
Statistical/Analytical Issues 
8.1 
Handling of Dropouts or Missing Data 
The handling of dropouts and missing disease status assessments for the efficacy 
variables is described in their definitions.   
Missing or partially missing dates will not be imputed at data level. However, 
assumptions for missing or partially missing dates for important variables will be made to 
allow inclusion of appropriate data records in the analyses.  
If a medication date or time is missing or partially missing, so it cannot be determined 
whether it was taken prior or concomitantly, it will be considered as a prior, concomitant, 
and a post-treatment medication.  
If the partial AE onset date information does not indicate whether the AE started prior to 
treatment or after the TEAE period, the AE will be classified as TEAEs. 
If the start day of subsequent anti-cancer therapy is missing, it will be assumed to be the 
first day of the month. 
8.2 
Interim Analysis and Data Monitoring 
The CSRC will review the clinical data of each dose cohort after three subjects have been 
treated for at least one cycle during phase 1 of the study.  Based on the number of 
subjects with dose-limiting toxicity, escalation to the next higher OPZ dose may occur, 
the cohort may be expanded to six subjects, or dosing at that dose level may stop and the 


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next-lower dose cohort may be expanded.  The committee must agree that dose escalation 
to the next cohort is appropriate before it proceeds.