Clinical trial NCT01999335
Conditions: Multiple Myeloma
Sponsor: Amgen
Start date: 2014-07-30; Completion date: 2019-04-25
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the Phase 1 part of the study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of oprozomib in combination with pomalidomide and dexamethasone in adults with primary refractory or relapsed and refractory multiple myeloma.

The purpose of the Phase 3 part of the study is to compare the efficacy for adults with primary refractory or relapsed and refractory multiple myeloma who are randomized to either oprozomib or placebo in combination with pomalidomide and dexamethasone.

Detailed description:
This was a phase 1b/3, multicenter study composed of 2 parts: part 1 was a phase 1b, open-label, dose-escalation and dose-expansion component and part 2 was to have been a phase 3, placebo-controlled, double-blind, randomized component. Part 2 was not conducted.

The Phase 1 dose-escalation portion of the study followed a standard 3 + 3 dose-escalation design. For each of the 2 schedules, groups of 3 to 6 patients were enrolled. The starting doses of oprozomib were 150 and 210 mg in the 5/14 and 2/7 schedules, respectively. The starting dose of pomalidomide was 4 mg in both schedules. As long as \< 33% of patients experienced a dose-limiting toxicity (DLT) in a given cohort, the dose of oprozomib was escalated in 30-mg increments for successive cohorts.

Once the recommended dose and schedule for the expansion phase had been selected, additional participants were enrolled in the dose expansion portion of part 1 to continue the evaluation of the safety and efficacy of the regimen and determine the recommended phase 3 dose. Enrollment was halted during the dose expansion phase and part 2 was not conducted.

Arms: arm 1: Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. arm 2: Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 2 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. arm 3: Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. arm 4: Participants received oprozomib 240 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. arm 5: Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity.
Interventions: intervention 1: Oprozomib intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Extended release (ER) tablets administered orally intervention 2: Capsules for oral administration intervention 3: Tablets for oral administration

Protocol documents:
Prot_000.pdf: 
16.1.1 
Protocol and Amendments 
Protocol Amendment 3, dated 07 March 2018 was generated and approved.  Shortly 
thereafter, a decision was made to terminate the study program, the amendment was 
not implemented.  The last version of the protocol, under which the study was active, 
was Amendment 2, dated 2014 March 20. 
Product: 
Date: 
Oprozomib
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1b Multicenter Study of Oprozomib, Pomalidomide, 
and Dexamethasone in Primary Refractory or Relapsed 
and Refractory Multiple Myeloma Subjects 
Protocol Number: 
OPZ007 
Name of Investigational 
Product: 
Oprozomib ER Tablets 
IND Number: 
117,851 
NCT Number: 
NCT01999335 
Sponsor: 
Onyx Therapeutics, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone:  (805) 447-1000 
Study Medical Monitor: 
 MD 
Medical Director, Early Development 
1120 Veterans Blvd 
South San Francisco, CA 94080 USA 
Phone: 
Email: 
Investigator(s): 
 MD 
Assistant Professor 
Department of Lymphoma/Myeloma 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 429 
Houston, Texas 77030 
Office: 
Cell: 
Email: 
Date of Original Protocol: 
15 August 2013 
Date of Amendment 1.0: 
21 March 2014 
Date of Amendment 2.0: 
08 July 2014 
Date of Amendment 3.0: 
07 March 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 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
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. 
Compliance Statement: 
This study will be conducted in accordance with 
Protocol OPZ007, the International Council for 
Harmonisation (ICH), Good Clinical Practice (GCP) 
guidelines, and the applicable country and regional 
regulatory requirements. 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
PROTOCOL ACCEPTANCE PAGE 
Issue/Date:  OPZ007 (07 March 2018) 
 
I have read this protocol for Study OPZ007 entitled: 
Phase 1b Multicenter Study of Oprozomib, Pomalidomide, and Dexamethasone in Primary 
Refractory or Relapsed and Refractory Multiple Myeloma Subjects 
 
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) while conducting this clinical investigation.  Once signed, the original of this form should be detached 
from the protocol and returned to Onyx Therapeutics or its designee (please retain a copy for your files). 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
1 
SYNOPSIS 
Name of 
sponsor/compan
y: 
Onyx Therapeutics 
Name of 
product: 
Oprozomib 
Title of study 
and protocol 
number and 
phase: 
Protocol Number:  OPZ007 
Phase 1b Multicenter Study of Oprozomib, Pomalidomide, and Dexamethasone in Primary 
Refractory or Relapsed and Refractory Multiple Myeloma Subjects 
Study objective(
s): 
Primary Objectives 
 
To determine the maximum tolerated dose (MTD) and identify the recommended 
Phase 3 dose (RP3D) and schedule of oprozomib in combination with pomalidomide 
and dexamethasone (OPomd) in subjects with primary refractory or relapsed and 
refractory multiple myeloma 
 
To evaluate the safety and tolerability of the OPomd combination in subjects with 
primary refractory or relapsed and refractory multiple myeloma 
Secondary Objectives 
 
To estimate the overall response rate (ORR) of OPomd, defined as the proportion of 
subjects with an overall response of stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), or partial response (PR) as 
determined by investigator according to the International Myeloma Working 
Group - Uniform Response Criteria (IMWG-URC)  
 
To estimate the clinical benefit rate (CBR) of OPomd, defined as the proportion 
of subjects with an overall response of minimal response (MR) or better as 
determined by investigator according to the IMWG-URC and modified European 
Group for Blood and Marrow Transplantation (EBMT) criteria 
 
To characterize the pharmacokinetics (PK) of oprozomib in the OPomd regimen 
Exploratory Objectives 
 
To evaluate the pharmacodynamic (PDn) biomarkers that may correlate with 
antitumor activity 
 
To evaluate genomic biomarkers that may correlate with antitumor activity and 
resistance following treatment with proteasome inhibitors 
 
To evaluate (in the dose-expansion portion only) the patient-reported outcomes (PRO) 
using the tools listed below: 
o 
Bone pain and the impact of bone pain measured with the Brief Pain 
Inventory - Short Form (BPI-SF) 
o 
Health-related quality of life (HRQoL) measured by the global health 
status/QoL scale of the European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Core Module (QLQ-C30) questionnaire 
o 
Health status assessed by the EQ-5D-5L  
o 
Disease symptoms as measured by the disease symptoms subscale of the 
EORTC Multiple Myeloma Module (QLQ-MY20) questionnaire 
o 
Neurotoxicity symptoms as measured by the neurotoxicity subscale of the 
Functional Assessment of Cancer Therapy / Gynecological Oncology 
Group - Neurotoxicity (FACT/GOG-Ntx4 [(Version 4]) questionnaire  
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design: 
This is a Phase 1b study of oprozomib in combination with pomalidomide and 
dexamethasone in subjects with primary refractory or relapsed and refractory multiple 
myeloma.  This study includes an open-label, Phase 1b, dose-escalation and dose-expansion 
portion (equivalent to a small Phase 2), during which the RP3D will be identified.  Further 
evaluation of safety and activity will be assessed during the dose-expansion portion.  During 
this study, subjects will receive Oprozomib extended release (ER) Tablets according to their 
assigned dose cohort.   
This study will include subjects with primary refractory or relapsed and refractory multiple 
myeloma, ie, those who have demonstrated disease progression on or within 60 days of their 
last therapy, and who have received at least 2 prior lines of therapy (including bortezomib 
and lenalidomide and/or thalidomide, and in the dose-expansion portion of the study only, 
been treated with adequate alkylator therapy).  Subjects whose last therapy was bortezomib 
and who were not refractory but developed bortezomib intolerance, as defined by the 
development of Grade 2 peripheral neuropathy with pain or ≥ Grade 3 peripheral neuropathy 
after ≥ 2 consecutive cycles, are eligible. 
Treatment cycles are 28 days in duration.  Two (2) oprozomib dosing schedules will be 
assessed during dose escalation.  All study subjects will receive oprozomib once daily either 
on Days 1–5 and 15–19, referred to hereafter as the 5/14 schedule, or an alternate schedule 
of once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23, referred to hereafter as the 2/7 schedule.  
Pomalidomide will be given on Days 1–21 and dexamethasone will be given on Days 1, 2, 
8, 9, 15, 16, 22, and 23 of every 28-day cycle. 
 
5/14 Schedule Study Dosing Schema 
 
Approved 
 
 
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CONFIDENTIAL 
Study design 
(cont’d): 
2/7 Schedule Study Dosing Schema 
 
 
The safety, MTD, PK/PDn, and RP3D of oprozomib when given in combination with 
pomalidomide and dexamethasone will be assessed using a standard 3+3 dose-escalation 
design.  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 dose-limiting toxicity (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.  If the starting dose of oprozomib 
cannot be safely administered with the labeled pomalidomide dose, or at sponsor discretion, 
then up to 2 possible alternative paths for oprozomib with lower pomalidomide doses will be 
explored.  (See tables below for primary and alternative dose-escalation paths.)  Dose 
escalation will continue until sponsor discretion, the maximum planned dose of 
pomalidomide is reached, or ≥ 2 DLTs occur in a cohort, whichever occurs first.  The prior 
cohort will be expanded to at least 6 subjects if not previously done to establish that dose as 
the MTD.  There may be more than 1 MTD for oprozomib if more than 1 dose level of 
pomalidomide is studied.  The MTD of oprozomib associated with each dose level of 
pomalidomide assessed will be the dose level where < 2 DLTs in 6 subjects are observed. 
There is no planned maximum dose of oprozomib to be studied as it is being added to the 
FDA-approved regimen of pomalidomide/dexamethasone, however, this could be imposed 
at any time during the course of the study, based on Sponsor discretion.  The starting dose of 
oprozomib for the 5/14 schedule is 150 mg, 3 dose levels below the established 
5/14 single-agent MTD of 240 mg.  The starting dose of oprozomib for the 2/7 schedule is 
210 mg, 3 dose levels below the established 2/7 single-agent MTD of 300 mg.  Following 
dose escalation, the sponsor has the option of expanding 1 or both schedules in order to 
establish the RP3D and schedule. 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design 
(cont’d): 
Dose-Escalation Schema for the 5/14 Oprozomib Dosing Schedule 
The starting dose for the 5/14 schedule will be 150 mg of oprozomib and 4 mg of 
pomalidomide.  The 5/14 primary and alternate paths are summarized below; these are 
examples, and are not inclusive of all possible dose-escalation paths. 
5/14 Schedule Primary Study Dose-Escalation Pathsa 
 
5/14 = Dosing on Days 1–5 and 15–19; Dex = dexamethasone; 
OPZ = oprozomib; Pom = pomalidomide. 
a There is no predefined maximum dose level of oprozomib  
being studied. 
 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design 
(cont'd): 
Primary Dose-Escalation Path for Oprozomib on 5/14 Schedule  
with Pomalidomide 4mg in Phase 1b 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1a (initial cohort) 
150 
4 
2a 
180 
4 
3a 
210 
4 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
Note:  This is an example of the primary dose-escalation cohort.  Dose escalation 
will continue in 30-mg increments of oprozomib at sponsor discretion or until the 
MTD has been identified. 
Alternative Dose-Escalation Path 1 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1a Exceeds the MTD,  
or at Sponsor Discretion 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1b 
150 
3 
2b 
180 
3 
3b 
210 
3 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
 
Alternative Dose-Escalation Path 2 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1b Exceeds the MTD,  
or at Sponsor Discretion 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1c 
150 
2 
2c 
180 
2 
3c 
210 
2 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design 
(cont'd): 
Dose-Escalation Schema for the 2/7 Oprozomib Dosing Schedule 
The starting doses for the 2/7 oprozomib dosing schedule will be 210 mg of oprozomib and 
4 mg of pomalidomide.  The 2/7 primary and alternate paths are summarized below; these 
are examples, and are not inclusive of all possible dose-escalation paths. 
2/7 Schedule Primary Study Dose-Escalation Pathsa  
 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; Dex = dexamethasone; 
OPZ = oprozomib; Pom = pomalidomide. 
a There is no predefined maximum dose level of oprozomib  
being studied. 
 
Primary Dose-Escalation Path for Oprozomib on 2/7 Schedule  
with Pomalidomide 4 mg in Phase 1b 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
101a (initial cohort) 
210 
4 
201a 
240 
4 
301a 
270 
4 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated 
dose. 
Note:  This is an example of the primary dose-escalation cohort.  Dose 
escalation will continue in 30-mg increments of oprozomib at sponsor 
discretion or until the MTD has been identified. 
 
Approved 
 
 
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Date: 
Oprozomib
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CONFIDENTIAL 
Study design 
(cont'd): 
Alternative Dose-Escalation Path 1 for Oprozomib on 2/7 Schedule with Pomalidomide 
in Phase 1b if Cohort 101a Exceeds the MTD, or at Sponsor Discretion 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
101b 
210 
3 
201b 
240 
3 
301b 
270 
3 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated 
dose 
 
Alternative Dose-Escalation Path 2 for Oprozomib on 2/7 Schedule with Pomalidomide 
in Phase 1b if Cohort 101b Exceeds the MTD, or at Sponsor Discretion 
Cohort 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
101c 
210 
2 
201c 
240 
2 
301c 
270 
2 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated 
dose 
 
At the sponsor’s discretion, once the MTD for oprozomib is reached on 1 or both schedules, 
or if the initial cohort exceeds the MTD, additional dose escalation with oprozomib may 
continue with lower doses of pomalidomide down to the 2-mg dose level. 
The sponsor, with input from the Cohort Safety Review Committee ([CSRC] consisting of 
investigators, sponsor’s medical monitor, and sponsor’s drug safety representative), will 
determine which dose and schedule of oprozomib in combination with Pomd to use for the 
dose-expansion (ie, the RP3D) portion of the study.  The sponsor has the option of 
expanding 1 or both schedules in order to establish the RP3D and schedule.  The RP3D may 
differ from the MTD, but will not be higher than the MTD, and will be selected based upon 
the assessment of the safety, tolerability, PK, PDn, preliminary activity, and other variables 
to be observed across multiple cycles of combination therapy.   
Dose-Limiting Toxicities 
During this study, assessment of DLTs will occur during the 28-day period of Cycle 1 
combination therapy.  For the purposes of this study, a DLT is defined as any of the study 
drug-related events listed below occurring within the 4 weeks after the first dose of 
combination therapy.  Study drug is defined as the combination of oprozomib, 
pomalidomide, and dexamethasone.  Study drug-related is defined as a reasonable likelihood 
of clinical causality based on time of event, biology, dechallenge improvement, and that the 
adverse event (AE) was not likely explained by the subject’s clinical state, underlying 
disease, concomitant medication, or study/nonstudy procedure. 
 
Any toxicity requiring a dose reduction or requiring that a dose of oprozomib or 
pomalidomide be held in Cycle 1 that does not meet the criteria for DLT will be 
discussed by the CSRC to determine whether the subject should be considered 
evaluable for DLT determination.  If it is determined that the subject is not evaluable 
for DLT, the subject will be replaced.   
 
A delay in ability to receive Day 1 dose of Cycle 2 due to a hematologic or 
nonhematologic drug-related toxicity persisting beyond 14 days from Cycle 1 Day 28 
will be considered a DLT 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design 
(cont'd): 
 
For a nonhematologic DLT, any ≥ Grade 3 toxicity will be considered a DLT with 
exceptions as described below: 
o 
Grade 3 asymptomatic electrolyte abnormalities will not be considered a DLT 
o 
Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours will not 
be considered a DLT 
o 
Grade 3 nausea and vomiting will not be considered a DLT unless persisting 
longer than 3 days despite optimal supportive care, which at a minimum must 
include a 5-hydroxytryptamine type-3 (5-HT3) antagonist and aprepitant 
o 
Grade 3 diarrhea will not be considered a DLT unless persisting longer than 
3 days despite optimal supportive care, which at a minimum must include 
loperamide (Imodium) and atropine diphenoxylate (Lomotil) 
o 
 Grade 3 fatigue lasting < 14 days is not considered a DLT 
o 
≥ Grade 3 hyperglycemia or toxicity attributed to dexamethasone is not 
considered a DLT 
o 
≥ Grade 3 rash attributed specifically to pomalidomide is not considered a 
DLT 
 
Hematologic DLTs consist of the following: 
o 
Grade 4 neutropenia: 
– Absolute neutrophil count (ANC) < 0.5 × 109/L lasting ≥ 7 days despite 
adequate growth factor support (eg, granulocyte-colony stimulating factor 
[G-CSF]) 
– 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 < 1.0 × 109/L) 
o 
Thrombocytopenia: 
– Grade 4 lasting ≥ 7 days, or  
– Grade 4 lasting < 7 days with Grade 2 clinically significant bleeding or 
< 10,000 platelets requiring platelet transfusion, or  
– Grade 3 with clinically significant bleeding or requiring platelet transfusion 
Note:  Grade 4 anemia is not considered a DLT 
Subject Replacement 
Subjects must meet the following criteria to be considered evaluable for MTD determination 
during the 4-week DLT evaluation period unless a DLT occurs before the subject receives 
all planned doses of oprozomib for both the 5/14 and 2/7 dosing schedules: 
 
A minimum of 17 of 21 planned doses of pomalidomide must be received 
 
A minimum of 6 of 8 planned doses of dexamethasone must be received 
 
All planned doses of oprozomib must be received 
Subjects not meeting all of the above criteria or assessed as unevaluable by the CSRC will 
be replaced.  Each subject in the cohort under review will be discussed and assessed.  Once 
all data have been presented, the CSRC will decide on the most appropriate course of action 
regarding dose escalation based on guidance in Section 5.1.  
 
Approved 
 
 
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Date: 
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CONFIDENTIAL 
Study design 
(cont'd): 
Dose Expansion 
The criteria for selecting the RP3D for 1 or both schedules of oprozomib at the sponsor’s 
discretion will include assessment of the safety, tolerability, and preliminary activity 
observed across multiple cycles of therapy.  In addition, both PK and PDn assessments to 
demonstrate adequate exposure and proteasome inhibition will be a key factor.  Therefore, 
the RP3D may differ from the MTD.  Once the MTD(s) has been determined and the 
recommended dose for the expansion phase has been selected, a minimum of 20 additional 
subjects for 1 or both schedules of oprozomib at the sponsor’s discretion will be enrolled in 
the dose-expansion portion of the study in order to continue the evaluation of the safety and 
efficacy of the regimen.  The safety of subjects in the Dose Expansion will be monitored on 
an ongoing basis by the CSRC during regularly scheduled calls.  This information will 
inform the selection of a RP3D and schedule by the sponsor and CSRC.  
 
Number of 
investigational 
sites: 
Approximately 35 study sites will participate in this study (15 sites for the dose-escalation 
and 20 additional sites for the dose-expansion portions of the study). 
Planned number 
of subjects: 
A total enrollment of approximately 82 subjects is planned for this study.  During the 
Dose-Escalation portion, approximately 21 subjects will be enrolled for each schedule.  The 
estimate assumes the need to enroll up to 6 subjects in 3 different dose cohorts and the need 
for replacement of 1 in 6 subjects in order to enable MTD determination.  The RP3D may 
differ from the MTD depending on observed safety and activity data during dose escalation.  
A minimum of 20 additional subjects are planned for enrollment for each schedule at the 
sponsor’s discretion and treatment at the RP3D during the Dose-Expansion portion of the 
study.   
 
Sample size 
justification: 
The estimated sample size for the dose-escalation part of the study is based on standard 
3 + 3 dose-escalation rules, with the expectation that 2–3 dosing cohorts of 3–6 subjects per 
cohort will be required to establish the MTD.   
A minimum of 20 additional subjects will be enrolled for each schedule at the sponsor’s 
discretion during the dose expansion to acquire additional safety and efficacy experience for 
the RP3D in the population before initiation of the Phase 3 portion of the study.  In the 
dose-expansion portion of the study, if the true ORR ≥ 40% then the probability of seeing 
at least 7 responses among the 26 subjects (6 treated at the MTD during escalation + 20 in 
the expansion) in either schedule is approximately 94%. 
 
Study populatio
n: 
The study population will consist of subjects with primary refractory or relapsed and 
refractory, multiple myeloma, ie, those who have demonstrated disease progression on or 
within 60 days of their last therapy, and who have received at least 2 prior lines of therapy 
(including bortezomib and lenalidomide and/or thalidomide, and in the dose-expansion 
portion of the study only, been treated with adequate alkylator), and who are considered to 
be appropriate for this clinical study by their treating physicians. 
Test product, 
dose, and mode 
of 
administration: 
Oprozomib ER Tablet in strengths of 150, 180, 210, 240, and 270 mg 
Oral pomalidomide with capsule strengths of 1, 2, 3, and 4 mg 
Oral dexamethasone with tablet strengths of 4 and 6 mg 
Reference 
therapy, dose, 
and mode of 
administration: 
Active control 
Oral pomalidomide with capsule strengths of 1, 2, 3, and 4 mg  
Oral dexamethasone with tablet strengths of 4 and 6 mg 
Approved 
 
 
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Date: 
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Treatment 
regimen(s): 
Oral oprozomib taken Days 1–5 and 15–19 or Days 1, 2, 8, 9, 15, 16, 22, and 23, 
pomalidomide taken on 21 of 28 days, and oral dexamethasone taken on Days 1, 2, 8, 9, 15, 
16, 22, and 23 
Inclusion 
criteria: 
Disease Related 
1. Multiple myeloma that is primary refractory, relapsed and refractory, or intolerant after 
at least 2 lines of standard therapy for multiple myeloma including: 
a. ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide 
(alone or in combination) 
b. In the dose-expansion portion of the study only:  In addition to the above, 
treatment with adequate alkylator therapy, defined as: 
i. High-dose melphalan or other alkylating agent as conditioning for 
autologous or allogeneic stem cell transplant (SCT), or 
ii. ≥ 6 cycles of induction therapy, or  
iii. Progressive disease after ≥ 2 cycles 
2. Measurable disease as indicated by 1 or more of the following: 
a. Serum M-protein ≥ 500 mg/dL  
b. Urine M-protein ≥ 200 mg/24 h 
c. Only for subjects without measurable M-protein by serum protein electrophoresis 
(SPEP) and urine protein electrophoresis (UPEP), involved free light chain (FLC) 
concentration ≥ 10 mg/dL provided serum free light chain (SFLC) ratio is 
abnormal  
3. Disease progression on or within 60 days of completion of the last therapy, or 
intolerance to bortezomib if received as their last therapy 
a. 
Patients who received bortezomib as their last therapy who were not refractory 
but developed bortezomib intolerance, as defined by the development of 
Grade 2 peripheral neuropathy with pain or ≥ Grade 3 peripheral neuropathy 
after ≥ 2 consecutive cycles, are eligible 
4. Prior carfilzomib is allowed if a subject was not removed from carfilzomib therapy due 
to toxicity, unless approved by the Sponsor’s study medical monitor. 
Demographic 
5. Males and females ≥ 18 years old 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–2 
Laboratory 
7. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal (ULN) 
in the absence of Gilbert’s disease or hemolysis, and alanine aminotransferase (ALT) 
and aspartate aminotransferase (AST) ≤ 3 times ULN 
8. ANC ≥ 1500/mm3.  Screening ANC should be independent of myeloid growth factor 
support for at least 1 week or 2 weeks for pegylated growth factors. 
9. Hemoglobin ≥ 8.0 g/dL.  Patients may receive red blood cell (RBC) transfusions or 
receive erythropoietin or darbepoetin alfa in accordance with institutional guidelines 
up to 1 week before Screening.  
10. Platelet count ≥ 75,000 mm3.  Patients should not have received platelet transfusions 
for at least 1 week before Screening. 
11. Uric acid, if elevated, must be correct to within laboratory normal range before dosing 
12. Calculated or measured creatinine clearance (CrCl) ≥ 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.   
Approved 
 
 
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Inclusion 
criteria (cont'd): 
Ethical/Other 
13. Patient must sign a written informed consent form in accordance with federal, local, 
and institutional guidelines 
14. Female patients of childbearing potential must have a negative pregnancy test (with 
a sensitivity of at least 50 mIU/mL) within 1 day of the first dose of study drug, and 
agree to use 2 effective methods of contraception during the study and for 28 days 
following the last dose of study drug.  Postmenopausal females (> 45 years old and 
without menses for ≥ 2 years) and surgically sterilized females are exempt from these 
requirements. 
15. Male patients, including those with prior vasectomy, 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.  Additionally, they must agree 
not to donate sperm while being treated and for up to 3 months after discontinuing 
treatment. 
Exclusion 
criteria: 
Disease Related 
1. Systemic chemotherapy with approved or investigational anticancer therapeutics, 
intended to treat underlying malignancy, within 3 weeks before the first dose of study 
treatment or 6 weeks for antibody therapy 
2. Dexamethasone at cumulative doses greater than 160 mg or equivalent within 21 days 
prior to the first dose of study treatment is not allowed.  Use of topical or inhaled 
steroids is acceptable. 
3. Radiation therapy within 3 weeks before first dose of study drug.  
Radioimmunotherapy within 8 weeks before first dose of study drug. 
4. 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. 
5. Autologous SCT within 8 weeks and allogeneic SCT within 16 weeks prior to 
initiation of study treatment.  Patients with prior allogeneic SCT should not have 
evidence of moderate-to-severe graft-versus-host disease (as defined in 
Filipovich 2005) and must be approved by the Sponsor’s study medical monitor. 
6. Known hypersensitivity to any immunomodulatory drugs (IMiDs), including rash 
7. Prior pomalidomide exposure 
a. For the Dose-Escalation portion of the study:  Subjects requiring pomalidomide 
dose reduction or removal due to toxicity 
b. For the Dose-Expansion portion of the study:  Prior pomalidomide treatment of 
any duration 
8. Known hypersensitivity/toxicity or intolerance to dexamethasone 
9. Prior exposure to oprozomib 
10. Hypersensitivity, intolerance, or inability to take antithrombotic prophylaxis 
Concurrent Conditions 
11. Major surgery within 3 weeks before first dose of study drug 
12. Congestive heart failure (New York Heart Association Class III to IV), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, or 
myocardial infarction within 6 months before first dose of study drug 
13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 
2 weeks before first dose of study drug 
14. History of previous clinically significant gastrointestinal (GI) bleed in the 6 months 
prior to first dose of study drug 
Approved 
 
 
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Exclusion 
criteria (cont'd): 
15. Known or suspected human immunodeficiency virus (HIV) infection or patients who 
are HIV seropositive 
16. Active hepatitis A, B, or C infection 
17. Significant neuropathy (Grade 2 with pain or ≥ Grade 3) at the time of the first dose of 
study drug 
18. Other malignancy within the past 3 years, except those considered cured by surgical 
resection; examples include some cases of:  
a. 
Adequately treated basal or squamous cell carcinoma of the skin 
b. Thyroid cancer 
c. 
Carcinoma in situ of the cervix or breast 
d. Prostate cancer with Gleason Score of 6 or less with stable prostate-specific 
antigen levels 
19. Plasma cell leukemia 
20. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) 
21. Known amyloidosis 
22. Female patients who are pregnant or nursing 
23. Uncontrolled diabetes or hypertension 
24. Inability to swallow medication, inability or unwillingness to comply with the drug 
administration requirements, or gastrointestinal condition that could interfere with the 
oral absorption or tolerance of treatment 
25. Any contraindication to oral hydration (e.g., preexisting cardiac impairment or fluid 
restriction) 
26. Any clinically significant psychiatric, social, or medical condition that, in the opinion 
of the investigator, could increase patient risk, interfere with protocol adherence, or 
affect a patient’s ability to give informed consent 
Overview of 
treatment and 
assessments: 
Treatment cycles will last 28 days.  Disease response assessments will be performed at the 
end of every 4-week cycle for the first 18 months on study, and at the end of every other 
cycle (every 8 weeks) thereafter, beginning with Month 20. 
Details are provided in Appendices A1, A2, B1, and B2 (Schedule of Assessments). 
Criteria for 
evaluation: 
 
Efficacy 
variables: 
Disease response assessments will be performed at the end of every 4-week cycle for the 
first 18 months of study treatment, and at the end of every other cycle (every 8 weeks) 
thereafter, beginning with Month 20, according to the IMWG-URC and modified EBMT 
criteria. 
Safety 
variables: 
Safety assessments will include monitoring and assessment of all AEs, clinical laboratory 
parameters, electrocardiograms (ECGs), and vital signs.  Safety assessments will begin after 
the subject has signed the informed consent form and will continue until 30 days after the 
End of Study Treatment.  The safety and tolerability of the study treatment will be assessed 
through documentation of AEs graded according to National Cancer Institute-Common 
Terminology Criteria for Adverse Events ([NCI-CTCAE] Version 4.03). 
Approved 
 
 
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Other: 
 
Pharmacokinetics 
In the Dose-Escalation and Dose-Expansion portions of the study, blood samples will be 
collected from all subjects for determination of plasma concentrations of oprozomib at 
1 predose time point and up to 7 postdose time points on Day 1 of Cycle 1 and Cycle 2 
(0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose) and 1 predose time point on Day 2 of Cycle 1 for 
both schedules. 
Population PK parameter estimates and variability in these estimates will be determined 
using a population-based analysis method.   
Pharmacodynamics 
Blood samples for quantitation of proteasome inhibition by oprozomib will be collected 
from all subjects in this study.   
Genomics 
Analysis of genomic biomarkers that may predict response and resistance following 
treatment with proteasome inhibitors will be conducted for all subjects receiving oprozomib 
who consent to optional genomic biomarker analysis.  These analyses will be performed on 
the required bone marrow aspirate obtained at Baseline (within 45 days prior to Cycle 1 
Day 1 dosing; a portion of the bone marrow aspirate sample obtained at Baseline will be 
used; no additional sample is required), as well as a sample of blood and saliva also 
collected at Baseline.  Bone marrow aspirate or biopsy collection does not need to be 
repeated if previously completed within 45 days prior to Cycle 1 Day 1 dosing.  Additional 
bone marrow samples for biomarkers may be collected at disease progression (End of Study 
Treatment due to progressive disease [PD]) from all subjects who consent. 
Statistical 
methods and 
analyses: 
Safety Population (All Subjects) 
The safety population includes all subjects receiving any amount of study treatment 
(oprozomib, pomalidomide, or dexamethasone).   
Efficacy Population  
For this study, the efficacy population is equivalent to the safety population. 
Endpoints 
Primary Endpoints 
 
DLTs 
 
Adverse events and laboratory abnormalities graded according to NCI-CTCAE, 
Version 4.03 
 
Vital signs and clinical laboratory results during and following study drug 
administration  
Secondary Endpoints 
 
Overall response, defined as the best response of sCR, CR, VGPR, or PR, 
as determined by investigator according to the IMWG-URC 
 
Clinical benefit, defined as the best response of MR or better, as determined by the 
investigator, according to the IMWG-URC and modified EBMT criteria 
 
Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time 
to maximum concentration (Tmax), area under the plasma concentration time curve 
from time 0 to last time point (AUC0-), and area under the plasma concentration time 
curve from time 0 to time infinity (AUC0-) using noncompartmental methods 
Approved 
 
 
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Statistical 
methods and 
analyses 
(cont’d): 
Exploratory Endpoints 
 
Pharmacodynamic biomarkers that may be correlated with antitumor activity 
 
Genomic biomarkers that may be correlated with antitumor activity and resistance 
following treatment with proteasome inhibitors 
 
Change over time in bone pain and the impact of bone pain measured with the BPI-SF 
(Dose Expansion only) 
 
Change over time in the global health status/QoL scale of the EORTC QLQ-C30 
(Dose Expansion only) 
 
Change over time in health status assessed by EQ-5D-5L (Dose Expansion only) 
 
Change over time in the disease symptoms subscale of the EORTC QLQ-MY20 
(Dose Expansion only) 
 
Change over time in neurotoxicity symptoms measured by the FACT/GOG-Ntx4 
score (Version 4) (Dose Expansion only)  
 
Efficacy Analyses 
Progression-free survival and duration of response will be listed for all subjects by dose 
level and schedule.  Overall response rate and clinical benefit rate will be estimated for all 
subjects treated at the RP3D along with the associated 95% exact binomial confidence 
intervals (CIs). 
 
Safety Analyses 
For this study, safety will be assessed through summaries of DLTs, AEs, changes in 
laboratory test results, ECGs, vital signs, and oprozomib, pomalidomide, and 
dexamethasone exposure.  All AE data collected will be listed by study site, cohort, subject 
number, and study day. 
Approved 
 
 
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TABLE OF CONTENTS 
Page 
CLINICAL STUDY PROTOCOL .........................................................................................1 
PROTOCOL ACCEPTANCE PAGE ....................................................................................3 
1 
SYNOPSIS ....................................................................................................................4 
TABLE OF CONTENTS ......................................................................................................18 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................25 
3 
BACKGROUND INFORMATION .........................................................................29 
3.1 
Introduction ......................................................................................................29 
3.2 
Multiple Myeloma Background .......................................................................30 
3.3 
Proteasome Background ..................................................................................31 
3.4 
Oprozomib Background ...................................................................................31 
3.4.1 
Relevant Nonclinical Background ....................................................32 
3.4.2 
Relevant clinical Background ...........................................................32 
3.5 
Dose Rationale .................................................................................................36 
3.5.1 
Oprozomib ........................................................................................36 
3.5.2 
Dexamethasone .................................................................................37 
3.5.3 
Pomalidomide ...................................................................................38 
3.6 
Study Rationale ................................................................................................40 
4 
STUDY OBJECTIVES ..............................................................................................43 
4.1 
Primary Objectives ...........................................................................................43 
4.2 
Secondary Objectives .......................................................................................43 
4.3 
Exploratory Objectives ....................................................................................43 
5 
STUDY DESIGN ........................................................................................................44 
5.1 
Dose-Escalation and Dose-Expansion Portions of the Study ..........................45 
5.1.1 
Dose-Escalation Schema for the 5/14 Oprozomib Dosing 
Schedule ............................................................................................46 
5.1.2 
Dose-Escalation Schema for the 2/7 Oprozomib Dosing 
Schedule ............................................................................................48 
5.1.3 
Dose-Limiting Toxicities ..................................................................51 
5.1.4 
Subject Replacement .........................................................................51 
5.1.5 
Dose Expansion ................................................................................51 
Approved 
 
 
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5.2 
Estimated Study Duration and Study Closure .................................................52 
5.3 
Minimizing Bias...............................................................................................52 
5.3.1 
Blinding.............................................................................................52 
6 
SUBJECT SELECTION ...........................................................................................52 
6.1 
Inclusion Criteria .............................................................................................52 
6.2 
Exclusion Criteria ............................................................................................54 
7 
SUBJECT SCREENING ...........................................................................................56 
8 
SUBJECT ENROLLMENT ......................................................................................56 
9 
STUDY DRUG ...........................................................................................................57 
9.1 
Oprozomib .......................................................................................................57 
9.1.1 
Oprozomib Physical Description ......................................................57 
9.1.2 
Oprozomib Formulation....................................................................57 
9.1.3 
Oprozomib Packaging and Labeling .................................................58 
9.1.4 
Oprozomib Storage ...........................................................................58 
9.2 
Pomalidomide ..................................................................................................58 
9.2.1 
Pomalidomide Physical Description .................................................58 
9.2.2 
Pomalidomide Packaging and Labeling............................................58 
9.2.3 
Pomalidomide Storage ......................................................................58 
9.3 
Dexamethasone ................................................................................................59 
9.3.1 
Dexamethasone Packaging and Labeling .........................................59 
9.3.2 
Dexamethasone Storage ....................................................................59 
9.4 
Study Drug Accountability ..............................................................................59 
10 
OPROZOMIB TREATMENT ADMINISTRATION ............................................60 
10.1 
Oprozomib Treatment Administration .............................................................60 
10.2 
Pomalidomide Treatment Administration ........................................................60 
10.3 
Dexamethasone Treatment Administration .....................................................61 
10.4 
Dose Modification Guidelines .........................................................................61 
10.4.1 
Dose Reductions ...............................................................................61 
10.4.2 
Dose Modification Guidelines ..........................................................64 
10.5 
Definition of Dose-limiting Toxicity ...............................................................71 
10.6 
Concomitant Medications ................................................................................72 
10.6.1 
Required Concomitant Medications .................................................72 
10.6.2 
Optional and Allowed Concomitant Medications.............................76 
Approved 
 
 
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10.6.3 
Excluded Concomitant Medications .................................................76 
11 
STUDY PROCEDURES ...........................................................................................77 
11.1 
Study-Specific Procedures ...............................................................................78 
11.1.1 
Vital Signs .........................................................................................78 
11.1.2 
Complete Physical Examination .......................................................78 
11.1.3 
Electrocardiogram .............................................................................78 
11.2 
Laboratory Evaluations for Safety ...................................................................78 
11.2.1 
Chemistry ..........................................................................................79 
11.2.2 
Hematology .......................................................................................79 
11.2.3 
Coagulation .......................................................................................80 
11.2.4 
Pregnancy ..........................................................................................80 
11.3 
Disease Response Assessments .......................................................................80 
11.4 
Correlative Studies ...........................................................................................82 
11.4.1 
Pharmacokinetic Measurements .......................................................82 
11.4.2 
Pharmacodynamic Measurements ....................................................82 
11.4.3 
Genomic Measurements ....................................................................82 
11.5 
Patient-Reported Outcomes Assessments ........................................................83 
12 
STUDY AND STUDY TREATMENT DISCONTINUATION .............................84 
12.1 
Study Treatment Discontinuation ....................................................................84 
12.2 
Study Discontinuation ......................................................................................85 
12.3 
Long-term Follow-up .......................................................................................86 
12.4 
Study Termination ...........................................................................................86 
13 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................86 
13.1 
Adverse Event Reporting .................................................................................86 
13.1.1 
Definitions.........................................................................................86 
13.2 
Causality ..........................................................................................................88 
13.3 
Adverse Events Reporting Procedures.............................................................89 
13.3.1 
General ..............................................................................................89 
13.3.2 
Disease Progression ..........................................................................90 
13.4 
Serious Adverse Events Definitions ................................................................90 
13.5 
Serious Adverse Event Reporting and Documentation Requirements ............91 
13.6 
Pregnancy Reporting ........................................................................................92 
14 
STATISTICS ..............................................................................................................94 
Approved 
 
 
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14.1 
Study Endpoints ...............................................................................................95 
14.1.1 
Primary Endpoints ............................................................................95 
14.1.2 
Secondary Endpoints ........................................................................95 
14.1.3 
Exploratory Endpoints ......................................................................95 
14.2 
Analysis of the Conduct of the Study ..............................................................95 
14.3 
Data Monitoring Committee ............................................................................96 
14.4 
Analysis of Treatment Group Comparability ..................................................96 
14.4.1 
Treatment Exposure and Medication Compliance ............................96 
14.5 
Statistical Methods ...........................................................................................97 
14.5.1 
Analysis Populations .........................................................................97 
14.5.2 
Efficacy Analyses .............................................................................97 
14.5.3 
Safety Analysis .................................................................................98 
14.5.4 
Pharmacokinetic Analyses ................................................................98 
14.6 
Handling of Missing Data ................................................................................99 
14.7 
Determination of Sample Size .........................................................................99 
15 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS .............................101 
15.1 
Compliance Statement ...................................................................................101 
15.2 
Institutional Review Board or Independent Ethics Committee .....................101 
15.3 
Informed Consent and Human Subject Protection.........................................101 
15.4 
Direct Access to Source Data, Source Documents, and Study Records ........102 
15.5 
Data Collection and Handling ........................................................................102 
15.6 
Confidentiality ...............................................................................................103 
16 
REFERENCES .........................................................................................................105 
APPENDIX A1 
SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B 
DOSE ESCALATION 5/14 SCHEDULE ..............................................................109 
APPENDIX A2 
SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B 
DOSE ESCALATION 2/7 SCHEDULE ................................................................114 
APPENDIX B1 
SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B 
DOSE EXPANSION 5/14 SCHEDULE .................................................................119 
APPENDIX B2 
SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B 
DOSE EXPANSION 2/7 SCHEDULE ...................................................................124 
APPENDIX C 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA ........129 
Approved 
 
 
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APPENDIX D 
EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER (EORTC) CORE MODULE (QLQ-C30) 
AND EORTC MULTIPLE MYELOMA MODULE (QLQ-MY20) ...................132 
APPENDIX E 
NEUROTOXICITY SUBSCALE OF THE 
GYNECOLOGIC ONCOLOGY GROUP’S 
FUNCTIONAL ASSESSMENT OF CANCER THERAPY 
(FACT/GOG-NTX4 [VERSION 4]) .......................................................................133 
APPENDIX F 
EQ-5D-5L (V.2) .............................................................................134 
APPENDIX G 
EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE SCALE ......................................................................135 
APPENDIX H 
DRUG-DRUG INTERACTION POTENTIAL OF 
OPROZOMIB AND POMALIDOMIDE ..............................................................136 
APPENDIX I 
POMALIDOMIDE RISKS OF FETAL EXPOSURE, 
PREGNANCY TESTING GUIDELINES, AND ACCEPTABLE BIRTH 
CONTROL METHODS ..........................................................................................138 
APPENDIX J 
POMALIDOMIDE EDUCATION AND COUNSELLING 
GUIDANCE DOCUMENT .....................................................................................143 
APPENDIX K 
POMALIDOMIDE INFORMATION SHEET FOR 
PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES ....................147 
APPENDIX L 
ACTG BRIEF PERIPHERAL NEUROPATHY 
SCREENING TOOL ...............................................................................................150 
APPENDIX M 
SAMPLE BRIEF PAIN INVENTORY – 
SHORT FORM (BPI-SF) ........................................................................................153 
APPENDIX N 
EXAMPLE ELECTRONIC SERIOUS ADVERSE EVENT 
CONTINGENCY REPORT FORM ......................................................................155 
APPENDIX O 
EXAMPLE AMGEN PREGNANCY 
NOTIFICATION WORKSHEET ..........................................................................158 
APPENDIX P 
EXAMPLE AMGEN LACTATION 
NOTIFICATION WORKSHEET ..........................................................................159 
APPENDIX Q 
SUMMARY OF CHANGES IN STUDY OPZ007 
AMENDMENT 3.0 ..................................................................................................160 
 
Approved 
 
 
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LIST OF TABLES 
Table 1 
Phase 1 Response Rates for Subjects with Multiple Myeloma, 
by Schedule and Formulation ................................................................................33 
Table 2 
Phase 1 Response Rates for Subjects with Waldenström macroglobulinemia, 
by Schedule and Formulation ................................................................................34 
Table 3 
Primary Dose-Escalation Path for Oprozomib  on 5/14 Schedule with 
Pomalidomide 4 mg in Phase 1b ............................................................................47 
Table 4 
Alternative Dose-Escalation Path 1 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1a Exceeds the MTD or at Sponsor 
Discretion ...............................................................................................................48 
Table 5 
Alternative Dose-Escalation Path 2 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1b Exceeds the MTD or at Sponsor 
Discretion ...............................................................................................................48 
Table 6 
Primary Dose-Escalation Path for Oprozomib on the 2/7 Schedule with 
Pomalidomide 4 mg in Phase 1b ............................................................................50 
Table 7 
Alternative Dose-Escalation Path 1 for Oprozomib on 2/7 Schedule with 
Pomalidomide in Phase 1b if Cohort 101a Exceeds the MTD or at Sponsor 
Discretion ...............................................................................................................50 
Table 8 
Alternative Dose-Escalation Path 2 for Oprozomib on 2/7 Schedule with 
Pomalidomide in Phase 1b if Cohort 101b Exceeds the MTD or at Sponsor 
Discretion ...............................................................................................................50 
Table 9 
Dose Decrements for Oprozomib – 5/14 Schedule ................................................62 
Table 10 Dose Decrements for Oprozomib – 2/7 Schedule ..................................................62 
Table 11 Dose Decrements for Pomalidomide .....................................................................63 
Table 12 Dose Decrements for Dexamethasone ...................................................................63 
Table 13 Guidelines for Dose Modification of Oprozomib/Placebo and Pomalidomide 
for Hematologic Toxicities ....................................................................................65 
Table 14 Guidelines for Dose Modification of Oprozomib/Placebo and Pomalidomide 
for Nonhematologic Toxicities ..............................................................................67 
Table 15 Treatment Guidelines for Dexamethasone-Related Toxicity ................................70 
Table 16 Full Chemistry Panel ..............................................................................................79 
Table 17 Toxicity Grading for Adverse Events Not Covered in the NCI-CTCAE 
(Version 4.03) ........................................................................................................87 
Table 20 Properties of the Dose-Escalation Rules for Different Underlying DLT Rates ...100 
 
Approved 
 
 
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LIST OF FIGURES 
Figure 1 
Study Dosing Schema for the 5/14 Dosing Schedule ............................................46 
Figure 2 
5/14 Schedule Primary Study Dose-Escalation Pathsa ..........................................47 
Figure 3 
Study Dosing Schema for the 2/7 Dosing Schedule ..............................................49 
Figure 4 
2/7 Schedule Primary Study Dose-Escalation Pathsa ............................................49 
Approved 
 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-HT3 
5-hydroxytryptamine type-3 
ADCC 
antibody‐dependent cytotoxic T‐cell activity 
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 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration time curve from time 0 to time infinity 
AUC0-t 
area under the curve at the last measurable time point 
BPI-SF 
Brief Pain Inventory – Short Form 
C 
Cycle 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
Cmax 
maximum plasma concentration  
CPomd 
carfilzomib + pomalidomide + dexamethasone  
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CSRC 
Cohort Safety Review Committee 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-L 
chymotrypsin-like  
CYP1A2 
cytochrome P450, 1A2 (enzyme) 
CYP3A 
cytochrome P450 3A (enzyme) 
D 
Day 
D/C 
discontinue 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep vein thrombosis 
EBMT 
European Group for Blood and Marrow Transplantation 
ECG 
electrocardiogram 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 26 of 223 
CONFIDENTIAL 
Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture  
ELISA 
enzyme-linked immmunosorbent assay 
EORTC 
European Organization for Research and Treatment of Cancer 
ER 
Extended Release 
EU 
European Union 
EQ-5D-5L 
European Quality of Life – Descriptive system of health-related quality of life states 
consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) 
FACT/GOG-Ntx 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 
subscale questionnaire 
FCBP 
females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
GCP 
Good Clinical Practice 
G-CSF  
granulocyte-colony stimulating factor 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GLP 
Good Laboratory Practices 
H2 
histamine 2 blocker 
HIV 
human immunodeficiency virus 
HR 
hazard ratio  
HRQoL 
health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMiDs 
immunomodulatory drug(s) 
IMWG-URC 
International Myeloma Working Group-Uniform Response Criteria  
IND 
Investigational New Drug 
IP 
investigational product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous(ly) 
/ 
kappa lambda 
MAD 
maximum administered dose 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 27


Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 27 of 223 
CONFIDENTIAL 
Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
MTD 
maximum tolerated dose 
NA 
not applicable or not available 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events  
NF-Kappa B 
nuclear factor kappa light chain enhancer of activated B cells 
NHL 
non-Hodgkin lymphoma 
OPomd 
oprozomib + pomalidomide + dexamethasone 
ORR 
overall response rate  
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PDn 
pharmacodynamic(s) 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PN 
peripheral neuropathy 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes 
Pomd 
pomalidomide + dexamethasone 
PR 
partial response 
PRO 
patient-reported outcomes 
QLQ-C30 
Quality of Life Core Module 
QOL 
quality of life  
QTc 
corrected QT interval 
RBC 
red blood cell 
RP3D 
recommended Phase 3 dose 
SAE 
serious adverse event 
SAH 
subachnoid hemorrhage 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SCT 
stem cell transplant 
SD 
stable disease 
SFLC 
serum free light chain 
SPEP 
serum protein electrophoresis 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 28


Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 28 of 223 
CONFIDENTIAL 
Abbreviation 
Definition 
UPEP 
urine protein electrophoresis 
US 
United States  
VGPR 
very good partial response 
WBC 
white blood cell 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
WM 
Waldenström macroglobulinemia 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 29


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INTRODUCTION 
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3.2
MULTIPLE MYELOMA BACKGROUND 
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 31 of 223 
CONFIDENTIAL 
3.3 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of 
a wide variety of protein substrates within normal and transformed cells.  Intracellular 
proteins targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin 
conjugation system.  Ubiquitinated proteins are cleaved within the proteasome by 1 or more 
of 3 separate N-terminal threonine protease activities:  a chymotrypsin-like (CT-L) activity, 
a trypsin-like activity, and a caspase-like activity. 
Proteasome inhibitors have been shown to have antiproliferative, proapoptotic, 
antiangiogenic, and antitumor activities across multiple tumor models.  Treatment with 
oprozomib, carfilzomib, or bortezomib results in an increase in the accumulation of 
proapoptotic proteins, promotion of autophagy, and an increase in the stability of negative 
regulators of the cell cycle (Boccadoro 2005; Shen 2013; Zang 2012).   
3.4 
OPROZOMIB BACKGROUND 
Oprozomib (formerly ONX 0912) is a tripeptide epoxyketone proteasome inhibitor and 
structural analogue of carfilzomib (Kyprolis) that primarily targets the CT-L activity of the 
20S proteasome.  Carfilzomib received accelerated approval in the 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]).  Similar to carfilzomib, oprozomib is a potent, selective, and 
irreversible inhibitor of the CT-L activity of the constitutive proteasome (the form of 
proteasome found in most cell types) and the immunoproteasome (the form of proteasome 
found in many hematopoietic cells) (Zhou 2009).  In addition, when measured against 
a broad panel of proteases containing metallo-, aspartyl, cysteine, and serine proteases, 
oprozomib demonstrated minimal reactivity against nonproteasomal proteases. 
Exposure to oprozomib is associated with potent pro-apoptotic 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 carcinoma) and 
Approved 
 
 
Product: 
Date: 
Oprozomib
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30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 32 of 223 
CONFIDENTIAL 
hematologic (multiple myeloma, non-Hodgkin lymphoma [NHL]) tumors, where its activity 
was equivalent to carfilzomib (Zhou 2009). 
3.4.1 
RELEVANT NONCLINICAL BACKGROUND 
Oprozomib is orally bioavailable in plasma following solution administration in rodents and 
dogs.  Pharmacodynamic (PDn) determinations demonstrate that proteasome inhibition of 
> 80% was readily achieved in blood and a wide variety of tissues at tolerated doses in 
rodents and in whole blood in dogs. 
The safety of oprozomib has been established in Good Laboratory Practices (GLP)-compliant 
toxicity studies in rats and dogs.  In 28-day repeat-dose studies, a suspension formulation of 
oprozomib was administered orally, once daily, for 5 consecutive days with 9 days rest 
(5 consecutive days bimonthly) for 2 complete 14-day cycles.  Oprozomib was administered 
to rats at doses of 20, 30, and 40 mg/kg (120, 180, and 240 mg/m2) and to dogs at 3, 6, and 
10 mg/kg (60, 120, and 200 mg/m2).  A GLP-compliant, single-dose cardiovascular safety 
pharmacology study in dogs was also performed.  The results of these studies show that 
oprozomib can be safely administered at doses that result in > 80% proteasome inhibition.  
This level of proteasome inhibition with carfilzomib has been shown to correlate with 
antitumor activity in subjects with malignancies. 
Further information about the preclinical pharmacology and toxicology of oprozomib is 
presented in the Oprozomib Investigator’s Brochure (IB). 
3.4.2 
RELEVANT CLINICAL BACKGROUND 
3.4.2.1 
Study 2009-003:  Solid Tumors 
Efficacy 
In Study 2009-003, oprozomib, dosed as powder in capsule, was studied in solid tumor 
subjects.  In the Phase 1 study in refractory solid tumors (n = 44), no subject achieved an 
objective response.  Stable disease (SD) was observed in 6 subjects (30%) in the once daily 
dosing group and 4 subjects (23.5%) in the split daily dosing group. 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 33 of 223 
CONFIDENTIAL 
Safety 
The majority of adverse events (AEs) were Grade 1 and 2, manageable, and there were no 
apparent cumulative toxicities.  The most common AEs were in the GI system organ class.  
This was consistent with preclinical animal studies with oprozomib.  Dose-limiting toxicities 
for the once daily dose group in Study 2009-003 included Grade 3 dehydration/vomiting and 
Grade 3 hypophosphatemia in the 180 mg cohort.  The maximum tolerated dose (MTD) for 
the once daily x5 days dose group is 150 mg.  Dose-limiting toxicities for the split 
daily x5 days dosing group in Study 2009-003 included Grade 3 hypophosphatemia at 
180 mg and Grade 5 upper GI hemorrhage and Grade 3 hallucinations at 210 mg.  The MTD 
for the split dosing is 180 mg. 
3.4.2.2 
Study 2011-001:  Hematologic Malignancies 
Efficacy 
As of 21 January 2014, the Phase 1b portion of Study 2011-001 has completed enrollment; 
61 response-evaluable subjects with hematologic malignancies have 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.  
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, respectively.  
Table 1 
Phase 1 Response Rates for Subjects with Multiple Myeloma, 
by Schedule and Formulation 
Formulation/Schedule (n) 
Dose Range (mg) 
ORR 
Clinical Benefit Rate 
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. 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
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30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 34 of 223 
CONFIDENTIAL 
Table 2 
Phase 1 Response Rates for Subjects with Waldenström macroglobulinemia, 
by Schedule and Formulation 
Formulation/Schedule (n) 
Dose Range (mg) 
ORRa 
Major Responseb 
Tablets 5/14 (11) 
150–270 
63.6% 
54.5% 
Tablets 2/7 (7) 
150–330 
42.9% 
14.3% 
MR = minimal response; ORR = overall response rate; PR = partial response. 
a ORR is defined as ≥ MR. 
b Major response is defined as ≥ PR. 
The Phase 2 portion of Study 2011-001 is ongoing.  Eight (8) response-evaluable subjects 
have received Oprozomib Tablets on the 5/14 schedule with once daily dosing in Phase 2; 
7 subjects had SD, and 1 subject was off study prior to any disease response assessment. 
Safety 
In the Phase 1 portion of the study (as of 21 January, 2014):   
 Thirty-two (32) subjects have been enrolled on the 5/14 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 initially selected for the Phase 2 portion 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 2/7 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.  With the opening of 
Amendment 6, 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 Phase 2 portion for the 2/7 schedule. 
In 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 (19) 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 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 35


Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 35 of 223 
CONFIDENTIAL 
(fatigue/dehydration/nausea; events could be counted in more than 1 category).  All of these 
are expected events based on the Oprozomib IB (Version 6).  There were 2 cases of renal 
failure.  There were also 2 Grade 5 GI hemorrhages at the 240 mg dose level on the 
5/14 schedule. 
3.4.2.3 
Study 2012-001:  Oprozomib in Combination with Dexamethasone in 
Multiple Myeloma 
Efficacy 
For the 2012-001 Phase 1b/2 study, as of 31 March 2014, 5 response-evaluable relapsed 
and/or refractory multiple myeloma subjects received Oprozomib Tablets on a 5 consecutive 
day bimonthly (5/14) schedule with daily dosing; 1 subject had MR and 4 subjects had SD as 
their best response.  As of 31 March 2014, 8 response-evaluable subjects have received 
Oprozomib Tablets administered orally, once daily, on Days 1, 2, 8, and 9 of a 14-day 
cycle (2/7) in combination with 20 mg of dexamethasone; 1 subject had a VGPR 
(unconfirmed), 2 subjects had a partial response ([PR] confirmed or unconfirmed), 1 subject 
had a MR, and 4 subjects had SD as the best response.  
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 (3) subjects 
have experienced DLTs at the 210 mg dose, including 1 subject with a subarachnoid 
hemorrhage (SAH), 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).  Data suggest that the 180-mg dose level will be the tolerable dose in 
combination with dexamethasone.  This dose level exceeds the starting dose for the 
combination of oprozomib, pomalidomide, and dexamethasone (OPomd) of 150 mg. 
 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.  Dose 
escalation is ongoing at the 300-mg dose level, suggesting that doses of 270 mg in 
combination with dexamethasone are tolerable.  Current doses explored in this schedule 
exceed the starting dose for the combination of OPomd of 210 mg. 
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As of 31 March 31 2014, ten (10) subjects experienced serious adverse events (SAEs) across 
both schedules.  The 3 treatment-related SAEs were 1 subject with a SAH, hypertension, and 
headache, 1 subject with thrombocytopenia, pneumonia, and sepsis, and 1 subject with 
delirium.  Thrombocytopenia and infection were expected events based on the Oprozomib IB 
(Version 6), but the SAH, hypertension, headache, and delirum were not.   
3.4.2.4 
Study OPZ003:  Oprozomib in Combination with Lenalidomide and 
Dexamethasone in Multiple Myeloma 
Efficacy 
No efficacy data are available at this time. 
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, 3 subjects have been 
enrolled.  Two (2) subjects remain on study.  One subject, a
year old
 experienced 
a treatment-related SAE of Grade 3 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. 
3.5 
DOSE RATIONALE 
3.5.1 
OPROZOMIB 
Early development of oprozomib focused on the 5 consecutive day bimonthly (either once or 
twice daily) (5/14) and 2 consecutive days weekly (2/7) schedules, both on 14-day treatment 
cycles.  The MAD for Oprozomib Tablets administered once daily on a 5 consecutive day 
bimonthly schedule has been reached with a total daily dose of up to 270 mg in subjects with 
hematologic malignancies, with 1 dose-limiting toxicity (DLT) of TLS and 1 Grade 3 
vomiting out of 6 subjects.  At the 240-mg dose, 6 subjects were dosed with 1 DLT of TLS, 
therefore 240 mg was the declared as the MTD.  For the 5/14 schedule, the starting dose of 
150 mg of oprozomib will be added to the Food and Drug Administration (FDA)-approved 
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regimen of pomalidomide/dexamethasone, 3 dose levels below the MTD in the single-agent 
study.   
For the 2/7 schedule, the MAD was reached with a total daily dose of 330 mg with 1 DLT of 
Grade 3 diarrhea and 1 DLT of Grade 4 thrombocytopenia.  One DLT of Grade 3 orthostatic 
hypotension was reported in the 300-mg cohort, therefore 300 mg was declared the MTD.  
The starting dose for the 2/7 schedule in combination with Pomd will be 210 mg, 3 dose 
levels below the single agent MTD of 300 mg.   
This study will assess both schedules in this study, as oprozomib has demonstrated 
preliminary activity in subjects with hematologic malignancies on both schedules 
(Kaufman, 2013). 
3.5.2 
DEXAMETHASONE 
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 improved efficacy when administered 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 a previous study, the addition of steroids to a proteasome inhibitor reduced GI toxicity 
when compared with single-agent bortezomib (Jagannath, 2006).  The addition of low doses 
of 4 mg of dexamethasone to oprozomib appears to reduce GI toxicity in Study 2011-001.  
Given that GI AEs have been the most frequent events observed in subjects treated with 
oprozomib, it is anticipated that Oprozomib ER Tablets will have even less GI toxicity in 
combination with antimyeloma doses of 20 to 40 mg of dexamethasone once weekly, and 
therefore may be safely dosed at the same level as or higher than oprozomib monotherapy. 
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3.5.3 
POMALIDOMIDE 
Pomalidomide (Pomalyst), a thalidomide analogue, is an IMiD that displays similar 
antiangiogenic activity but far greater antiproliferative and immunomodulatory activity 
compared with the parent drug (Bartlett, 2007; Payvandi, 2004).  Pomalidomide has also 
been shown to stimulate antibody‐dependent cytotoxic T-cell activity (ADCC) 
(Bartlett, 2007). 
Pomalidomide received accelerated approval in the EU in August 2013 and in the US in 
February 2013.  The European Commission has granted approval for pomalidomide in 
combination with dexamethasone, for the treatment of relapsed and refractory multiple 
myeloma who received at least two prior therapies and have demonstrated disease 
progression on the last drug taken and the US FDA granted accelerated approval for patients 
with multiple myeloma with 2 prior therapies including both bortezomib and lenalidomide 
and who are refractory to their last therapy or progressed within 60 days.  The approved dose 
of pomalidomide is 4 mg given 21 days of a 28-day cycle until progressive disease (PD). 
Approval was based on Study MM002, a randomized Phase 2 comparison of pomalidomide 
in combination with low-dose therapeutic dexamethasone (POM + LoDex) to pomalidomide 
alone (Jagannath, 2012).  The overall response rate (ORR) was 34%, with a median PFS of 
4.6 months and median OS of 16.5 months.  Grade 3 or 4 AEs reported in > 5% of subjects 
were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue 
(14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%).  
Grade 3 or 4 neutropenia occurred in 46% of subjects aged ≤ 65 years and in 35% of subjects 
aged > 65 years.  Febrile neutropenia was observed in only 1 subject in each age group (2%).  
Overall, 78% of subjects who developed Grade 3 or 4 neutropenia were treated with 
granulocyte-colony stimulating factor (G-CSF) during study treatment.  There was no 
Grade 3 or 4 peripheral neuropathy (PN) reported, although Grade 1 or 2 PN occurred in 
7% of subjects treated with POM + LoDex.  Deep vein thrombosis (DVT) occurred in 
2 subjects (2%).  Pomalidomide appears to provide an efficacious option with a manageable 
toxicity profile for subjects with refractory or relapsed and refractory multiple myeloma. 
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The MM003 randomized Phase 3 study was designed to assess relapsed and/or refractory 
subjects with multiple myeloma who had been previously treated with bortezomib and 
lenalidomide or thalidomide, and progressed on or within 60 days of the last therapy.  
A regimen of pomalidomide and dexamethasone was compared to high-dose dexamethasone. 
Subjects were randomized 2:1 to receive 28-day cycles of pomalidomide 4 mg on 
Days 1-21 + dexamethasone 40 mg (20 mg for subjects more than 75 years old) weekly or 
dexamethasone 40 mg (20 mg for subjects more than 75 years old) on Days 1–4, 9–12, 
and 17–20.  Treatment continued until PD or unacceptable toxicity.  The primary endpoint 
was PFS.  Secondary endpoints included OS, ORR (≥ PR), and safety.  Analyses were based 
on intent-to-treat.  A total of 455 subjects were randomized to pomalidomide + low-dose 
dexamethasone (n = 302) or high-dose dexamethasone (n = 153).  The median number of 
prior therapies was 5 (range:  1−17).  Seventy-two percent (72%) of subjects were refractory 
to lenalidomide and bortezomib.  Median follow-up was 4 months.  
Pomalidomide + low-dose dexamethasone significantly extended median PFS (3.6 versus 
1.8 months, hazard ratio [HR] = 0.45, p < 0.001) and OS (not reached versus 7.8 months, 
HR = 0.53, p < 0.001) compared with high-dose dexamethasone.  The OS benefit was 
observed despite 29% of high-dose dexamethasone subjects receiving pomalidomide after 
PD (Jagannath, 2012).  With updated data, the ORR was 21% for pomalidomide + low-dose 
dexamethasone versus 3% for high-dose dexamethasone (p < 0.001) and 24% versus 3% for 
subjects randomized ≥ 6 months after enrollment (p < 0.001).  Median OS was 12.7 months 
for pomalidomide + low-dose dexamethasone and 8.1 months for high-dose dexamethasone; 
HR = 0.74 (p = 0.28).  The most frequent Grade 3/4 AEs for pomalidomide + low-dose 
dexamethasone versus high-dose dexamethasone were neutropenia (42% versus 15%), 
anemia (27% versus 29%), and infection (24% versus 23%).  Discontinuation due to AEs 
was infrequent (7% versus 6%) (San Miguel, 2013). 
Lacy et al. (2011) conducted a study to assess efficacy and toxicity of 2- and 4-mg doses of 
pomalidomide.  Pomalidomide was given orally on Days 1–28 of a 28-day cycle at a dose of 
2 or 4 mg, with dexamethasone administered at 40 mg weekly.  Thirty-five (35) subjects 
were enrolled in each cohort.  Based on confirmed responses, the ORR was 49% in the 
2-mg cohort and 43% in the 4-mg cohort.  Overall survival at 6 months was 78% and 67% in 
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the 2- and 4-mg cohorts, respectively.  Myelosuppression was the most common toxicity.  
Grade 3 or 4 hematologic toxicity, regardless of attribution, occurred in 83% (2-mg cohort) 
and 80% (4-mg cohort) of subjects, and was considered to be at least possibly related to the 
regimen in 71% (2-mg cohort) and 74% (4-mg cohort).  Grade 3 or 4 neutropenia (regardless 
of attribution) was seen in 51% (2-mg cohort) and 66% (4-mg cohort) of subjects.  Grade 3 
or 4 nonhematologic toxicity, regardless of attribution, occurred in 69% (2-mg cohort) and 
54% (4-mg cohort) of subjects, and was considered to be at least possibly related to the 
regimen in 26% (2-mg cohort) and 26% (4-mg cohort).  These data obtained from 
nonrandomized subjects suggest no advantage for 4 mg over the 2 mg daily dose.  This is the 
basis for the dose de-escalation to 2 mg of pomalidomide in the event the initial dose level of 
4 mg or the first dose de-escalation to 3 mg is not tolerated (Lacy, 2011). 
3.6 
STUDY RATIONALE 
The clinical activity of proteasome inhibition in hematologic malignancies has been 
demonstrated in multiple myeloma in the clinical setting.  Specifically, bortezomib, which is 
a covalent, slowly reversible proteasome inhibitor that primarily targets the CT-L activity of 
the proteasome, was the first approved proteasome inhibitor.  Because of the benefit of 
bortezomib observed in subjects with relapsed or refractory myeloma in Phase 1 and 2 trials, 
the drug received accelerated approval by the US FDA, and was made available to subjects 
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) is an irreversible inhibitor of the epoxyketone class (proteasome) that 
received accelerated approval in the 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]).  Carfilzomib 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 
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equal potency, but greater selectivity for the CT-L 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 9 days rest; and daily dosing for 2 consecutive days for 3 weeks [Days 1, 2, 8, 9, 15, and 
16] and 12 days rest).  Prolonged proteasome inhibition was believed to have greater 
antitumor activity and would be pursued if tolerable. 
Data collected in these 2 trials 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 dose and schedule and have provided data 
indicating both tolerability and efficacy in advanced stage, heavily pretreated multiple 
myeloma subjects.  Both schedules will be assessed with oprozomib to determine which 
schedule provides an advantage in tolerability and efficacy. 
Oprozomib, a structural analogue of carfilzomib, is a synthetic small-molecule peptide that 
specifically functions as an irreversible and highly selective inhibitor of the CT-L 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, 
patient convenience, and potentially prolong treatment duration. 
Preclinical studies show that lenalidomide sensitizes multiple myeloma to the proteasome 
inhibitor bortezomib, suggesting combination therapy may enhance clinical activity.  
The combination of a proteasome inhibitor and an IMiD is attractive, as the expected 
overlapping toxicities would be manageable.  This concept was confirmed in Phase 1 and 
2 studies of lenalidomide, high-dose dexamethasone, and bortezomib, which demonstrated 
synergistic effects in relapsed and refractory multiple myeloma (Richardson, 2006a; 
Anderson, 2009), although treatment-emergent peripheral neuropathy (observed in 35% of 
subjects) may limit the utility of that combination (Richardson, 2006b).  An ongoing, 
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Phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose 
dexamethasone in subjects with newly diagnosed multiple myeloma has demonstrated 
excellent activity and tolerability, with 62% of 53 subjects achieving near complete response 
or better and with only Grade 1/2 peripheral neuropathy in 23% of the subjects 
(Jakubowiak, 2012). 
Stadtmauer et al. (2013) demonstrated the activity of carfilzomib in combination with 
pomalidomide and dexamethasone (CPomd) in a Phase 1b/2 study.  In this ongoing 
82-subject trial, the primary objective is to assess the safety, tolerability, and MTD of 
carfilzomib in combination with pomalidomide and low-dose therapeutic dexamethasone.  
Secondary objectives include a preliminary assessment of efficacy as measured by best ORR, 
PFS, and OS.  All subjects were refractory to prior lenalidomide and relapsed and refractory 
to their most recent therapy at the time of enrollment.  The MTD of carfilzomib was 
determined to be 20/27 mg/m2 in combination with 4 mg of pomalidomide per day on 
Days 1–21, and 40 mg/week of dexamethasone.  Drug-related AEs occurring in > 20% of 
subjects included fatigue, anemia, thrombocytopenia, neutropenia, diarrhea, dyspnea, skin 
rash/pruritis, elevated creatinine, and hypocalcemia.  Notable SAEs were Grade 3 pneumonia 
(n = 3), pulmonary embolism (n = 1), and congestive heart failure (n = 1).  The ORR was 
50% and the 6-month PFS was 71%.  The OS at 12 months was 90%.  The authors concluded 
that this regimen was safe and adequately tolerated and led to compelling improvements in 
outcome for subjects with advanced myeloma. 
The rationale for this study is based on the results of the previously described study 
(Stadtmauer, 2013), as well as the similarities between carfilzomib and oprozomib in 
mechanism of action, preclinical toxicity profile, clinical profile, and the non-overlapping 
toxicity profile of oprozomib and pomalidomide.  Subjects treated with carfilzomib have 
demonstrated an ORR of 23% and an OS of 15.6 months (Siegel, 2012), while subjects 
treated with pomalidomide in combination with dexamethasone have demonstrated an ORR 
of 30% and an OS of 16.5 months (Jagannath, 2012).  The proposed study of oprozomib in 
combination with pomalidomide and dexamethasone will assess whether this triplet can 
confer improvements in outcome as measured by PFS when compared with pomalidomide 
and dexamethasone alone. 
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4 
STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVES 
 To determine the maximum tolerated dose (MTD) and identify the recommended Phase 3 
dose (RP3D) and schedule of oprozomib in combination with pomalidomide and 
dexamethasone (OPomd) in subjects with primary refractory or relapsed and refractory 
multiple myeloma 
 To evaluate the safety and tolerability of the OPomd combination in subjects with 
primary refractory or relapsed and refractory multiple myeloma 
4.2 
SECONDARY OBJECTIVES 
 To estimate the overall response rate (ORR) of OPomd, defined as the proportion of 
subjects with an overall response of stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), or partial response (PR) as 
determined by investigator according to the International Myeloma Working 
Group- Uniform Response Criteria (IMWG-URC)  
 To estimate the clinical benefit rate (CBR) of OPomd, defined as the proportion of 
subjects with an overall response of minimal response (MR) or better as determined by 
investigator according to the IMWG-URC and modified European Group for Blood and 
Marrow Transplantation (EBMT) criteria   
 To characterize the pharmacokinetics (PK) of oprozomib in the OPomd regimen 
4.3 
EXPLORATORY OBJECTIVES 
 To evaluate the pharmacodynamic (PDn) biomarkers that may correlate with antitumor 
activity 
 To evaluate genomic biomarkers that may correlate with antitumor activity and resistance 
following treatment with proteasome inhibitors 
 To evaluate (in the dose-expansion portion only) the patient-reported outcomes (PRO) 
using the tools listed below: 
o Bone pain and the impact of bone pain measured with the Brief Pain 
Inventory- Short Form (BPI-SF) 
o Health-related quality of life (HRQoL) measured by the global health 
status/QoL scale of the European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Core Module (QLQ-C30) questionnaire 
o Health status assessed by the EQ-5D-5L  
o Disease symptoms as measured by the disease symptoms subscale of the 
EORTC Multiple Myeloma Module (QLQ-MY20) questionnaire 
o Neurotoxicity symptoms as measured by the neurotoxicity subscale of the 
Functional Assessment of Cancer Therapy /Gynecological Oncology 
Group-Neurotoxicity (FACT/GOG-Ntx4 [Version 4]) questionnaire  
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5 
STUDY DESIGN 
This is a Phase 1b study of oprozomib in combination with pomalidomide and 
dexamethasone in subjects with primary refractory or relapsed and refractory multiple 
myeloma.  This study includes an open-label, Phase 1b, dose-escalation and dose-expansion 
portion (the equivalent of a small Phase 2) during which the RP3D will be identified.  Further 
evaluation of safety and efficacy will be assessed during the dose-expansion portion.  During 
this study, subjects will receive Oprozomib ER Tablets according to their assigned dose 
cohort.   
This study will include subjects with primary refractory or relapsed and refractory multiple 
myeloma, ie, those who have demonstrated disease progression on or within 60 days of their 
last therapy, and who have received at least 2 prior lines of therapy (including bortezomib 
and lenalidomide and/or thalidomide, and in the dose-expansion portion of the study only, 
been treated with adequate alkylator therapy).  Subjects whose last therapy was bortezomib 
and who were not refractory but developed bortezomib intolerance, as defined by the 
development of Grade 2 peripheral neuropathy with pain or ≥ Grade 3 peripheral neuropathy 
after ≥ 2 consecutive cycles, are eligible. 
Treatment cycles are 28 days in duration.  Two (2) oprozomib dosing schedules will be 
assessed during dose escalation.  Subjects will receive oprozomib once daily either on 
Days 1–5 and 15–19, referred to hereafter as the 5/14 schedule, or an alternate schedule of 
once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23, referred to hereafter as the 2/7 schedule.  
Pomalidomide will be given on Days 1–21 and dexamethasone will be given on Days 1, 2, 8, 
9, 15, 16, 22, and 23 of every 28-day cycle. 
Approximately 35 study sites will participate in this study (15 sites for the dose-escalation 
and 20 additional sites for the dose-expansion portions of the study). 
Disease assessments will be performed every 4 weeks for subjects in both arms for 
18 months.  Further disease assessments will be conducted every 8 weeks after this period, 
beginning with Month 20.  Details of the study assessments required for this study are 
provided in Appendices A1, A2, B1, and B2. 
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5.1 
DOSE-ESCALATION AND DOSE-EXPANSION PORTIONS OF THE 
STUDY 
In this study, the safety, MTD, PK/PDn, and RP3D of oprozomib when given in combination 
with pomalidomide and dexamethasone will be assessed using a standard 
3 + 3 dose-escalation design.  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.  If the starting dose of oprozomib cannot be 
safely administered with the labeled pomalidomide dose or at sponsor discretion, then up to 
2 possible alternative dose-escalation paths for oprozomib with lower pomalidomide doses 
will be explored (See tables below for primary and alternative dose-escalation paths).  
Dose escalation will continue until until sponsor discretion, the maximum planned dose of 
pomalidomide is reached, or ≥ 2 DLTs occur in a cohort, whichever occurs first.  The prior 
cohort will be expanded to at least 6 subjects if not previously done to establish it as the 
MTD.  There may be more than 1 MTD of oprozomib if more than 1 dose level of 
pomalidomide is studied.  The MTD for oprozomib associated with each dose level of 
pomalidomide assessed will be the dose level where < 2 DLTs in 6 subjects are observed.   
There is no planned maximum dose of oprozomib to be evaluated as it is being added to the 
FDA-approved regimen of pomalidomide/dexamethasone, however, this could be imposed at 
any time during the course of the study, based on sponsor discretion.  The starting dose of 
oprozomib for the 5/14 schedule is 150 mg, 3 dose levels below the established single-agent 
MTD of 240 mg.  The starting dose of oprozomib for the 2/7 schedule is 210 mg, 3 dose 
levels below the established 2/7 single-agent MTD of 300 mg.  The MTD will be determined 
as outlined in the protocol for each schedule.  Following dose escalation, the sponsor has the 
option of expanding 1 or both schedules in order to establish the RP3D and schedule.  
The sponsor, with input from the Cohort Safety Review Committee ([CSRC] consisting of 
investigators, sponsor’s medical monitor, and sponsor’s drug safety representative), will 
determine which dose and schedule of oprozomib in combination with Pomd to use for the 
dose-expansion (ie, the RP3D) portion of the study.  The sponsor has the option of expanding 
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1 or both schedules in order to establish the RP3D and schedule.  The RP3D may differ from 
the MTD, but will not be higher than the MTD, and will be selected based upon the 
assessment of the safety, tolerability, PK, PDn, preliminary activity, and other variables to be 
observed across multiple cycles of combination therapy. 
5.1.1 
DOSE-ESCALATION SCHEMA FOR THE 5/14 OPROZOMIB DOSING 
SCHEDULE 
The study dosing schema for the 5/14 schedule is displayed in Figure 1.  The potential doses 
to be evaluated on the 5/14 dosing schedule are displayed in Figure 2.  The primary and 
alternative pathways for dose escalation of oprozomib and pomalidomide for the 
5/14 Schedule are summarized in Table 3 through Table 5; these are examples, and are not 
inclusive of all possible dose-escalation paths. 
Figure 1 Study Dosing Schema for the 5/14 Dosing Schedule 
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Figure 2 5/14 Schedule Primary Study Dose-Escalation Pathsa 
 
5/14 = Dosing on Days 1–5 and 15–19; Dex = Dexamethasone; 
OPZ = oprozomib; Pom = pomalidomide 
a There is no predefined maximum dose level of oprozomib being studied. 
 
Table 3 
Primary Dose-Escalation Path for Oprozomib  
on 5/14 Schedule with Pomalidomide 4 mg in Phase 1b  
Cohort 5/14 Schedule 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1a (initial cohort) 
150 
4 
2a 
180 
4 
3a 
210 
4 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
Note:  This is an example of the primary dose-escalation cohort.  Dose 
escalation will continue in 30-mg increments of oprozomib until the MTD is 
identified. 
 
If Cohort 1a exceeds the MTD, or at the sponsor’s discretion, the alternative path 1 described 
in Table 4 may be followed. 
Approved 
 
 
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Table 4 
Alternative Dose-Escalation Path 1 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1a Exceeds the MTD or at Sponsor Discretion 
Cohort 5/14 Schedule 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1b 
150 
3 
2b 
180 
3 
3b 
210 
3 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
 
If Cohort 1b exceeds the MTD, or at the sponsor’s discretion, the alternative path 2 described 
in Table 5 may be followed. 
Table 5 
Alternative Dose-Escalation Path 2 for Oprozomib on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1b Exceeds the MTD or at Sponsor Discretion 
Cohort 5/14 Schedule 
Oprozomib Dose 
(mg/day) 
Pomalidomide Dose 
(mg/day) 
1c 
150 
2 
2c 
180 
2 
3c 
210 
2 
5/14 = Dosing on Days 1–5 and 15–19; MTD = maximum tolerated dose. 
 
5.1.2 
DOSE-ESCALATION SCHEMA FOR THE 2/7 OPROZOMIB DOSING 
SCHEDULE 
The study dosing schema for the 2/7 schedule is displayed in Figure 3.  The potential doses to 
be evaluated on the 2/7 dosing schedule are displayed in Figure 4.  The primary and 
alternative pathways for dose escalation of oprozomib and pomalidomide in the Phase 1b 
portion of the study for the 2/7 schedule are summarized in Table 6 through Table 8; these 
are examples, and are not inclusive of all possible dose-escalation paths.   
Approved 
 
 
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Figure 3 Study Dosing Schema for the 2/7 Dosing Schedule 
 
 
Figure 4 2/7 Schedule Primary Study Dose-Escalation Pathsa 
 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; Dex = Dexamethasone; 
OPZ = oprozomib; Pom = pomalidomide 
a There is no predefined maximum dose level of oprozomib being studied. 
 
Approved 
 
 
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Table 6 
Primary Dose-Escalation Path for Oprozomib on the 2/7 Schedule with 
Pomalidomide 4 mg in Phase 1b  
Cohort 2/7 Schedule 
Oprozomib Dose (mg/day) 
Pomalidomide Dose (mg/day) 
101a (initial cohort) 
210 
4 
201a 
240 
4 
301a 
270 
4 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated dose. 
Note:  This is an example of the primary dose-escalation cohort.  Dose escalation will continue in 
30-mg increments of oprozomib until the MTD is identified. 
 
If Cohort 101a exceeds the MTD, or at the sponsor’s discretion, the alternative path 1 
described in Table 7 may be followed. 
Table 7 
Alternative Dose-Escalation Path 1 for Oprozomib on 2/7 Schedule with 
Pomalidomide in Phase 1b if Cohort 101a Exceeds the MTD or at Sponsor Discretion 
Cohort 2/7 Schedule 
Oprozomib Dose (mg/day) 
Pomalidomide Dose (mg/day) 
101b 
210 
3 
201b 
240 
3 
301b 
270 
3 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated dose. 
 
If Cohort 101b exceeds the MTD, or at the sponsor’s discretion, the alternative path 2 
described in Table 8 may be followed. 
Table 8 
Alternative Dose-Escalation Path 2 for Oprozomib on 2/7 Schedule with 
Pomalidomide in Phase 1b if Cohort 101b Exceeds the MTD or at Sponsor Discretion 
Cohort 2/7 Schedule 
Oprozomib Dose (mg/day) 
Pomalidomide Dose (mg/day) 
101c 
210 
2 
201c 
240 
2 
301c 
270 
2 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; MTD = maximum tolerated dose. 
 
Approved 
 
 
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5.1.3 
DOSE-LIMITING TOXICITIES 
Subjects in both dosing schedules will be evaluated for DLTs according to the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version 4.03 during the 28-day period of Cycle 1 combination therapy.  Intrasubject dose 
escalation to the RP3D may be permitted once that dose has been determined and after 
a discussion has occurred between the treating physician and the Sponsor’s study medical 
monitor.  The decision to escalate to the next higher dose of oprozomib in this study will be 
based on an assessment of study drug-related DLTs during Cycle 1 by the CSRC.  The CSRC 
consists of investigators, the Sponsor’s study medical monitor, and the Sponsor’s drug 
safety representative.  Each subject in the cohort under review will be discussed and 
assessed.  Once all data have been presented, the CSRC will decide on the most appropriate 
course of action regarding dose escalation based on guidance in Section 5.1. 
Study drug is defined as the combination of oprozomib, pomalidomide, and dexamethasone.  
Study drug-related is defined as a reasonable likelihood of clinical causality based on time of 
event, biology, dechallenge improvement and that the AE was not likely explained by the 
subject’s clinical state, underlying disease, concomitant medication, or study/nonstudy 
procedure.  Definition of DLTs and additional details are provided in Section 10.5. 
5.1.4 
SUBJECT REPLACEMENT 
Subjects must meet the following criteria to be considered evaluable for MTD determination 
during the 4-week DLT evaluation period unless a DLT occurs before the subject receives all 
planned doses of oprozomib for both the 5/14 and 2/7 dosing schedules: 
 A minimum of 17 of 21 planned doses of pomalidomide must be received 
 A minimum of 6 of 8 planned doses of dexamethasone must be received 
 All planned doses of oprozomib must be received 
Subjects not meeting all of the above criteria or assessed as unevaluable by the CSRC will be 
replaced.   
5.1.5 
DOSE EXPANSION 
The criteria for selecting the RP3D for 1 or both schedules of oprozomib at the sponsor’s 
discretion will include assessment of the safety, tolerability, and preliminary activity 
Approved 
 
 
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observed across multiple cycles of therapy.  In addition, both PK and PDn assessments to 
demonstrate adequate exposure and proteasome inhibition will be a key factor.  Therefore, 
the RP3D may differ from the MTD.  Once the MTD and the recommended dose for the 
expansion phase have been determined, a minimum of 20 additional subjects at 1 or both 
schedules of oprozomib at the sponsor’s discretion will be enrolled in the dose-expansion 
portion of the study in order to continue the evaluation of the safety and efficacy of the 
regimen.  The safety of subjects in the Dose Expansion will be monitored on an ongoing 
basis by the CSRC during regularly scheduled calls.   
5.2 
ESTIMATED STUDY DURATION AND STUDY CLOSURE 
The total study duration is expected to be approximately 12-13 months.   
 The Phase 1b portion of the study will take approximately 7–8 months to complete   
 Approximately 5 months will be required to enroll and evaluate response status of 
subjects in the dose-expansion portion of the study   
5.3 
MINIMIZING BIAS 
5.3.1 
BLINDING 
Both the dose-escalation and dose-expansion portions of this study are open-label. 
6 
SUBJECT SELECTION 
6.1 
INCLUSION CRITERIA 
Disease Related 
2. Multiple myeloma that is primary refractory, relapsed and refractory, or intolerant 
after at least 2 lines of standard therapy for multiple myeloma, including:  
a. ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide 
(alone or in combination) 
b. In the dose-expansion portion of the study only:  In addition to the above, 
treatment with adequate alkylator therapy, defined as: 
i. High-dose melphalan or other alkylating agent as conditioning for 
autologous or allogeneic SCT, or 
ii. ≥ 6 cycles of induction therapy, or  
iii. Progressive disease after ≥ 2 cycles 
Approved 
 
 
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3. Measurable disease as indicated by 1 or more of the following: 
a. Serum M-protein ≥ 500 mg/dL  
b. Urine M-protein ≥ 200 mg/24 h 
c. Only for subjects without measurable M-protein by serum protein 
electrophoresis (SPEP) and urine protein electrophoresis (UPEP), involved free 
light chain (FLC) concentration ≥ 10 mg/dL provided serum free light chain 
(SFLC) ratio is abnormal   
4. Disease progression on or within 60 days of completion of the last therapy, or 
intolerance to bortezomib if received as their last therapy 
a. Patients who received bortezomib as their last therapy who were not refractory 
but developed bortezomib intolerance, as defined by the development of 
Grade 2 peripheral neuropathy with pain or ≥ Grade 3 peripheral neuropathy 
after ≥ 2 consecutive cycles, are eligible  
5. Prior carfilzomib is allowed if a subject was not removed from carflizomib therapy 
due to toxicity, unless approved by the Sponsor’s study medical monitor.  
Demographic 
6. Males and females ≥ 18 years old 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–2 
(Appendix H) 
Laboratory 
8. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal 
(ULN) in the absence of Gilbert’s disease or hemolysis, and alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) ≤ 3 times ULN 
9. Absolute neutrophil count (ANC) ≥ 1500/mm3.  Screening ANC should be 
independent of myeloid growth factor support for at least 1 week or 2 weeks for 
pegylated growth factors. 
10. Hemoglobin ≥ 8.0 g/dL.  Patients may receive red blood cell (RBC) transfusions or 
receive erythropoietin or darbepoetin alfa in accordance with institutional guidelines 
up to 1 week before screening.  
11. Platelet count ≥ 75,000 mm3.  Patients should not have received platelet transfusions 
for at least 1 week before screening. 
12. Uric acid, if elevated, must be corrected to within laboratory normal range before 
dosing. 
13. Calculated or measured creatinine clearance (CrCl) ≥ 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. 
Approved 
 
 
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Ethical/Other 
14. Patient must sign a written informed consent form in accordance with federal, local, 
and institutional guidelines. 
15. Female patients of childbearing potential must have a negative pregnancy test (with a 
sensitivity of at least 50 mIU/mL) within 1 day of the first dose of study drug and 
agree to use 2 effective methods of contraception during the study and for 28 days 
following the last dose of study drug.  Postmenopausal females (> 45 years old and 
without menses for ≥2 years) and surgically sterilized females are exempt from these 
requirements.  
16. Male patients, including those with prior vasectomy, 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.  Additionally, they must agree 
not to donate sperm while being treated and for up to 3 months after discontinuing 
treatment. 
6.2 
EXCLUSION CRITERIA 
Disease Related 
1. Systemic chemotherapy with approved or investigational anticancer therapeutics, 
intended to treat underlying malignancy, within 3 weeks before the first dose of study 
treatment or 6 weeks for antibody therapy. 
2. Dexamethasone at cumulative doses of greater than 160 mg or equivalent within 
21 days prior to the first dose of study treatment is not allowed.  Use of topical or 
inhaled steroids is acceptable. 
3. Radiation therapy within 3 weeks before first dose of study drug.  
Radioimmunotherapy within 8 weeks before first dose of study drug. 
4. 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. 
5. Autologous SCT within the prior 8 weeks or allogeneic SCT within 16 weeks prior to 
initiation of study treatment.  Patients with prior allogeneic SCT should not have 
evidence of moderate-to-severe graft-versus-host disease (as defined in 
Filipovich 2005) and must be approved by the Sponsor’s study medical monitor. 
6. Known hypersensitivity to any IMiDs, including rash 
Approved 
 
 
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7. Prior pomalidomide exposure 
a. For the dose-escalation portion of the study:  Subjects requiring pomalidomide 
dose reduction or removal due to toxicity 
b. For the dose-expansion portion of the study:  Prior pomalidomide treatment of 
any duration 
8. Known hypersensitivity/toxicity or intolerance to dexamethasone 
9. Prior exposure to oprozomib 
10. Hypersensitivity, intolerance, or inability to take antithrombotic prophylaxis 
Concurrent Conditions 
11. Major surgery within 3 weeks before first dose of study drug 
12. Congestive heart failure (New York Heart Association Class III to IV), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, or 
myocardial infarction within 6 months before first dose of study drug 
13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 
2 weeks before first dose of study drug 
14. History of previous clinically significant GI bleed in the 6 months prior to first dose 
of study drug 
15. Known or suspected human immunodeficiency virus (HIV) infection or patients who 
are HIV seropositive 
16. Active hepatitis A, B, or C infection 
17. Significant neuropathy (Grade 2 with pain or ≥ Grade 3) at the time of the first dose 
of study drug 
18. Other malignancy within the past 3 years except those considered cured by surgical 
resection; examples include some cases of:  
a. Adequately treated basal or squamous cell carcinoma of the skin 
b. Thyroid cancer 
c. Carcinoma in situ of the cervix or breast 
d. Prostate cancer with Gleason Score of 6 or less with stable prostate-specific 
antigen levels 
19. Plasma cell leukemia 
20. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) 
21. Known amyloidosis 
Approved 
 
 
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22. Female patients who are pregnant or nursing 
23. Uncontrolled diabetes or hypertension 
24. 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 
25. Any contraindication to oral hydration (eg, preexisting cardiac impairment or fluid 
restriction) 
26. Any clinically significant psychiatric, social, or medical condition that, in the opinion 
of the investigator, could increase patient risk, interfere with protocol adherence, or 
affect a patient’s ability to give informed consent 
7 
SUBJECT SCREENING 
A signed and dated informed consent form will be obtained before any screening procedures 
are performed.  Evaluations obtained as part of routine medical care and performed during 
the screening period may be used in place of the study-specific evaluations, provided they 
meet the time windows described below.  Subjects will acknowledge and agree to the 
possible use of this information for the study by giving informed consent.  The screening 
period for a particular subject commences at the point, after informed consent is signed, at 
which the subject undergoes the first study-specific screening assessment, and must be 
completed within 28 days of receiving the first dose of study drug. 
8 
SUBJECT ENROLLMENT 
All subjects who sign consent will be assigned a unique study number.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  The Sponsor’s study medical monitor or designee will 
review the subject’s information before enrollment.  Only subjects who are approved by the 
Sponsor’s study medical monitor will be allowed to enroll into the study.  A minimum time 
of 24 hours during weekdays (Monday through Friday) will be required for the Sponsor’s 
study medical monitor or designee to approve a subject for enrollment, and additional time 
may be required when approval is sought during a weekend or holiday.  Subjects are only 
considered enrolled when the Sponsor’s study medical monitor or designee approves the 
patient for enrollment.  
Approved 
 
 
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9 
STUDY DRUG 
No changes in drug product, dosage, or treatment-regimen occurred in this protocol 
amendment from the previous version. 
9.1 
OPROZOMIB 
9.1.1 
OPROZOMIB PHYSICAL 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-phenylprop
an-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 CT-L activity of the 20S proteasome, which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis. 
9.1.2 
OPROZOMIB FORMULATION 
Oprozomib will be provided as a tablet for oral administration.  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 ER Tablets are white to off-white tablets manufactured at 5 dosage strengths: 
 Oprozomib 150 mg oval shape tablets are debossed with “H” on one side and contain 
150 mg of oprozomib 
 Oprozomib 180 mg oval shape tablets are debossed with “I” on one side and contain 
180 mg of oprozomib 
 Oprozomib 210 mg oval shape tablets are debossed with “J” on one side and contain 
210 mg of oprozomib 
 Oprozomib 240 mg oval shape tablets are debossed with “K” on one side and contain 
240 mg of oprozomib 
 Oprozomib 270 mg oval shape 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 5 dosage strengths. 
Approved 
 
 
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9.1.3 
OPROZOMIB PACKAGING AND LABELING 
The Oprozomib ER Tablets will be available in 150, 180, 210, 240, and 270 mg of 
oprozomib.  Details are provided in the Pharmacy Manual. 
9.1.4 
OPROZOMIB STORAGE 
Oprozomib must be stored at room temperature (15°C–30°C; 59°F–86°F) in a secured area to 
which access is limited to appropriate study personnel. 
9.2 
POMALIDOMIDE 
Pomalidomide is available as a capsule containing 1, 2, 3, and 4 mg of pomalidomide drug 
substance for oral administration.  Additional product information is provided in the 
Pomalidomide Prescribing Information (Celgene Corporation, 2013). 
9.2.1 
POMALIDOMIDE PHYSICAL DESCRIPTION  
POMALYST is available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration.  
Each capsule contains pomalidomide as the active ingredient and the following inactive 
ingredients:  mannitol, pregelatinized starch, and sodium stearyl fumarate.  The 1-mg capsule 
shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, and 
black ink.  The 2-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow 
iron oxide, FD&C red 3, and white ink.  The 3-mg capsule shell contains gelatin, titanium 
dioxide, FD&C blue 2, yellow iron oxide, and white ink.  The 4-mg capsule shell contains 
gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2, and white ink. 
9.2.2 
POMALIDOMIDE PACKAGING AND LABELING  
Pomalidomide is commercially available as capsules for oral administration. 
9.2.3 
POMALIDOMIDE STORAGE 
Store at 20°C–25°C (68°F–77°F); excursions permitted to 15°C–30°C (59°F–86°F).  See 
USP Controlled Room Temperature. 
Approved 
 
 
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9.3 
DEXAMETHASONE 
Dexamethasone, a synthetic adrenocortical steroid, is available as tablets containing 4 or 
6 mg of dexamethasone drug substance for oral administration. 
9.3.1 
DEXAMETHASONE PACKAGING AND LABELING 
Dexamethasone is commercially available both as tablets for oral administration and as 
various sterile formulations for parenteral administration.  Additional information is provided 
in the Dexamethasone Prescribing Information (Pfizer Laboratories, 2012). 
9.3.2 
DEXAMETHASONE STORAGE 
Dexamethasone is not to be stored above 30°C (86°F).  Additional storage and usage 
instructions are provided in the Dexamethasone Prescribing Information (Pfizer 
Laboratories, 2012). 
9.4 
STUDY DRUG ACCOUNTABILITY 
The Sponsor (or designee) and the investigator will maintain records of each shipment of 
investigational product (IP).  Upon receipt of IP, the designated recipient at the study site will 
inspect the shipment, verify the number and condition of the bottles or blister packs, and 
prepare an inventory or drug accountability record.  The records will document shipment 
dates, method of shipment, batch numbers, product presentation, quantity of bottles or blister 
packs contained in the shipment, and dispensation to individual subjects using the subject 
identification number. 
Sites will be required to record and document subject compliance with oprozomib, 
pomalidomide, and dexamethasone dosing. 
Additional details for oprozomib are provided in the Pharmacy Manual. 
Approved 
 
 
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10 
OPROZOMIB TREATMENT ADMINISTRATION 
It is recommended that oprozomib not be taken on an empty stomach.  Subjects will be 
instructed to take the oprozomib doses after eating with approximately 8 ounces of water.  
On the PK collection days, dosing of oprozomib in relation to the meal intake (within 2 hours 
before and 1 hour after dose) will be recorded. 
10.1 
OPROZOMIB TREATMENT ADMINISTRATION 
Oprozomib ER Tablets will be administered in single daily doses.  Oprozomib will be 
administered orally, once daily for 5 consecutive days every other week ([5/14 schedule] 
ie, on Days 1–5 and 15–19) or once daily for 2 consecutive days of every week 
([2/7 schedule] ie, on Days 1, 2, 8, 9, 15, 16, 22, and 23) of each 28-day treatment cycle.  
Treatment with oprozomib will continue until disease progression, unacceptable toxicity, or 
study treatment discontinuation for any reason.  On days on which oprozomib and 
dexamethasone are administered concurrently, dexamethasone should be taken at least 
30 minutes before oprozomib.  Subjects are to be informed not to break, chew, or crush the 
Oprozomib ER Tablets. 
In the dose-escalation and dose-expansion portions of the study, subjects who permanently 
discontinue pomalidomide or oprozomib may continue on study.  If both pomalidomide and 
oprozomib are permanently discontinued, study treatment will be discontinued but the 
subject will be followed until disease progression. 
10.2 
POMALIDOMIDE TREATMENT ADMINISTRATION 
Pomalidomide will be administered at 4 mg, orally, in the fasted condition (2 hours before or 
after meals) according to the Prescribing Information (Celgene Corporation, 2013) on 
Days 1–21.  Pomalidomide may be taken with water.  Subjects are to be informed not to 
break, chew, or open the capsules. 
The starting dose of pomalidomide for this study is 4 mg once daily, orally, on Days 1–21 of 
repeated 28-day cycles until disease progression.  Pomalidomide may be given at the same 
time as dexamethasone; however, dexamethasone must be given at least 30 minutes prior to 
oprozomib. 
Approved 
 
 
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10.3 
DEXAMETHASONE TREATMENT ADMINISTRATION 
Dexamethasone will be administered at 20 mg, orally, on Days 1, 2, 8, 9, 15, 16, 22, and 23 
of each 28-day cycle.  On days of concurrent oprozomib and dexamethasone administration, 
dexamethasone should be taken at least 30 minutes prior to oprozomib.  Subjects may take 
dexamethasone with or without food.  Dexamethasone may be given at the same time as 
pomalidomide; however, dexamethasone must be given at least 30 minutes prior to 
oprozomib. 
Dexamethasone may be administered intravenously (IV), if needed, at the investigator’s 
discretion, but IV dexamethasone will not be provided by the sponsor. 
10.4 
DOSE MODIFICATION GUIDELINES 
This section provides dose reduction and other modification guidelines for oprozomib, 
pomalidomide, and dexamethasone to manage possible toxicity.  Administration of 
oprozomib or pomalidomide will be discontinued in the event of a treatment-related toxicity 
that, in the opinion of the investigator, warrants permanent discontinuation. 
Monotherapy with dexamethasone is not allowed in the dose-escalation and dose-expansion 
portions of the study. 
Exceptions to the dose modification guidelines are permitted with written approval from the 
Sponsor’s study medical monitor. 
10.4.1 
DOSE REDUCTIONS 
For this study, the initial cohort will start at an oprozomib dose level of 150 mg for the 
5/14 schedule and 210 mg for the 2/7 schedule.  For these subjects, oprozomib or 
pomalidomide or dexamethasone dose reductions are discouraged during the DLT 
assessments.  Subjects requiring dose reductions in Cycle 1 will be referred to the CSRC for 
determination if the subject is considered evaluable and for DLT assessment per 
Section 5.1.4.  Dose reduction levels for oprozomib subsequent to Cycle 1 for the 5/14 and 
2/7 dosing schedules are provided in Table 9 and Table 10, respectively.  Modifications of 
the dose of oprozomib will occur in up to three 30-mg decrements down to a minimum dose 
of 150 mg.  Additional reductions will be managed by schedule change.   
Approved 
 
 
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Table 9 
Dose Decrements for Oprozomib – 5/14 Schedule 
Nominal 
Dose Level 
Reduced Oprozomib Doses 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
150 mg 
Continue 150 mg AND 
change to 3/14a schedule 
(Days 1, 2, 3, 15, 16, 17 of 
28-day schedule) 
D/C oprozomib 
NA 
180 mg 
Dose − 30 mg 
Dose − 30 mg AND change 
to 3/14 schedule 
(Days 1, 2, 3, 15, 16, 17 of 
28-day schedule) 
D/C oprozomib 
210 mg 
Dose − 30 mg 
Dose − 60 mg 
Dose − 60 mg AND change 
to 3/14 schedule 
(Days 1, 2, 3, 15, 16, 17 of 
28-day schedule) 
≥ 240 mg 
Dose − 30 mg 
Dose − 60 mg 
Dose − 90 mg 
5/14 = Dosing on Days 1–5 and 15–19; D/C = discontinue; NA = not applicable. 
a The minimum oprozomib dose is 150 mg; thus, additional reductions will be managed by schedule change 
to the 3/14 schedule where doses of oprozomib will be skipped on Days 4, 5, 18, and 19. 
 
Table 10 Dose Decrements for Oprozomib – 2/7 Schedule 
Nominal 
Dose Level 
Reduced Oprozomib Doses 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
210 mg 
Dose − 30 mg 
Dose − 60 mg 
Dose − 60 mg AND change 
to 1/7a schedule 
(Days 1, 8, 15, 22 of 28-day 
schedule) 
≥ 240 mg 
Dose − 30 mg 
Dose − 30 mg 
Dose − 90 mg 
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23. 
a The minimum oprozomib dose is 150 mg; thus, additional reductions will be managed by schedule change 
to the 1/7 schedule where doses of oprozomib will be skipped on Days 2, 9, 16, and 23. 
 
The dose reduction levels for pomalidomide are provided in Table 11.  Dose adjustments 
should, in general, follow the instructions provided in the Pomalidomide Prescribing 
Information 2013 (Celgene Corporation, 2013). 
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Table 11 Dose Decrements for Pomalidomide 
Dose 
Reduced Pomalidomide Doses 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
4 mg  
3 mg 
2 mg 
1 mg 
 
If the dose of either the pomalidomide or oprozomib is reduced during the previous cycle, the 
reduced dose level will be continued on Day 1 of the next cycle.  If the reduced dose level is 
well tolerated for a complete cycle, the subject may, at the investigator’s discretion, be 
rechallenged with the dose level prior to the reduction at the start of the next cycle. 
Treatment guidelines for specific hematologic toxicities are outlined in Section 10.4.2.1.1 
and nonhematologic toxicities in Section 10.4.2.1.2.  In addition to dose reductions, 
administration of oprozomib, pomalidomide, and dexamethasone may be temporarily 
interrupted for a maximum of 4 weeks in the event of a treatment-related toxicity.  If the dose 
delay because of toxicity is longer than 4 weeks, the subject will be discontinued from study 
treatment.  If a subject misses more than 4 consecutive weeks for reasons other than toxicity 
after completing Cycle 1, the subject will be discontinued from study treatment unless it is 
determined that the subject was benefiting from therapy and the Sponsor’s study medical 
monitor permits the subject to resume therapy. 
Dose reduction levels for dexamethasone are provided in Table 12. 
Table 12 Dose Decrements for Dexamethasone 
Nominal Dose 
Reduced Dexamethasone Doses 
Dose -1 
Dose -2 
20 mg 
12 mg 
8 mg 
Cycle 2 +:  Age > 75 yrs per 
investigator discretion 10 mg 
8 mg 
4 mg 
 
For subjects over 75 years old, after the first cycle and at the investigator’s discretion, 
dexamethasone can be reduced to 10 mg.  Dexamethasone will be permanently discontinued 
after 2 dose reductions for either nominal dose in the event of additional 
dexamethasone-related toxicity.  At the investigator’s discretion, dexamethasone may be 
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tapered prior to complete discontinuation according to institutional practice.  If the 
dexamethasone dose is reduced during the previous cycle, the reduced dose level will be 
continued on Day 1 of the new cycle.  If the reduced dose level is well tolerated for a 
complete cycle, the subject may, at the investigator’s discretion, be rechallenged with the 
dose level prior to the reduction at the start of the next cycle. 
If dexamethasone dosing is permanently stopped due to toxicity in accordance with the dose 
modification guidelines described in Table 15, the subject should stay on oprozomib and/or 
pomalidomide, depending on the arm to which they are randomized, and continue to follow 
protocol required therapy, procedures, and assessments.  Subjects may continue to take 
antiemetic doses of dexamethasone (4 mg) on days of oprozomib dosing, if tolerated, at the 
investigator’s discretion.   
10.4.2 
DOSE MODIFICATION GUIDELINES 
10.4.2.1 
Oprozomib Dose Modification Guidelines  
10.4.2.1.1 
Hematologic Toxicities 
Dose modification guidelines for oprozomib/placebo and pomalidomide for hematologic 
toxicities are summarized in Table 13. 
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Table 13 Guidelines for Dose Modification of Oprozomib/Placebo and Pomalidomide 
for Hematologic Toxicities 
Findings 
Oprozomib 
Pomalidomide 
Findings on Day 1 of Cycle 
Recommended Action 
Platelets < 25 × 109/L 
Hold dosea until recovery 
 ≥ 25 × 109/L; restart at previous 
dose. 
Not applicable. 
Platelets < 30 x 109/L 
Not Applicable. 
Hold dosea, follow CBCs. 
Hold prophylactic 
anticoagulation until platelets 
return to ≥ 30 × 109/La, then 
resume at 1 dose decrement. 
ANC < 0.5 × 109/L or febrile 
neutropenia (fever ≥ 38.5°C and 
ANC < 1.0 × 109/L) 
Hold dosea. 
Add colony stimulating factorb 
With resolution to ≥ 1.0 × 109/L, 
restart at previous dose. 
Hold dosea. 
Add colony stimulating 
factorb 
With resolution to  
≥ 0.5 × 109/L, restart at 1 dose 
decrement. 
Findings on Subsequent Days of Cycle 
Recommended Action 
Platelets 25 to < 50 × 109/L without 
≥ Grade 2 bleeding/hemorrhage  
Full dose. 
Full dose. 
Platelets 25 to < 50 × 109/L with 
≥ Grade 2 bleeding/hemorrhage 
Hold dosea until platelets return 
to ≥ 50 × 109/L and/or bleeding 
is controlled, then resume at 
1 dose decrement. 
Hold dosea until platelets 
return to ≥ 50 × 109/L and/or 
bleeding is controlled, then 
resume at 1 dose decrement. 
Platelets < 25 × 109/L or 
thrombocytopenia with ≥ Grade 2 
bleeding/hemorrhage 
Hold dosea until recovery to 
≥ 25 × 109/L; restart at 1 dose 
decrement. 
Hold dosea. 
Hold prophylactic 
anticoagulation until platelets 
return to ≥ 30 × 109/La, then 
resume at 1 dose decrement. 
Neutropenic fever (ANC  < 1.0 × 109/L 
and single temperature > 38.3°C or 
temperature > 38.0°C sustained for more 
than 1 hour) 
Hold dosea; follow CBC at least 
3 times per week. 
Add colony stimulating factor.b 
With resolution of fever and 
ANC ≥ 1.0 × 109/L, restart at 
1 dose decrement. 
Hold dosea; follow CBCs. 
Add colony stimulating 
factorb. 
With resolution of fever and 
ANC ≥ 1.0 × 109/L, restart at 
1 dose decrement. 
ANC < 0.5 × 109/L  
Hold dosea; follow CBC at least 
3 times per week; administration 
of colony stimulating factorb is 
permitted. 
Resume at full dose if ANC 
≥ 0.5 × 109/L within < 7 days.  
Resume at 1 dose decrement if 
ANC returns to ≥ 0.5 × 109/L 
≥ 7 days. 
Hold dosea until ANC 
increases to ≥ 0.5 × 109/L. 
Administer colony 
stimulating growth factorb. 
Resume at 1 dose decrement 
each subsequent decrease to 
< 0.5 × 109/L). 
ANC = absolute neutrophil count; CBC = complete blood count. 
a The maximum allowed dose interruption is 4 weeks for treatment-related toxicity. 
b Colony stimulating factors such as filgrastim or sargramostim as examples. 
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Additional guidance regarding hematologic toxicities and dosing actions is as follows: 
 To initiate a new cycle of pomalidomide, the neutrophil count must be at least 500 per µL 
and the platelet count must be at least 50,000 per µL.  If toxicities continue to occur after 
dose reductions down to 1 mg, then discontinue pomalidomide. 
 Nontreatment-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 of 
oprozomib may be permitted after discussion with the Sponsor’s study medical monitor.  
No more than 3 dose reductions down to a minimum of 150 mg will be permitted for an 
individual subject on study and additional reductions will be managed by schedule 
change.  If toxicity continues, oprozomib should be discontinued. 
10.4.2.1.2 
Nonhematologic Toxicities 
Table 14 provides oprozomib dosing actions that should be taken for nonhematologic 
toxicities. 
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Table 14 Guidelines for Dose Modification of Oprozomib/Placebo and Pomalidomide 
for Nonhematologic Toxicities 
Symptom 
Findings 
Recommended Actiona 
Oprozomib 
Pomalidomide 
Tumor Lysis 
Syndrome  
Generally recognized in at least 3 or 
more of the following categories: 
(1) Increase in creatinine, uric acid, 
or 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 both oprozomib and pomalidomide until all 
abnormalities in serum chemistries have resolved to 
baseline; resume at full doses. 
Neuropathy 
Grade 2 neuropathy with pain or 
≥ Grade 3 neuropathy 
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug at 
1 dose decrement. 
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug 
1 dose decrement from 
previous dose. 
Infection  
Grade 3 or 4 
Hold both oprozomib and pomalidomide until 
systemic treatment for infection complete.   
If ANC ≥ 1.0 × 109/L, resume both drugs at full 
dose. 
If ANC < 1.0 × 109/L, follow hematologic toxicities 
dose reduction guidelines (Table 13).  
Nausea, 
vomiting, 
diarrhea, or 
constipation 
≥ Grade 3 without optimal supportive 
care as defined by use of both a 
5-HT3 antagonist and aprepitant 
Oprozomib-related:  Full 
dose oprozomib but 
institute optimal 
supportive care. 
Pomalidomide-related:  
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug at 
1 dose decrement from 
previous dose. 
≥ Grade 3 with optimal supportive 
care as defined by use of both a 
5-HT3 antagonist and aprepitant 
Oprozomib-related:  Hold 
dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug at 
1 dose decrement. 
Fatigue 
Grade 3 fatigue lasting < 14 days 
Full dose. 
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug at 
1 dose decrement from 
previous dose. 
Grade 3 fatigue lasting ≥ 14 days 
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
has returned to baseline.  
Resume study drug at 
1 dose decrement. 
 
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Table 14 Guidelines for Dose Modification of Oprozomib/Placebo and Pomalidomide 
for Nonhematologic Toxicities (cont'd) 
Symptom 
Findings 
Recommended Actiona 
Oprozomib 
Pomalidomide 
Renal 
Dysfunction 
CrCl 30 to < 50 mL/min (Grade 2) 
Full dose. 
Full dose. 
CrCl 15 to < 30 mL/min (Grade 3) 
Hold dose.  When CrCl 
recovers to ≤ Grade 2, 
resume at 1 dose 
decrement.  
Hold dose.  When CrCl 
recovers to ≤ Grade 2, 
resume dose at 1 dose 
decrement.  If Grade 3 
CrCl reappears, then 
hold dose until CrCl 
recovers to ≤ Grade 2 
and reduce dose an 
additional 1 dose 
decrement.   
CrCl 0 to < 15 mL/min (Grade 4) 
Discontinue. 
Discontinue. 
Elevation in 
Liver Function 
Tests  
≥ Grade 3 
(AST, ALT, or total bilirubin)b 
Hold until resolves to 
baseline.  Resume at 
1 dose decrement.   
Hold pomalidomide and 
restart treatment at 
1 dose decrement less 
than the previous dose 
when toxicity has 
resolved to ≤ Grade 2 at 
physician discretion. 
Other 
Nonhematologic 
Toxicity 
Assessed as oprozomib-related 
and ≥ Grade 3c 
Hold oprozomib dose until 
toxicity resolves to 
≤ Grade 1 or baseline; 
restart at 1 dose 
decrement. 
Full dose. 
Other 
Nonhematologic 
Toxicity 
Assessed as pomalidomide-related 
and ≥ Grade 3c,d 
Full dose. 
Hold pomalidomide and 
restart treatment at 
1 dose decrement less 
than the previous dose 
when toxicity has 
resolved to ≤ Grade 2 at 
physician discretion. 
Grade 1 or 2 GI 
hemorrhage 
Assessed as oprozomib-related 
DELAY until Grade 0 
DECREASE one dose 
level for Grade 2 
Full dose at physician 
discretion 
Grade 3 or 4 GI 
Hemorrhage 
Assessed as oprozomib-related 
Discontinue. 
Full dose when AE 
resolves to ≤ Grade 2 at 
physician discretion. 
5-HT3 = 5-hydroxytryptamine type-3; AE = adverse event; ALT = alanine aminotransferase; ANC = absolute 
neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine clearance; eCRF = electronic case 
report form; GI = gastrointestinal; LDH = lactate dehydrogenase; ULN = upper limit of normal. 
a The maximum allowed dose interruption is 4 weeks for treatment-related toxicity. 
b If AST or ALT is ≥ 3 × ULN, the “evaluation of treatment emergent liver abnormalities” eCRF should be 
completed. 
c If cardiac or pulmonary treatment-emergent toxicities occur, the “cardiopulmonary AE” eCRF should be 
completed. 
d See Celgene Corporation, 2013. 
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Additional guidance regarding nonhematologic toxicities and dosing actions is as follows: 
 Nontreatment-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 the subject tolerates the reduced dose for 1 cycle, the subject’s dose may be 
re-escalated to the dose being taken prior to the dose reduction 
 If required by continued or recurrent toxicity, a second or third dose reduction of 
oprozomib may be permitted after discussion with the Sponsor’s study medical monitor.  
No more than 3 dose reductions down to a minimum of 150 mg will be permitted for an 
individual subject on study and additional reductions will be managed by schedule 
change.  If toxicity continues, oprozomib should be discontinued. 
 Subjects who develop Grade 3 or 4 GI hemorrhage should not be rechallenged with 
oprozomib.  Oprozomib should be permanently discontinued.  Endoscopy should be 
strongly considered for any subject with GI hemorrhage. 
10.4.2.2 
Dexamethasone Dose Modification Guidelines  
Guidelines for dexamethasone dose modifications and treatment are summarized in Table 15. 
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Table 15 Treatment Guidelines for Dexamethasone-Related Toxicity 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
Grade 1 or 2 (requiring 
medical management) 
Continue dexamethasone at same dose and treat with 
therapeutic doses of H2 blockers, or proton pump 
inhibitor.  May consider adding sucralfate or other 
antiulcer treatment as clinically indicated.  If 
symptoms persist despite above measures, decrease 
dexamethasone dose by 1 dose level. 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
≥ Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms return to 
baseline.  Restart dexamethasone at 1 dose decrement 
along with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole.  If symptoms persist 
despite above measures, discontinue dexamethasone 
permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently.   
General Disorders 
Edema > Grade 3 (> 30% 
limb discrepancy in volume; 
gross deviation from normal 
anatomic contour; limiting 
self-care activities of daily 
living ) 
Hold dexamethasone until symptoms return to 
baseline.  Administer diuretics as needed, and restart 
dexamethasone at 1 dose decrement; if edema persists 
despite above measures, decrease dose another level.  
Discontinue dexamethasone permanently if symptoms 
persist despite second reduction. 
Psychiatric 
Disorders 
Confusion or mood alteration 
≥ Grade 2 (interfering with 
function ± interfering with 
activities of daily living) 
Hold dexamethasone until symptoms return to 
baseline.  Restart dexamethasone at 1 dose decrement.  
If symptoms persist despite above measures, reduce 
by another dose decrement. 
Musculoskeletal 
Muscle weakness ≥ Grade 2 
(symptomatic and interfering 
with function ± interfering 
with activities of daily living) 
Hold dexamethasone until symptoms return to 
baseline.  Restart dexamethasone at 1 dose decrement.  
If weakness persists, decrease dose by 1 more dose 
level.  Discontinue dexamethasone permanently if 
symptoms persist. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ Grade 3 
(fasting glucose 
> 250 mg/dL) 
Hold dexamethasone until glucose is ≤ Grade 2 
(< 250 mg/dL) and treat with insulin or other 
hypoglycemic agents as needed.  If uncontrolled 
despite above measures, decrease dose by 1 dose level 
until ≤ Grade 2 (< 250 mg/dL) 
All Other 
Other nonhematologic 
toxicity ≥ Grade 3 felt related 
to dexamethasone 
Hold dexamethasone dose.  Resume at 1 dose 
decrement when toxicity has resolved to Grade 2 or 
less or to baseline.  If toxicity recurs, hold 
dexamethasone dose until toxicity has resolved to 
Grade 2 or less or to baseline and resume 
dexamethasone dose by 1 more dose decrements.  If 
toxicity recurs despite 2 dose decrements, discontinue 
dexamethasone permanently.  
H2 = histamine 2 blocker. 
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10.5 
DEFINITION OF DOSE-LIMITING TOXICITY 
During this study, assessment of DLTs will occur during the 28-day period of Cycle 1 
combination therapy.  For the purposes of this study, a DLT is defined as any of the study 
drug-related events listed below occurring within the 4 weeks after the first dose of 
combination therapy.  Study drug-related is defined as a reasonable likelihood of clinical 
causality based on time of event, biology, dechallenge improvement and that the AE was not 
likely explained by the subject’s clinical state, underlying disease, concomitant medication, 
or study/nonstudy procedure. 
 Any toxicity requiring a dose reduction or requiring that a dose of oprozomib or 
pomalidomide be held in Cycle 1 that does not meet the criteria for DLT will be 
discussed by the CSRC to determine whether the subject should be considered evaluable 
for DLT determination.  If it is determined that the subject is not evaluable for DLT, the 
subject will be replaced.   
 A delay in ability to receive Day 1 dose of Cycle 2 due to a hematologic or 
nonhematologic drug-related toxicity persisting beyond 14 days from Cycle 1 Day 28 
will be considered a DLT 
 For a nonhematologic DLT, any ≥ Grade 3 toxicity will be considered a DLT with 
exceptions as described below:   
o Grade 3 asymptomatic electrolyte abnormalities will not be considered a DLT 
o Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours will not 
be considered a DLT 
o Grade 3 nausea and vomiting will not be considered a DLT unless persisting 
longer than 3 days despite optimal supportive care, which at a minimum must 
include a 5-hydroxytryptamine type-3 (5-HT3) antagonist and aprepitant 
o Grade 3 diarrhea will not be considered a DLT unless persisting longer than 
3 days despite optimal supportive care, which at a minimum must include 
loperamide (Imodium) and atropine diphenoxylate (Lomotil) 
o Grade 3 fatigue lasting < 14 days is not considered a DLT 
o ≥ Grade 3 hyperglycemia or toxicity attributed to dexamethasone is not 
considered a DLT (see dose reduction guidelines for dexamethasone in 
Section 10.4.1) 
o ≥ Grade 3 rash attributed specifically to pomalidomide is not to be considered 
a DLT 
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 Hematologic DLTs consist of the following: 
o Grade 4 neutropenia: 
– Absolute neutrophil count (ANC) < 0.5 × 109/L lasting ≥ 7 days despite 
adequate growth factor support (eg, G-CSF) 
– 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 < 1.0 × 109/L) 
o Thrombocytopenia:   
– Grade 4 lasting ≥ 7 days, or 
– Grade 4 lasting < 7 days with Grade 2 clinically significant bleeding or 
< 10,000 platelets requiring platelet transfusion, or 
– Grade 3 with clinically significant bleeding or requiring platelet 
transfusion. 
Note:  Grade 4 anemia is not considered a DLT 
10.6 
CONCOMITANT MEDICATIONS 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  All concomitant medications from 30 days before 
Day 1 until 30 days after the subject’s last dose of study drug or before start of subsequent 
anticancer treatment (whichever occurs first) must be recorded on the electronic case report 
form (eCRF).  Blood or blood products are not considered concomitant medications and must 
be recorded on the appropriate eCRF. 
10.6.1 
REQUIRED CONCOMITANT MEDICATIONS 
10.6.1.1 
Contraception 
Females of reproductive potential must commit either to abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of effective contraception simultaneously 
(1 highly effective form of contraception—tubal ligation, intrauterine device [IUD], 
hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or 
partner’s vasectomy and 1 additional effective contraceptive method—male latex or synthetic 
condom, diaphragm, or cervical cap).  Contraception must begin 4 weeks prior to initiating 
treatment and continue during therapy, dose interruptions, and for 28 days after 
discontinuation of therapy.  Reliable contraception is indicated even where there has been 
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a history of infertility, unless this is due to hysterectomy.  Females of reproductive potential 
should be referred to a qualified provider of contraceptive methods, if needed.  Additional 
details are provided in Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods (Appendix J), Pomalidomide Education and 
Counseling Guidance Document (Appendix K), and Pomalidomide Information Sheet for 
Subjects Enrolled in Clinical Research Studies (Appendix L). 
Females of reproductive potential must have 2 negative pregnancy tests before initiating 
study treatment.  The first test should be performed within 10–14 days of study treatment and 
the second test should be performed within 24 hours before study treatment.  Once treatment 
has started and during dose interruptions, pregnancy testing for female subjects of 
reproductive potential should occur weekly during the first 4 weeks of treatment.  Pregnancy 
testing should be repeated every 4 weeks thereafter for female subjects with regular 
menstrual cycles.  For female subjects with irregular menstrual cycles (± 7 days of a 28-day 
cycle), pregnancy testing should be performed every 2 weeks.  Pregnancy testing and 
counseling should be performed if a subject misses her period or if there is any abnormality 
in her menstrual bleeding.  Study treatment must be discontinued during this evaluation. 
Postmenopausal females (> 45 years old and without menses for > 2 years) and surgically 
sterilized females are exempt. 
Male subjects 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. 
Because pomalidomide is present in the semen of male subjects who receive it, they must 
always use a latex or synthetic condom during any sexual contact with females of 
reproductive potential and for up to 3 months after discontinuation of study treatment, even if 
they have undergone a successful vasectomy.  Male subjects must agree not to donate sperm 
while being treated and for up to 3 months after discontinuing treatment. 
10.6.1.2 
Antinausea and Antiemetics 
It is strongly recommended that subjects be premedicated with a 5-HT3 inhibitor, such as 
ondansetron or granisetron, prior to administration of the first dose of oprozomib each day 
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and throughout the day as needed to prevent nausea and vomiting.  If nausea/vomiting at any 
grade persists, aprepitant or fosaprepitant is recommended.  Additional antiemetics may be 
used per investigator discretion. 
10.6.1.3 
Antidiarrheals 
For subjects developing any grade of diarrhea, loperamide (Imodium) is strongly 
recommended at the first onset of symptoms.  For subjects with persistent diarrhea despite 
the use of Imodium, the use of diphonoxylate/atropine (Lomotil) is strongly recommended.  
Other antidiarrheal agents may be used if necessary; a work-up for other etiologies is 
suggested if diarrhea continues despite the prior 2 agents. 
10.6.1.4 
Antivirals 
Valacyclovir or an equivalent antiviral is recommended for the duration of treatment to 
prevent Herpes zoster (additional prophylaxis is at the investigator’s discretion). 
10.6.1.5 
Acid-related Medications 
Lansoprazole or another oral proton-pump inhibitor is required (unless subject has 
intolerance or hypersensitivity) for the duration of treatment to prevent peptic disease or 
other GI toxicities. 
10.6.1.6 
Thrombo-prophylaxis 
Aspirin (or other anticoagulant or antiplatelet medication such as clopixisdogrel bisulfate, 
low-molecular-weight heparin, or warfarin based on subject risk factors for deep vein 
thrombosis) while taking pomalidomide is required to prevent thrombosis (refer to the 
Pomalidomide Prescribing Information [Celgene Corporation, 2013] for more information). 
10.6.1.7 
Tumor Lysis Syndrome 
Monitoring and Prophylaxis Guidelines:  Oral hydration of 1.5–2 liters per 24 hours must be 
instituted in all subjects 24–48 hours prior to initiation of therapy for every cycle and 
continued throughout every day 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:  Durie-Salmon or International Staging System 
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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. 
Tumor Lysis Syndrome Laboratory Abnormalities 
Subjects with laboratory abnormalities prior to dosing that are consistent with lysis of tumor 
cells (e.g., as defined by abnormalities in at least 3 of the following 4 categories:  [1] a 2-fold 
increase of lactate dehydrogenase above the ULN; [2] increases in serum creatinine, uric 
acid, or phosphorus > 50% over baseline; [3] potassium increases > 30% above the ULN; or 
[4] calcium decreases from baseline of > 20% in the absence of concomitant bisphosphonate 
therapy) (Sezer, 2006).  Subjects must not receive the scheduled dose prior to institution of 
the aforementioned preventive measures.   
Tumor Lysis Syndrome Treatment Guidelines 
If TLS occurs as defined by the laboratory abnormalities described above, cardiac rhythm, 
fluid, and serial laboratory monitoring 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 abnormalities consistent with TLS.  Once TLS has resolved, the subject can 
resume treatment at the initial dose level.  The Sponsor’s study medical monitor should be 
consulted if there is a treatment delay > 4 weeks. 
All cases of TLS must be reported to the Sponsor as an SAE as outlined in Section 13.5. 
10.6.1.8 
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.  An etiology should be sought for the orthostatic hypotension to determine if its 
cause is neurogenic, non-neurogenic or iatrogenic.  Dose modifications should be taken in 
accordance with Table 13 and Table 14. 
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 For those subjects with orthostatic hypotension who are taking antihypertensives, 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 6–8 eight ounce glasses of fluids in the 
24−48 hours prior to dosing and on every day 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 per investigator discretion, such as 
increased oral intake, florinef or midodrine, others depending on the etiology.  Holding 
the dose and dose reduction upon resolution may be a consideration. 
 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 (Appendices A1, A2, B1, and B2) 
10.6.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
The following medications are optional and are allowed during the study: 
 Mycostatin or oral fluconazole to prevent oral thrush is optional and may be given at the 
investigator’s discretion 
 Additional antiemetics, antidiarrheal agents, and/or laxatives as necessary 
 Myeloid growth factors (eg, G-CSF) may be used if neutropenia occurs, in accordance 
with American Society of Clinical Oncology (ASCO) Guidelines (Smith, 2006), but are 
not to be given prophylactically. 
 Red blood cell transfusions, erythropoietic stimulating agents, or platelet transfusions, if 
clinically indicated in accordance with institutional guidelines 
 Bisphosphonates 
 Palliative radiation for pain management is permitted with the written approval of the 
Sponsor’s study medical monitor 
10.6.3 
EXCLUDED CONCOMITANT MEDICATIONS 
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/µmol).  
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.  Cytochrome P450 3A substrates with narrow therapeutic range are drugs 
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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 are provided in Appendix I.  Investigators should 
consider switching to an alternative drug, or be alert to the need for dose adjustment. 
In accordance with the Pomalidomide Prescribing Information, use of concomitant 
medications including CYP3A, cytochrome P450 1A2 (CYP1A2) and P-glycoprotein (P-gp) 
inhibitors and inducers are to be carefully monitored and substituted for others if necessary 
(Appendix I).  
Glucocorticoid therapy that exceeds a cumulative dose of 160 mg of dexamethasone is not 
permitted within 21 days prior to randomization.  During the study, glucocorticoid therapy 
(in addition to dexamethasone) is only permitted at the discretion of the Sponsor’s study 
medical monitor to treat a concurrent medical condition (eg, asthma, inflammatory bowel 
disease, emesis, etc.). 
Other antimyeloma or investigational agents are not permitted prior to the subject developing 
confirmed progressive disease. 
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 requires 
plasmapheresis, or is anticipated to require plasmapheresis during or after the screening 
period, this patient will be considered ineligible and should not be enrolled.  Subjects 
requiring plasmapheresis while on study treatment should have every attempt made to 
document progressive disease by IMWG criteria first, and then will discontinue study 
treatment and will enter Long Term Follow-up for survival.  Subjects requiring 
plasmapheresis must have 2 serum samples (for SPEP and immunofixation) and at least one 
24-hour urine sample (for UPEP and immunofixation) obtained prior to the procedure. 
11 
STUDY PROCEDURES 
All protocol-required tests and observations, along with their chronology, are outlined in the 
Schedules of Assessments (Appendices A1, A2, B1, and B2).  A general summary of 
on-treatment tests and observations is provided below. 
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11.1 
STUDY-SPECIFIC PROCEDURES 
11.1.1 
VITAL SIGNS 
All vital sign assessments will include measurement of orthostatic blood pressure, pulse rate, 
respiration rate, and temperature.  Subjects should lie down for 5 minutes and then have 
blood pressure and pulse measured consistently in either arm.  Following the supine blood 
pressure/pulse reading, the subject should stand and the blood pressure and pulse should be 
repeated after 1 and 3 minutes.  Any drop of 20 mmHg systolic, 10 mmHg diastolic or 
lightheadedness/dizziness between supine and standing blood pressures would indicate 
orthostatic hypotension.  Usually an increase in pulse of 10 beats/min is associated with but 
not required for identification of orthostatic hypotension.  For time points where PK and vital 
signs are to be done together, vital signs should be obtained first as the act of phlebotomy 
may impact vital sign measurement results.  
11.1.2 
COMPLETE PHYSICAL EXAMINATION 
A complete physical examination will include examination of the skin, head and neck, chest 
(heart and lungs), abdomen, extremities, and a brief neurological examination including an 
assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern 
Cooperative Oncology Group (ECOG) performance status (assessed at the time of the 
physical examination) will be conducted (Appendix H). 
A limited physical examination will include an examination of the chest (heart and lungs) 
and abdomen, with additional examinations as clinically indicated or directed by AEs. 
11.1.3 
ELECTROCARDIOGRAM 
Twelve-lead electrocardiograms (ECGs), including corrected QT interval (QTc), will be 
performed locally. 
11.2 
LABORATORY EVALUATIONS FOR SAFETY 
Laboratory tests, including hematology, blood chemistries, and coagulation tests during 
scheduled visits, will be performed locally.  Unscheduled or additional laboratory samples 
may be collected and analyzed by local laboratories if results are necessary for management 
of treatment-emergent AEs or dose modification.  
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The schedule for laboratory evaluations for safety is outlined in Appendices A1, A2, B1, 
and B2.  The laboratory tests included in the full chemistry panel are defined in Table 16. 
11.2.1 
CHEMISTRY 
Table 16 Full Chemistry Panel 
Full Chemistry Panel 
Alanine aminotransferase 
Glucose 
Albumin 
Lactate dehydrogenase 
Alkaline phosphatase 
Magnesium 
Aspartate aminotransferase 
Phosphorous 
Bicarbonate 
Potassium 
Blood urea nitrogen 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Total protein 
Creatinine 
Uric acid 
Creatinine clearance  
(calculated or measured) 
 
 
11.2.2 
HEMATOLOGY 
The complete blood count (CBC) with differential includes the following: 
 Hemoglobin 
 Hematocrit 
 White blood cell (WBC) count with complete manual or automated differential (reported 
as absolute counts) 
o Total neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
 Red blood cell count 
 Platelet count 
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11.2.3 
COAGULATION 
 Prothrombin time 
 Activated partial thromboplastin time 
 International normalized ratio 
11.2.4 
PREGNANCY 
For females of childbearing potential (FCBP), both a serum pregnancy test that is confirmed 
negative at Screening and a serum pregnancy test that is confirmed negative within 24 hours 
prior to Day 1 of each cycle is required prior to dosing.  For the first cycle, negative 
pregnancy tests are required weekly.  Starting with the second cycle, a negative pregnancy 
test monthly is required.  For FBCP subjects with irregular menses (ie, other than 
28 ± 7 days) or whose menses are not present, a negative pregnancy test every other week is 
required.  More frequent pregnancy tests may be conducted if required according to local 
regulations. 
11.3 
DISEASE RESPONSE ASSESSMENTS 
The schedule of disease assessments for treated subjects is provided in Appendices A1, A2, 
B1, and B2.  Disease response will be assessed by the investigator.  Beginning with Cycle 1, 
assessments are to be completed at the end of every 4-week cycle for the first 18 months of 
study treatment, and then at the end of every other cycle (every 8 weeks), beginning with 
Month 20, for the remainder of study treatment.  Response assessment will be according to 
the IMWG-URC and modified EBMT guidelines (Appendix C).  Disease response and 
progression assessments include:   
 Serum protein electrophoresis (SPEP) 
 Urine protein electrophoresis (UPEP) 
 Serum immunofixation, serum free light chain (SFLC) 
 Urine immunofixation 
 Serum calcium 
 Bone marrow sample as clinically indicated to confirm CR  
 Radiographic assessments including plasmacytoma evaluation if baseline assessments 
were positive and as clinically indicated per the response criteria 
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 Skeletal survey if baseline assessments were positive and as clinically indicated per the 
response criteria   
Serum protein electrophoresis and immunofixation assessments will be conducted according 
to the schedule outlined in Appendices A1, A2, B1, and B2, Schedule of Assessments.  
Immunofixation will only be required after Screening, Baseline (Day -7 to 1), and End of 
Study Treatment, if results of the previous SPEP are zero/undetectable.  
Urine protein electrophoresis and immunofixation will be performed on a 24-hour urine 
specimen collected from all subjects during the Screening period, Baseline (Day -7 to 1), and 
at the End of Study Treatment visit.  The UPEP with 24-hour urine collection will be 
conducted according to the schedule outlined in Appendices A1, A2, B1, and B2, Schedule 
of Assessments, and is required:  1) only if Baseline UPEP was ≥ 200 mg/24 hours, and 2) to 
confirm a disease response or disease progression.  If the Baseline UPEP was negative, spot 
urine is required at each time point.  If positive for paraprotein, a 24-hour urine collection 
with UPEP must be done at the next assessment and at each subsequent assessment unless 
the UPEP shows an absence of paraprotein.  
Serum free light chain assay and kappa:lambda (/) ratio will be conducted according to the 
schedule outlined in the Schedule of Assessments, Appendices A1, A2, B1, and B2.  Only in 
subjects without measurable serum and urine M-protein levels (serum M-protein < 0.5 g/dL 
or urine M-protein < 200 mg/24 hours) at Baseline will SFLC assays be used to determine 
eligibility and response.  In subjects with measurable SPEP and/or UPEP, SFLC may be used 
in conjunction with those assessments to determine response per disease response criteria but 
only SPEP and/or UPEP will be used to determine eligibility. 
All response categories (CR, sCR, VGPR, PR, MR, PD) require 2 consecutive assessments 
made at any time before the institution of any new therapy.  All subjects will be followed 
until disease progression (confirmed by 2 consecutive measurements that are also verified by 
the Sponsor’s medical monitor prior to treatment discontinuation), unacceptable toxicity, or 
withdrawal of consent, whichever occurs first.   
Disease progression will be determined and confirmed with the medical monitor by two 
consecutive assessments using the IMWG-URC (Appendices A1, A2, B1, and B2).  
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Serum M component increases of ≥ 1.0 g/dL are sufficient to define progression if the 
starting component is ≥ 0.5 g/dL according to these criteria.  However, it is understood from 
these criteria that a single measurement is adequate in cases of clear increased bone marrow 
plasma cell percentage, development of new or worsened bone lesions from a skeletal 
survey, or development of new or worsened soft tissue plasmacytomas. 
11.4 
CORRELATIVE STUDIES 
11.4.1 
PHARMACOKINETIC MEASUREMENTS 
In the dose-escalation and dose-expansion portions of the study, blood samples will be 
collected from all subjects from both schedules to measure plasma concentrations of 
oprozomib at 1 predose time point and up to 7 postdose time points on Day 1 of Cycle 1 and 
Cycle 2 (0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose) and 1 predose time point on Day 2 of 
Cycle 1.  Estimates of oprozomib PK parameters will be determined when possible. 
11.4.2 
PHARMACODYNAMIC MEASUREMENTS 
In the dose-escalation and dose-expansion portions of the study, blood samples for the 
quantitation of proteasome inhibition by oprozomib will be collected from all subjects for 
both schedules at 1 predose time point, up to 2 postdose time points (4 and 6 hours postdose) 
on Day 1 of Cycle 1 and Cycle 2, and 1 predose timepoint on Day 2 of Cycle 1.  These 
timepoints are also specified in the Laboratory Manual.  Details about collection times and 
volumes, and processing and shipping of PDn samples, are provided in the Laboratory 
Manual.  Measurement of proteasome activity in whole blood and peripheral blood 
mononuclear cells (PBMCs) will be performed using a fluorogenic substrate assay and/or 
enzyme-linked immunosorbent assay. 
11.4.3 
GENOMIC MEASUREMENTS 
Analysis of genomic biomarkers that may predict for response and resistance following 
treatment with proteasome inhibitors will be conducted for all subjects in the study who 
consent to optional genomic biomarker analysis.  These analyses will be performed on the 
required bone marrow aspirate obtained at Baseline (within 45 days prior to Cycle 1 Day 1 
dosing; a portion of the bone marrow aspirate sample obtained at Baseline will be used; no 
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additional sample is required), as well as a sample of blood and saliva, also collected at 
Baseline.  Bone marrow aspirate or biopsy collection does not need to be repeated if 
previously completed within 45 days prior to Cycle 1 Day 1 dosing.  Additional bone marrow 
samples for biomarkers may be collected at disease progression (End of Study Treatment due 
to PD) from all subjects who consent.   
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 (eg, saliva or 
peripheral blood) in order to determine the presence of somatic mutations in tumor cell 
samples.  Data will be analyzed to examine specific hypotheses about 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 cell (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 enzyme-linked immmunosorbent 
assay (ELISA) and/or other protein quantification methods.  These data will also be used to 
derive new hypotheses about mechanisms of drug response, resistance, and safety. 
The schedule for genomic sampling is provided in the Laboratory Manual and in the 
Schedule of Assessments (Appendices A1, A2, B1, and B2). 
11.5 
PATIENT-REPORTED OUTCOMES ASSESSMENTS 
Beginning with Cycle 1, HRQoL/PRO assessments are to be completed at the beginning of 
every cycle prior to drug administration through End of Study Treatment/Early 
Discontinuation visit during the dose-expansion portion of the trial, and at the beginning of 
every cycle prior to drug administration through End of Study Treatment/Early 
Discontinuation visit.  The HRQoL/PRO assessments include:   
 BPI-SF (See Appendix M for a sample Brief Pain Inventory – Short Form) 
 EORTC QLQ-C30 (Appendix D) 
 EORTC QLQ-MY20 (Appendix D) 
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 Neurotoxicity subscale of the FACT/GOG-Ntx4 (Version 4; Appendix E) 
 EQ-5D-5L (Appendix F) 
12 
STUDY AND STUDY TREATMENT DISCONTINUATION 
Early discontinuation and End of Study Treatment assessments must be performed within 
30 days following the subject’s last dose of study drug and prior to initiation of any other 
treatment. 
All subjects must complete a visit approximately 4 weeks after the last cycle of treatment to 
allow for safety follow-up 30 days after the last dose of oprozomib.  An individual subject 
who discontinues study treatment for PD will be followed for OS in long-term follow-up.  
Any subject who withdraws without PD will no longer be followed with long-term 
assessments every 4 weeks through 18 months on study, and then every 8 weeks thereafter, 
beginning with Month 20, until progression or initiation of next therapy under 
Amendment 3.  The study will be completed once the last subject completes the last required 
follow-up visit.  The same methods of disease assessment must be used throughout the study.  
If 2 prior disease assessments show disease progression, assessments do not need to be 
repeated with End of Study Treatment assessments. 
12.1 
STUDY TREATMENT DISCONTINUATION 
For this study, subjects may withdraw from study treatment at any time. 
The investigator may remove a subject from study treatment for the following reasons: 
 Disease progression 
 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 
 Suspected pregnancy 
The primary reason for treatment discontinuation will be documented in the eCRF.  
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If the reason for treatment discontinuation is the occurrence of an AE, the subject will be 
followed by the investigator until such event(s) resolve, stabilize, or, according to the 
investigator’s judgment, there is no need of further follow-up.  
Subjects who discontinue from study treatment will be monitored for AEs for 30 days after 
the last dose of oprozomib or immediately before the start of subsequent anticancer treatment 
(whichever occurs first).  Treatment discontinuation due to progression should be recorded 
on the Study Drug Completion/Discontinuation eCRF as “Disease Progression.”  Verbatim 
terms such as “disease progression,” “progressive disease,” etc. should not be reported as 
AEs or SAEs as outlined in Section 13.3.2 unless the investigator considers the progression 
to be atypical, accelerated, or caused by the study drug, in which case it should also be 
recorded as an SAE in the AE eCRF. 
The Sponsor, or designee must be notified within 24 hours if a subject is withdrawn from 
treatment for any reason (ie, disease progression, toxicity, etc.).  Disease progression with 
2 consecutive disease assessments must be confirmed by the medical monitor before any 
subject is discontinued from study treatment. 
For dose escalation and expansion, subjects who withdraw from treatment before completing 
adequate safety or efficacy evaluations, or Cycle 1 dosing, will be considered unevaluable 
and may be replaced.  Additional subjects may be enrolled to account for subjects who have 
not had adequate safety or efficacy evaluations. 
12.2 
STUDY DISCONTINUATION 
Each subject will be followed until death or study closure.  The reason for discontinuation 
from the study will be documented on the eCRF. 
Reasons for complete withdrawal from the study (treatment and all follow-up) before 
documentation of subject death include:  
 Withdrawal of consent 
 Lost to follow-up 
 Sponsor decision 
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12.3 
LONG-TERM FOLLOW-UP 
After completion of the End of Study Treatment visit, subjects will be followed for OS.  
Subjects will be followed based on their disease progression status at End of Study 
Treatment. 
Progression and Overall Survival 
 For subjects who have not progressed at end of study treatment, disease response 
assessments will no longer be performed every 4 weeks through 18 months on study, and 
then every 8 weeks thereafter, beginning with Month 20, until progression or initiation of 
next therapy under Amendment 3 
 Subjects who have progressed at end of study treatment or long-term follow-up will be 
followed for survival status approximately every 3 months, or as needed  
Long-term follow-up will continue until the subject has withdrawn consent for further 
participation, is lost to follow-up, has died, or the sponsor makes a decision to close the 
study.  For any subject who is lost to follow-up, the study site will attempt to ascertain 
survival information via public database search. 
12.4 
STUDY TERMINATION 
The Sponsor has the right to terminate this study, either schedule, or a study site from 
participating in a study at any time.  Reasons for terminating the study overall or at a specific 
study site may include, but are not limited to, the following: 
 The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
 Subject enrollment is unsatisfactory 
 Data recording is inaccurate or incomplete 
 Investigator does not adhere to the protocol or applicable regulatory requirements in 
conducting the study 
13 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
13.1 
ADVERSE EVENT REPORTING 
13.1.1 
DEFINITIONS 
An AE is any untoward medical occurrence in a study subject administered an investigational 
product(s) regardless of the causal relationship with treatment. 
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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 drug-related.  In addition to new events, any increase in the 
severity or frequency of a preexisting condition that occurs after the subject signs the 
informed consent form (ICF) for participation is considered an AE.  This includes any side 
effect, injury, toxicity, or sensitivity reaction.  All reported AEs will be coded using the 
current version of Medical Dictionary for Regulatory Activities (MedDRA). 
Whenever possible, the NCI-CTCAE Version 4.03 should be used to describe the event and 
for assessing the severity of AEs.  For AEs not adequately addressed in the NCI-CTCAE 
Version 4.03, Table 17 below should be used. 
Table 17 Toxicity Grading for Adverse Events Not Covered in the 
NCI-CTCAE (Version 4.03) 
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 activities of daily living (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 
NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
current IB or is not listed at the specificity or severity that has been observed.  Adverse 
events or suspected adverse reactions that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with a particular study drug, are considered 
“unexpected.”  For example, an event more specific or more severe than described in the IB 
would be considered “unexpected.”  Any condition, laboratory abnormality, or physical 
finding with an onset date prior to the subject signing the ICF is considered to be preexisting 
in nature and part of the subject’s medical history. 
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Abnormal laboratory findings should be reported as AEs if medical intervention or corrective 
action (eg, transfusions, initiation of antibiotics or other treatment regimens, hydration, study 
drug placed on hold) is required or the event is deemed clinically significant by the treating 
physician. 
13.2 
CAUSALITY 
A suspected adverse event means any AE for which there is reasonable possibility that the 
study drug caused the AE.  “Reasonable possibility” means that there is evidence to suggest 
a causal relationship between the drug and the AE. 
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:  
 There is a clinically plausible time sequence between the AE onset and administration of 
study treatment; and/or 
 There is a biologically plausible mechanism for the study treatment to cause or contribute 
to the AE; and/or 
 The event improves or diminishes upon withdrawal of the study drug without the 
initiation of any specific treatment for the event (dechallenge) and/or recurs or worsens 
with rechallenge (when clinically feasible); and/or 
 The AE cannot be reasonably attributed to concurrent or underlying illness, other drugs, 
or procedures 
NO; the event is not suspected to be related if: 
 The AE is more likely to be explained by the subject’s clinical state, underlying disease, 
or concomitant medical, study, or nonstudy procedure; and/or 
 The time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
 The event is not related to the investigational product(s) 
In the event of a possible drug-related AE, the investigator should to the best of his/her 
ability assess its relationship to each of the study drugs:  oprozomib, pomalidomide, and 
dexamethasone. 
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13.3 
ADVERSE EVENTS REPORTING PROCEDURES 
13.3.1 
GENERAL 
All AEs (eg, any new event or worsening in severity or frequency of a preexisting condition 
or laboratory finding) with an onset date after the subject signs the informed consent for 
participation in the clinical trial must be promptly documented on the AE eCRF via the 
electronic data capture (EDC) system.  Details of the event must include severity, 
relationship to study drug(s), duration, action taken, and outcome.  Whenever possible, 
reporting a specific diagnosis is preferred when reporting AEs in the AE eCRF rather than 
reporting individual signs and symptoms. 
All AEs will be collected from the time the subject signs informed consent through 30 days 
after receiving the last dose of study drug or before start of subsequent anticancer treatment 
(whichever occurs first).  If initiation of new anticancer therapy occurs following the last 
dose of study drug(s), the date of new anticancer therapy will be recorded on the appropriate 
eCRF.  In addition, the investigator should report any AEs that may occur after this time 
period that are assessed to have a reasonable possibility of being associated with study drug.  
If the subject is randomized but discontinues participation in the study prior to receiving 
study drug, AEs must be reported through the End of Study Treatment visit. 
All AE severity changes will be recorded on the AE case report form (CRF) as separate 
events.  All AEs that are considered related to study drug and all SAEs regardless of 
relationship to study drug must be followed to resolution or to stabilization if improvement is 
not expected.  Adverse events that completely resolve and then recur should be recorded as a 
new AE.  For subjects who complete the End of Study Treatment visit less than 30 days 
following the last dose of study drug, a follow-up of ongoing AEs should be attempted by 
telephone and documented in the subject’s source file.  Adverse events continuing at 30 days 
after the last dose of study treatment should have a comment in the source file by the 
investigator that the event has stabilized or is not expected to improve. 
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The investigator is responsible for evaluating all AEs, obtaining supporting source 
documents, and determining that documentation of the event is adequate.  The investigator 
may delegate these duties to 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. 
13.3.2 
DISEASE PROGRESSION 
Disease progression will be documented on an eCRF intended to capture PD information and 
will be analyzed as a study endpoint.  Signs and symptoms related to disease progression 
(eg, pathologic fracture in a subject with progressive multiple myeloma) should be reported 
in the appropriate case report form as an AE or as a SAE (if the event in question meets the 
criteria for seriousness) while the cause of study treatment discontinuation should be reported 
as progression of disease.  Verbatim terms such as “disease progression,” “progressive 
disease,” etc. should not be reported as AEs or SAEs unless the investigator considers the 
progression to be atypical, accelerated, or caused by the study drug.  Similarly, deaths 
occurring as a result of disease progression should be reported on the eCRF intended to 
capture death information and should not be reported as SAEs. 
13.4 
SERIOUS ADVERSE EVENTS DEFINITIONS 
An SAE is an AE 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 sponsor or investigator, at immediate risk of death at the time of 
occurrence; ie, it does not include a reaction that, had it occurred in a more severe form, 
might have caused death 
 Requires inpatient hospitalization or prolongation of an existing hospitalization (except 
scheduled hospitalizations for a nonacute, unrelated cause such as elective surgery) 
 Results in persistent or significant disability/incapacity (ie, substantial disruption in a 
subject’s ability to conduct normal activities of daily living) 
 Is a congenital anomaly/ birth defect in the offspring of an exposed female subject or 
offspring of a female partner of a male subject 
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 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
the event jeopardizes the subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition 
13.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
Amgen Global Patient Safety must be notified of the occurrence of any SAE within 
24 hours of the investigator, designee, or site personnel’s knowledge of the event.  The SAE 
will be reported by completing and submitting the SAE report form through the EDC system.  
In the event that the EDC system is not available, paper SAE report forms may be used to 
report the 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 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 
Contingency Report Form (see Appendix N) 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 off line 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 off line, then the site can report this information on a paper Serious Adverse 
Event Report Form (see Appendix N). 
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. 
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The investigator will submit any updated serious adverse event 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) or 
Independent Ethics Committees (IEC), in accordance with local regulations, of all SAEs.  
The sponsor may request additional source documentation pertaining to the SAE from the 
investigational site.  If a subject is permanently withdrawn from the study due to an SAE, this 
information must be included in the initial or follow-up SAE report in the eCRF. 
The sponsor is responsible for notifying the appropriate global health authorities of SAEs, 
when required, and in accordance with applicable laws and regulations. 
13.6 
PREGNANCY REPORTING 
Pregnancy occurring in a female subject, or in a male subject’s partner, while enrolled in this 
clinical trial through 30 days after the subject’s last dose of study drug, although not 
considered an SAE, must be reported to Amgen Global Patient Safety on an Amgen 
Pregnancy Notification Worksheet (Appendix O) within 24 hours of the investigator, 
designee, or site personnel learning of the event.  If the subject is pregnant, all study 
treatment must be discontinued immediately and the pregnancy must be reported to the 
investigator and sponsor within 24 hours.  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 O).  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 
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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 13.5.  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 Notification Worksheet 
(Appendix O).  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. 
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 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 P) 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 22. 
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. 
14 
STATISTICS 
This section outlines the statistical analysis strategy and procedures for the study.  Specific 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
Plan (SAP).  If, after the study has begun but prior to the final analysis, important changes 
are made to the protocol that affect principal features of the primary and/or key secondary 
analyses, then the protocol and/or SAP will be amended, as appropriate.  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. 
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14.1 
STUDY ENDPOINTS 
14.1.1 
PRIMARY ENDPOINTS 
 DLTs   
 Adverse events and laboratory abnormalities graded according to NCI-CTCAE, Version 
4.03 
 Vital signs and clinical laboratory results during and following study drug administration  
14.1.2 
SECONDARY ENDPOINTS 
 Overall response, defined as the best response of sCR, CR, VGPR, or PR, as determined 
by investigator according to the IMWG-URC 
 Clinical benefit, defined as defined as the best response of MR or better, as determined 
by investigator according to the IMWG-URC and modified EBMT criteria   
 Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to 
maximum concentration (Tmax), area under the plasma concentration time curve from 
time 0 to last time point (AUC0-), and area under the plasma concentration time curve 
from time 0 to time infinity (AUC0-) using noncompartmental methods 
14.1.3 
EXPLORATORY ENDPOINTS 
 Pharmacodynamic biomarkers that may be correlated with antitumor activity 
 Genomic biomarkers that may be correlated with antitumor activity and resistance 
following treatment with proteasome inhibitors 
 Change over time in bone pain and the impact of bone pain measured with the BPI-SF 
(Dose Expansion only) 
 Change over time in the global health status/QoL scale of the EORTC QLQ-C30 (Dose 
Expansion only) 
 Change over time in health status assessed by EQ-5D-5L (Dose Expansion only) 
 Change over time in the disease symptoms subscale of the EORTC QLQ-MY20 (Dose 
Expansion only) 
 Change over time in neurotoxicity symptoms measured by the FACT/GOG-Ntx4 score 
(Version 4) (Dose Expansion only) 
14.2 
ANALYSIS OF THE CONDUCT OF THE STUDY 
Enrollment, subject disposition, study treatment administration, and discontinuation from the 
study will be summarized.  Eligibility exceptions and important protocol deviations will be 
summarized. 
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14.3 
DATA MONITORING COMMITTEE 
In this study, safety will be monitored by a CSRC for both the dose-escalation and 
dose-expansion portions of the study.  
 
14.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Descriptive statistics will be used to summarize baseline subject characteristics.  Summaries 
of discrete data will include number of subjects and incidence as a frequency and as a 
percentage.  Summaries of continuous data will include mean, standard deviation, median, 
minimum, maximum, and sample size. 
14.4.1 
TREATMENT EXPOSURE AND MEDICATION COMPLIANCE 
Extent of exposure to all study treatments (oprozomib, pomalidomide, and dexamethasone) 
will be evaluated by summary statistics (N, mean, standard deviation, median, and range).  
Percentage of subjects and cycles with dose delays and reductions will be calculated by 
treatment group. 
The dose intensity of oprozomib, pomalidomide, and dexamethasone (ie, the amount of drug 
delivered to a subject per week of treatment) will be calculated according to standard 
methodology (Hryniuk, 1990; Longo, 1991) that accounts for treatment delays on the 
calculated dose intensity result.  For each subject, the relative dose intensity (actual versus 
planned) of each treatment will be calculated.  The average relative dose intensity for each 
treatment group will be calculated by summarizing the average relative dose intensity for 
individual subjects.  The results for pomalidomide and dexamethasone will be provided to 
determine the presence of any major differences between the treatment groups for the 
planned versus actual dose and schedule of these two (2) study medications. 
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14.5 
STATISTICAL METHODS 
14.5.1 
ANALYSIS POPULATIONS 
14.5.1.1 
Safety Population  
All subjects receiving any amount of study treatment (oprozomib, pomalidomide, or 
dexamethasone) will be included in safety analyses.  A baseline measurement and at least 
1 laboratory, vital sign, or ECG measurement obtained after any amount of study treatment is 
required for inclusion in the analysis of a specific safety parameter when applicable. 
14.5.1.2 
Efficacy Population 
For this study, the efficacy population is equivalent to the safety population. 
14.5.1.3 
PK-Evaluable Population 
Subjects evaluable for PK are defined as those who have adequate oprozomib plasma 
concentration-versus-time data to allow proper estimation of PK parameters.   
14.5.2 
EFFICACY ANALYSES 
Overall response rate is defined as the proportion of subjects with a best response of sCR, 
CR, VGPR, or PR as determined by investigator according to the IMWG-URC. 
Clinical benefit rate is defined as the proportion of subjects with a best response of PR or 
better according to IMWG-URC or a best response of MR according to the EBMT criteria, as 
determined by the investigator.  A point estimate and 95% exact binomial confidence interval 
(CI) will be calculated for both ORR and CBR for all subjects treated at the RP3D (during 
dose escalation and expansion for each schedule).  A descriptive summary of ORR and 
responses will also be provided by dose cohort. 
Progression-free survival and duration of response (DOR) will be listed for all subjects in 
the efficacy population by dose cohort level and schedule. 
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14.5.3 
SAFETY ANALYSIS 
The safety population will be used in all safety analyses (see Section 14.5.1.1). 
For this study, safety data will be summarized for each cohort and for the pooled cohorts.  
Safety will be assessed through summaries of DLTs, AEs, changes in laboratory test results, 
ECGs, vital signs, and oprozomib, pomalidomide, and dexamethasone exposure.  Subgroup 
Analyses and Effects of Baseline Factors 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the hazard ratio (or odds ratio) for treatment group (with 95% CI) will be 
provided for the primary and selected secondary efficacy endpoints and plotted within each 
of the following baseline variables, provided there is a reasonable sample size in the 
subgroups of interest: 
 Number of prior therapies:  2 versus 3 or more (stratification factor) 
 Age (< 75 years versus ≥ 75 years) (stratification factor) 
 Prior carfilzomib (naïve/sensitive versus refractory) (stratification factor) 
 Refractory status:  Primary refractory versus relapsed-refractory versus 
bortezomib-intolerant 
 Refractory to lenalidomide 
 Refractory to bortezomib 
 Double refractory (refractory to lenalidomide and bortezomib) 
 FISH risk status:  High-risk group versus standard-risk group.   
 No prior transplant versus prior transplant 
 Bone marrow infiltration by plasma cells ≤ 50% versus > 50% at baseline 
 Renal function ≤ 60 mL/min versus > 60 mL/min at baseline 
 Age (< 65 years versus ≥ 65 years)  
 Race (Caucasian versus all others) 
 Sex (male versus female) 
14.5.4 
PHARMACOKINETIC ANALYSES 
In the Dose-Escalation and Dose-Expansion portions of the study, blood samples will be 
collected from all subjects for determination of plasma concentrations of oprozomib at 
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1 predose time point and up to 7 postdose time points on Day 1 of Cycle 1 and Cycle 2 
(0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose) and 1 predose time point on Day 2 of Cycle 1 for 
both schedules.  Individual and mean plasma-concentration-versus time data will be tabulated 
and plotted by dose level.   
The PK parameter estimates for oprozomib will be summarized, including total plasma 
exposure (AUC), maximum plasma concentration (Cmax), time to maximum concentration 
(Tmax), total plasma clearance, and plasma terminal half-life (t1/2, as appropriate for data 
collected).  Estimates for these parameters will be tabulated and summarized (mean, standard 
deviation). 
Unless otherwise specified, the PK parameter will be estimated based on noncompartmental 
methods.  These estimates will be summarized descriptively by dose cohort.  Exploratory 
analyses may be performed to evaluate the relationship between the estimate PK parameters 
and selected safety, biomarker, or clinical effect endpoints. 
14.6 
HANDLING OF MISSING DATA 
Missing data for partial dates on AEs or concomitant medication may be imputed according 
to prespecified, conservative imputation rules.  Censoring rules for PFS, OS, and DOR and 
details about the handling of missing data are explained in the SAP. 
14.7 
DETERMINATION OF SAMPLE SIZE 
A total enrollment of approximately 82 subjects is planned for this study.  During the 
dose-escalation portion of the study, approximately 21 subjects are expected to be enrolled 
for each schedule.  The estimated sample size for the dose-escalation part of the study is 
based on standard 3 + 3 dose-escalation rules, with expectations that 2–3 dosing cohorts of 
3–6 subjects per cohort will be required to establish the MTD.  A minimum of 6 subjects 
must be treated at the MTD.  For each schedule, more than 1 MTD for oprozomib may be 
established if additional dose levels of pomalidomide are assessed.  The MTD for oprozomib 
in combination with each dose level of pomalidomide will be the dose(s) where < 2 DLTs in 
6 subjects are observed.   
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The actual number of required subjects will depend on both the total number of cohorts, and 
the need to expand a given cohort from 3 to 6 subjects in order to identify the MTD.  
Properties of the dose-escalation rules for different underlying DLT rates are provided in 
Table 18.   
Table 18 Properties of the Dose-Escalation Rules for Different Underlying DLT Rates 
Underlying Rate 
of DLT 
Probability of Enrolling  
3 Additional Subjects 
Probability that Dose is 
Determined to be Tolerated 
0.10 
0.24 
0.91 
0.20 
0.38 
0.71 
0.33 
0.44 
0.43 
0.40 
0.43 
0.31 
0.50 
0.38 
0.17 
0.60 
0.29 
0.08 
DLT = dose-limiting toxicity. 
The criteria for selecting the RP3D for each schedule at the sponsor’s discretion will include 
assessment of the safety, tolerability, and preliminary activity of oprozomib observed across 
multiple cycles.  In addition, both PK and PDn assessments to demonstrate adequate 
exposure and proteasome inhibition will be a key factor.  The CSRC will review the data and 
provide guidance in selection of the RP3D.  Therefore the RP3D may differ from the MTD, 
but will not be higher than the MTD.  A minimum of 20 additional subjects are planned for 
enrollment and treatment for 1 or both schedules at the sponsor’s discretion at the RP3D 
during the dose-expansion portion of the study.  In the dose-expansion portion of the study, if 
the true ORR ≥ 40%, then the probability of seeing at least 7 responses among the 
26 subjects (6 treated at the MTD during escalation + 20 in the expansion) is approximately 
94%. 
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15 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
15.1 
COMPLIANCE STATEMENT 
This study will be conducted in accordance with the protocol and with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, as well as all 
applicable country and regional legal and regulatory requirements.  The investigator is 
responsible for ensuring that this protocol, the site’s informed consent form, and any other 
information that will be presented to potential subjects are reviewed and approved by the 
appropriate IRB or IEC prior to the enrollment of any study subjects. 
15.2 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, IB, and any other relevant 
supporting information to the appropriate IRB or IEC for review and approval prior to study 
initiation. 
Amendments to the protocol must also be approved by the IRB/IEC and the local regulatory 
agency, as appropriate, prior to the implementation of changes in this study.  No protocol 
deviations are allowed.  However, the investigator may implement a deviation from, or a 
change of, the protocol to eliminate an immediate hazard(s) to the study subjects without 
prior IRB/IEC/Sponsor approval/favorable opinion.  As soon as possible, the implemented 
deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment, 
should be submitted to the IRB/IEC/Sponsor.  Any deviations from the protocol must be 
fully explained and documented by the investigator. 
15.3 
INFORMED CONSENT AND HUMAN SUBJECT PROTECTION 
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. 
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The Sponsor or its designated representative will provide the investigator with a sample 
consent form.  Local and/or institutional requirements may require disclosure of additional 
information in the ICF.  Any changes to the consent form 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 consent form for approval.  A copy of the approved form must be submitted 
to the sponsor or its designated representative for its approval prior to initiation of the study.  
Before implementing any study procedure on a particular subject, informed consent shall be 
documented in such subject’s case histories and by the use of a written consent form 
approved by the Sponsor and 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 
informed consent will be given to the subject or subject’s legally authorized representative.  
The original signed consent must be maintained by the investigator and available for 
inspection by the Sponsor, its designated representative, or regulatory authority at any time. 
15.4 
DIRECT ACCESS TO SOURCE DATA, SOURCE DOCUMENTS, AND 
STUDY RECORDS 
The study will be carried out in keeping with applicable local laws and regulations.  
This may include an inspection by Onyx representatives/designees, and/or regulatory 
authority representatives at any time.  The investigator/institution must agree to the 
inspection of study-related records by the regulatory authority/Onyx 
representatives/designees, and must allow direct access to source documents to the regulatory 
authority/Onyx representatives/designees/IRB/IEC.  The investigator must allocate time 
(investigator and study staff) to discuss findings and relevant issues with the regulatory 
authority/Onyx representatives. 
15.5 
DATA COLLECTION AND HANDLING 
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 as 
part of the case histories.  These source documents may include subject diaries, laboratory 
reports, and other documents.  Onyx will supply the eCRF, which will be completed in 
English. 
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Data collection will involve the use of the EDC system, to which only authorized personnel 
will have access. 
The investigator or designee must enter all results collected during the clinical study into 
eCRFs (or CRFs).  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.  Detailed instructions may be found in the other study-specific 
documents. 
All entries made on the eCRF must be verifiable against source documents.  In addition to 
periodic monitoring occurring within the system by study monitors, programmatic edit 
checks and data listings will be used to review the data for completeness, logic, and 
adherence to study protocol.  As a result of this monitoring and these checks, queries may be 
electronically issued to the clinical study sites and electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated according to 
regulatory requirements and applicable guidance for electronic records.  Also, data will be 
stored and evaluated in such a way as to assure subject confidentiality in accordance with the 
legal and regulatory requirements applying to protected health information.  Study records 
(eg, copies of eCRFs, regulatory documents) will be retained at the study site, along with 
adequate source documentation.  The study file and all source data should be retained for the 
time period required by applicable regulatory requirements and will not be destroyed until 
written notification is given by the sponsor or designee for destruction. 
15.6 
CONFIDENTIALITY 
All records identifying the subject will be kept confidential and, in accordance with the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
on the CRF.  If the subject name appears on any other document or study materials, then that 
information must be redacted before a copy of the document is supplied to the sponsor.  
Study data stored on a computer will be stored in accordance with local data protection laws 
and regulations.  Subjects will be informed in writing that representatives of the sponsor, 
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CONFIDENTIAL 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws and 
regulations. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified in accordance 
with applicable laws and regulations and according to the terms agreed upon in such 
subjects’ signed consent forms. 
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16 
REFERENCES 
American Cancer Society. Cancer Facts & Figures 2005. Atlanta, GA: American Cancer 
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dexamethasone in relapsed/refractory multiple myeloma (MM): Encouraging outcomes and 
tolerability in a phase II study. J Clin Oncol. 2009;27(15_suppl). ASCO Annual Meeting 
2009. Abstract 8536. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
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Bartlett JB, Wu L, Adams M, et al. Lenalidomide and pomalidomide strongly enhance tumor 
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Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression 
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Boccadoro M, Morgan G, Cavenagh J.  Preclinical evaluation of the proteasome inhibitor 
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CONFIDENTIAL 
Durie BG, Harousseau JL, Miguel JS, et al. International Myeloma Working Group. 
International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 
1467–73. Erratum in: Leukemia 2006;20(12):2220. Leukemia 2007;21(5):1134. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, and Bottomley A, on behalf 
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Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits 
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have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated 
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Abstract 450. 
Jagannath S, Richardson RG, Barlogie B, et al. Bortezomib in combination with 
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Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone as a frontline treatment for 
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Kaufman JL, Seigel D, Vij R, et al. Clinical profile of once-daily, modified release 
oprozomib tablets in patients with hematologic malignancies: results of a phase 1b/2 trial. 
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Abstract P-771. 
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 
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Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia. 2009;23(1):3–9. 
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Lacy M, Jacob A, Gertz M. Pomalidomide plus low-dose dexamethasone in myeloma 
refractory to both bortezomib and lenalidomide:  comparison of two dosing strategies in dual 
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a comparison of published methods. J Clin Oncol. 1991;9(11):2042–51. 
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 
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Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple 
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May 29, 2009 (v4.03 June 14, 2010). NCI, NIH, DHHS. NIH publication # 09-7473. 
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and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients 
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2012. 
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partially IL-10-dependent manner. Cell Immunol. 2004;230(2):81–8. 
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Rajkumar SV, Harousseau JL, Durie B. Consensus recommendations for the uniform 
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Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, 
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Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide 
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Richardson PG, Jagannath S, Avigan DE, et al. Lenalidomide plus bortezomib (Rev-Vel) in 
relapsed and/or refractory multiple myeloma (MM): final results of a multicenter phase 1 
trial. Blood. 2006b;108(11). ASH Annual Meeting 2006. Abstract 405. 
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. 
San Miguel SJ, Weisel K, Moreau P. Updated survival for pomalidomide plus low-dose 
dexamethasone in relapsed refractory multiple myeloma. J Clin Oncol. 2013; 
31(15_suppl). ASCO Annual Meeting 2013. Abstract 8510. 
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Siegel D, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib 
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120(14):2817–25. 
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of white blood cell growth factors: an evidence-based clinical practice guideline. 
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Stadtmauer J, Shah R, Abonour A, et al. Carfilzomib, pomalidomide and dexamethasone 
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International Myeloma Workshop (IMW2013). April 3–7, 2013; Kyoto, Japan. Abstract 
P-250. 
Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib resistant 
adenocarcinoma cells. PLoS One. 2011;6(12):e27996. 
Zang Y, Thomas SM, Chan ET, et al. The next generation proteasome inhibitors carfilzomib 
and oprozomib activate prosurvival autophagy via induction of the unfolded protein response 
and ATF4. 2012;8(12):1873–74.  
Zhou HJ, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and 
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3028–38. 
 
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APPENDIX A1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 5/14 SCHEDULE 
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early 
Discon.a 
Long-
term 
Follow
-up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 1 Day 2 
Day  
3−4 Day 5 
Day  
6−7 Day 8  
Day 
9−14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15  
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
22−28 
Written Informed 
Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
Previous Treatment 
History 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological 
Assessment (BPNS and 
NCI-CTCAE Grading)c  
X 
X 
X 
X 
Vital Signsd,e,f
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg (Local) 
X 
X 
X 
X 
X 
Urinalysish
X 
X 
Serum Chemistryi,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsj,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Testsl 
X 
Pregnancy Testm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPEP/UPEP/Serum FLC 
Immunofixationn 
X 
X 
Day -7 
to 1 
X 
sFLC 
only 
X 
X 
X 
Footnotes are defined on next page  
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APPENDIX A1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 5/14 SCHEDULE (CONT'D)
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early 
Discon.a 
Long-
term 
Follow
-up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 1 Day 2 
Day  
3−4 Day 5 
Day  
6−7 
Day 
8  
Day 
9−14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
22−28 
β2 Microglobulin 
X 
Skeletal Surveyo 
X 
X 
Plasmacytoma 
Evaluationp 
X 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
X 
Optional – Genomic 
Biomarker Assessment:  
Bloodr 
X 
Optional − Genomic 
Biomarker Assessment:  
Salivar 
X 
Blood for PKs 
X 
X 
X 
Blood for PDn Assays 
X 
X 
X 
Oprozomib Dosingt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone 
Dosingu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pomalidomide Dosingv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsw 
Telephone or other 
contact for disease and 
survival statusx  
X 
Footnotes are defined on next page 
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APPENDIX A1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 5/14 SCHEDULE (CONT'D)
AE = adverse event; BPNS = Brief Peripheral Neuropathy Screen; C = Cycle; CBC = complete blood count; D = Day; Discon. = discontinuation; EBMT = European Group for Blood and Marrow 
Transplantation; ECG = electrocardiogram; FISH = fluorescence in situ hybridization; FLC = free light chain; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; 
NCI-CTCAE = National Cancer Institute – Common Terminology Criteria for Adverse Events; PDn = pharmacodynamic(s); PK = pharmacokinetic(s); SFLC = serum free light chain; SPEP = serum 
protein electrophoresis; UPEP = urine protein electrophoresis 
a All End of Study Treatment/Early Discontinuation Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other 
treatment, whichever comes first.   
b Complete physical examinations will be performed during Screening and at the End of Study Treatment/Early Discontinuation visits.  All other physical examinations will be limited physical 
examinations only if clinically indicated.  A complete physical examination will include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief 
neurological examination including an assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern Cooperative Oncology Group (ECOG) performance status 
(assessed only at the time of the Screening and End of Study Treatment/Early Discontinuation physical examination) will be conducted.  A limited physical examination will include an 
examination of the chest (heart and lungs) and abdomen, with additional examinations as clinically indicated or directed by AEs.  Screening physicals may be used for Cycle 1 Day 1 if done within 
7 days prior to Day 1.  Physical exams for additional cycles can be conducted within 3 days of Day 1 of the next cycle prior to dosing.  
c Neurological assessments (BPNS and if applicable record AEs with CTCAE grading) will be performed at Screening and on Day 1 of every cycle starting from Cycle 2 if clinically indicated and 
at the End of Study Treatment/Early Discontinuation (See Appendix M).  
d Vital signs:  On Cycle 1 Days 1–5, 8, 15, and 19.  On days when oprozomib is administered, measure vitals within 1 hour prior to oprozomib dose and approximately 1 hour after each oprozomib 
dose.  Include measurement of orthostatic blood pressure, temperature, respiration rate, and pulse on every study visit, including Screening and End of Study Treatment/Early Discontinuation. 
Subject should lie down for 5 minutes and then have blood pressure and pulse measured consistently in either arm.  This should be followed by having the subject stand and repeating the blood 
pressure and pulse at 1 and 3 minutes.  A drop of 20 mmHg systolic, 10 mmHg diastolic, or lightheadedness/dizziness between supine and standing blood pressures would indicate orthostatic 
hypotension.  Usually an increase in pulse of 10 beats/min is associated but not required.  Subject’s dosage and use of antihypertensive agents in the setting of orthostatic hypotension should be 
evaluated and reassessed on an ongoing basis while on study.  Fluid intake should be assessed to confirm the subject is acting in accordance with protocol requirements.  Re-education should occur 
if subject is not adhering to protocol requirements.  Fluid status should be repleted to normal levels.  If protocol requirements for oral intake of fluids are being met, additional measured should be 
taken to increase volume status, and ongoing monitoring is warranted and can be managed per investigator discretion.  For time points where PK and vital signs are to be done together, vital signs 
should be obtained first as the act of phlebotomy may impact vital sign measurement results. 
e At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above (d). 
f For Cycle 2, if clinically indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Days 1, 5, 15, and 19.  For Cycles 3 and higher, if clinically 
indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Day 1.   
g Perform ECG approximately within 1 hour before (predose) and approximately 1 hour after (postdose) administration of oprozomib for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24 and then every 6 months 
solely if clinically indicated, until progression or unacceptable toxicity.  Perform standard ECG assessment at Screening and End of Study Treatment/Early Discontinuation visit.   
h Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein analyses.  Urine samples and urinalysis, done locally. 
i 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), done locally if clinically indicated.  Calculate or measure creatinine clearance (CrCl).  Screening results may be used for Cycle 1 Day 1 if 
obtained within 72 hours of Cycle 1 Day 1.  
j CBC and serum chemistry obtained on Days 1, 5, 15, and 19 of Cycles 1 and 2, and on Days 3 and 8 of Cycle 1.  Day 1 samples for laboratory analyses can be drawn within 72 hours prior to 
dosing on Day 1 for all subsequent cycles after Cycle 1 only if clinically indicated.  
k Complete blood count (CBC) with differential, done locally, and includes the following:  Hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential 
(total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count.  Screening results may be used for Cycle 1 Day 1 if 
obtained within 72 hours of Cycle 1 Day 1.  
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APPENDIX A1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 5/14 SCHEDULE (CONT'D)
l Coagulation tests, done locally if clinically indicated, and includes the following:  Prothrombin time, activated partial thromboplastin time, and international normalized ratio.  
m Screening pregnancy testing, done locally, for females of childbearing potential (FCBP) must have a sensitivity of at least 50 mIU/mL with TWO medically supervised tests performed before 
pomalidomide dosing starts.  One test must be obtained within 10–14 days and one test within 24 hours prior to the start of pomalidomide on Cycle 1 Day 1.  A medically supervised, serum 
pregnancy test will be done weekly during Cycle 1 (Days 1, 8, 15, and 22).  Starting with Cycle 2, serum pregnancy tests will be done within 24 hours prior to each cycle of pomalidomide dosing 
in FCBP only.  Pregnancy tests will be repeated on Day 15 of Cycle 2 and beyond if menses are irregular (i.e., not within ± 7 days of a 28-day cycle) or menses are not present in FCBP. 
n Results for SPEP, UPEP, and SFLC, obtained locally, during Screening must be available before starting study drug treatment.  When the subject is on study drug, the disease response assessments 
will be performed at the end of each cycle (Day 22–28 or prior to dosing on Day 1 of the next cycle) for the first 18 months (Cycles 1–18), then every 8 weeks thereafter (starting with Cycle 20).  If 
the subject comes off study for reasons other than progressive disease, then disease response assessments will be performed every 4 weeks through 18 months on study, and then every 8 weeks 
thereafter.  Obtain blood for SPEP (please refer to Section 11.3 for collection times for SPEP Immunofixation, UPEP and UPEP Immunofixation with 24-hr urine, and sFLC) within 7 days prior to 
next Cycle study drug dosing.  If a response assessment indicates PD, confirmation of PD may be obtained any time at or before the next scheduled assessment. 
o Subjects are required to have a skeletal survey at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early Discontinuation.  This does not need to be repeated if 
previously done within 30 days of consent.  If a skeletal survey was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical monitor approval.  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.  If present at Baseline, bone 
lesion(s) must be monitored throughout the study only as needed to document response according to the IMWG-URC and modified EBMT criteria or if clinically indicated.  For subjects who did 
not progress during treatment with bone lesions present at Baseline, skeletal survey will no longer be required.  During long-term follow-up, skeletal survey evaluation will also no longer be 
required. 
p Subjects are required to have a plasmacytoma evaluation if known or suspected clinically at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment.  This does not 
need to be repeated if previously done within 30 days of consent.  If the assessment was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical monitor 
approval.  If present at Baseline, plasmacytoma evaluation is to be repeated during treatment only to document response according to the IMWG-URC and modified EBMT criteria or if clinically 
indicated.  If clinically indicated due to history of extramedullary disease, the same technique (may include ultrasound, CT scan, MRI, PET, or other standard-of-care method) must be employed 
for each measurement.  For subjects with plasmacytoma at Baseline and did not progress during treatment, plasmacytoma will no longer be required.  During long-term follow-up, plasmacytoma 
evaluation will also no longer be required. 
q Bone marrow aspirate or biopsy is required at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) to quantitate percent myeloma cell involvement.  Obtain bone marrow aspirate sample for 
fluorescence in situ hybridization (FISH) studies.  A portion of the sample may be used for optional genomic biomarker analysis, for all patients who consent.  If Baseline bone marrow aspirate or 
biopsy were previously obtained and included cytogenetics and FISH (with results available) within 45 days prior to Cycle 1 Day 1 dosing, collection does not need to be repeated unless the patient 
consents to the optional biomarker genomic samples, which include collection of additional bone marrow aspirate(s).  Repeat bone marrow aspirate when appropriate to confirm achievement of 
stringent complete response (sCR) or complete response (CR) within 30 days (+ 5 days) of confirmation assessment.  Bone marrow aspirate will also be collected at disease progression if clinically 
indicated (may be collected at End of Study Treatment/Early Discontinuation due to PD; it will no longer be required during Long-term Follow-up) for subjects who consent to optional genomic 
biomarker analysis.   
r Optional genomic biomarker samples- blood and saliva:  For subjects who consent to participate, blood and saliva samples (in addition to a portion of the bone marrow aspirate obtained for FISH 
analysis; no new sample is required, as applicable) will be collected at Baseline (within 45 days prior to Cycle 1 Day 1 dosing). 
s Sampling times are indicated in Section 11.4 of the protocol, and volumes are provided in the Laboratory Manual.  
t Oprozomib treatment will be administered on Days 1–5 and 15–19 during 28-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.  On days 
on which oprozomib and dexamethasone are administered concurrently (i.e., on Days 1, 2, 15, and 16 of each cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  
Oprozomib should be taken with food.  On the PK collection days, dosing of oprozomib in relation to the meal intake (within 2 hours before and 1 hour after dose) will be recorded. 
u Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle.  
v Pomalidomide will be administered Days 1–21 of each 28-day cycle up to Cycle 24.  Pomalidomide should be taken in the fasted state (i.e., 2 hours before or after a meal). 
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CONFIDENTIAL 
APPENDIX A1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 5/14 SCHEDULE (CONT'D)
w Record all AEs from time of consent through 30 days after the last dose of study drug or before start of subsequent anticancer treatment (whichever occurs first).  Start to record concomitant 
medications from 30 days prior to Day 1 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 
eCRF. 
x All patients will be followed for survival status by telephone contact or other method approximately every 3 months (± 1 week), or as needed, until study closure. 
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CONFIDENTIAL 
APPENDIX A2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 2/7 SCHEDULE 
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early 
Discon.a 
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−7 
Day 
8 
Day 
9−14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
22−28 
Day 
1 
Day 
22−28 
Written Informed 
Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
Previous Treatment 
History 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological Assessment 
(BPNS and NCI-CTCAE 
Grading)c  
X 
X 
X 
X 
Vital Signsd,e,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg (Local)  
X 
X 
X 
X 
X 
Urinalysish
X 
X 
Serum Chemistryi,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsj,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Testsl 
X 
Pregnancy Testm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPEP/UPEP/ Serum FLC 
Immunofixationn 
X 
X 
(Day -7 
to 1) 
X 
sFLC 
only 
X 
X 
X 
Footnotes are defined on next page 
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Page 115 of 223 
CONFIDENTIAL 
APPENDIX A2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE ESCALATION 2/7 SCHEDULE (CONT'D)
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early Discon.a 
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−7 
Day 
8  
Day 
9−14 
Day 
15  
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
22−28 
Day 
1
Day 
22−28 
β2 Microglobulin 
X 
Skeletal Surveyo 
X 
X 
Plasmacytoma 
Evaluationp 
X 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
X 
Optional – Genomic 
Biomarker Assessment:  
Bloodr 
X 
Optional - Genomic 
Biomarker Assessment:  
Salivar 
X 
Blood for PKs 
X 
X 
X 
Blood for PDn Assays 
X 
X 
X 
Oprozomib Dosingt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pomalidomide Dosingv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsw 
Telephone or other 
contact for disease and 
survival statusx  
X 
Footnotes are defined on next page 
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CONFIDENTIAL 
AE = adverse event; BPNS = Brief Peripheral Neuropathy Screen; C = Cycle; CBC = complete blood count; D = Day; s; Discon. = discontinuation; EBMT = European Group for Blood and 
Marrow Transplantation; ECG = electrocardiogram; FISH = fluorescence in situ hybridization; FLC = free light chain; IMWG-URC = International Myeloma Working Group-Uniform Response 
Criteria; NCI-CTCAE = National Cancer Institute – Common Terminology Criteria for Adverse Event; PDn = pharmacodynamic(s); PK = pharmacokinetic(s); SFLC = serum free light chain; 
SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis. 
a All End of Study Treatment/Early Discontinuation Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other 
treatment, whichever comes first.   
b Complete physical examinations will be performed during Screening and at the End of Study Treatment/Early Discontinuation visits.  All other physical examinations will be limited physical 
examinations only if clinically indicated.  A complete physical examination will include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief 
neurological examination including an assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern Cooperative Oncology Group (ECOG) performance status 
(assessed only at the time of the Screening and End of Study Treatment/Early Discontinuation physical examination) will be conducted.  A limited physical examination will include an 
examination of the chest (heart and lungs) and abdomen, with additional examinations as clinically indicated or directed by AEs.  Screening Physicals may be used for Cycle 1 Day 1 if done 
within 7 days prior to Day 1.  Physical exams for additional cycles can be conducted within 3 days of Day 1 of the next cycle prior to dosing.  
c Neurological assessments (BPNS and if applicable record AEs with CTCAE grading) will be performed at Screening and on Day 1 of every cycle starting from Cycle 2 if clinically indicated 
and at the End of Study Treatment/Early Discontinuation (See Appendix M). 
d Vital signs:  On Cycle 1 Days 1, 2, 8, 9, 15, 16, 22, and 23.  On days when oprozomib is administered measure vitals within 1 hour prior to oprozomib dose and approximately 1 hour after each 
oprozomib dose.  Include measurement of orthostatic blood pressure, temperature, respiration rate, and pulse on every study visit, including Screening and End of Study Treatment/Early 
Discontinuation.  Subject should lie down for 5 minutes and then have blood pressure and pulse measured consistently in either arm.  This should be followed by having the subject stand and 
repeating the blood pressure and pulse at 1 and 3 minutes.  A drop of 20 mmHg systolic, 10 mmHg diastolic or lightheadedness/dizziness between supine and standing blood pressures would 
indicate orthostatic hypotension.  Usually an increase in pulse of 10 beats/min is associated but not required.  Subject’s dosage and use of antihypertensive agents in the setting of orthostatic 
hypotension should be evaluated and reassessed on an ongoing basis while on study.  Fluid intake should be assessed to confirm the subject is acting in accordance with protocol requirements.
Re-education should occur if subject is not adhering to protocol requirements.  Fluid status should be repleted to normal levels.  If protocol requirements for oral intake of fluids are being met, 
additional measures should be taken to increase volume status, and ongoing monitoring is warranted and can be managed per investigator discretion.  For time points where PK and vital signs 
are to be done together, vital signs should be obtained first as the act of phlebotomy may impact vital sign measurement results. 
e At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above (d). 
f For Cycle 2, if clinically indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Days 1, 2, and 15.  For Cycles 3 and higher, if clinically indicated,
vital signs are required within approximately 1 hour prior to oprozomib administration on Day 1.  
g Perform ECG approximately within 1 hour before (predose) and approximately 1 hour after (postdose) administration of oprozomib for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24, and then every 6 months
solely if clinically indicated, until progression or unacceptable toxicity.  Perform standard ECG assessment at Screening and End of Study Treatment/Early Discontinuation visit.  
h Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein analyses.  Urine samples and urinalysis, done locally. 
i 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), done locally if clinically indicated.  Calculate or measure creatinine clearance (CrCl).  Screening results may be used for Cycle 1 
Day 1 if obtained within 72 hours of Cycle 1 Day 1.  
j CBC and serum chemistry obtained Days 1, 2, and 15 of Cycles 1 and 2, and on Days 8, 9, and 16 of Cycle 1.  Day 1 samples for laboratory analyses can be drawn within 72 hours prior to 
dosing on Day 1 for all subsequent cycles after Cycle 1 only if clinically indicated.  
k Complete blood count (CBC) with differential, done locally, and includes the following:  Hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential 
(total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count.  Screening results may be used for Cycle 1 Day 1 
if obtained within 72 hours of Cycle 1 Day 1.  
l Coagulation tests, done locally if clinically indicated, and includes the following:  Prothrombin time, activated partial thromboplastin time, and international normalized ratio.  
 
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CONFIDENTIAL 
m Screening pregnancy testing, done locally, for females of childbearing potential (FCBP) must have a sensitivity of at least 50 mIU/mL with TWO medically supervised tests performed before 
pomalidomide dosing starts.  One test must be obtained within 10–14 days and one test within 24 hours prior to the start of pomalidomide on Cycle 1 Day 1.  A medically supervised, serum 
pregnancy test will be done weekly during Cycle 1 (Days 1, 8, 15, and 22).  Starting with Cycle 2, serum pregnancy tests will be done within 24 hours prior to each cycle of pomalidomide 
dosing in FCBP only.  Pregnancy tests will be repeated on Day 15 of Cycle 2 and beyond if menses are irregular (i.e., not within ± 7 days of a 28-day cycle) or menses are not present in FCBP.  
n Results for SPEP, UPEP, and SFLC, obtained locally, during Screening must be available before starting study drug treatment.  When the subject is on study drug, the disease response 
assessments will be performed at the end of each cycle (Day 22–28 or prior to dosing on Day 1 of the next cycle) for the first 18 months (Cycles 1–18), then every 8 weeks thereafter (starting 
with Cycle 20).  If the subject comes off study for reasons other than progressive disease, then disease response assessments will be performed every 4 weeks through 18 months on study, and 
then every 8 weeks thereafter.  Obtain blood for SPEP (please refer to Section 11.3 for collection times for SPEP Immunofixation, UPEP and UPEP Immunofixation with 24-hr urine, and sFLC) 
within 7 days prior to next Cycle study drug dosing.  If a response assessment indicates PD, confirmation of PD may be obtained any time at or before the next scheduled assessment. 
o Subjects are required to have a skeletal survey at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early Discontinuation.  This does not need to be 
repeated if previously done within 30 days of consent.  If a skeletal survey was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical monitor approval.
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.  If present at Baseline, 
bone lesion (s) must be monitored throughout the study only as needed to document response according to the IMWG-URC and modified EBMT criteria or if clinically indicated.  For subjects 
who did not progress during treatment with bone lesions present at Baseline, skeletal survey will no longer be required.  During long-term follow-up, skeletal survey evaluation will also no 
longer be required. 
p Subjects are required to have a plasmacytoma evaluation if known or suspected clinically at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early 
Discontinuation.  This does not need to be repeated if previously done within 30 days of consent.  If the assessment was done more than 30 days before consent, it may be acceptable with the 
Sponsor’s study medical monitor approval.  If present at Baseline, plasmacytoma evaluation is to be repeated during treatment only to document response according to the IMWG-URC and 
modified EBMT criteria or if clinically indicated.  If clinically indicated due to history of extramedullary disease, the same technique (may include ultrasound, CT scan, MRI, PET, or other 
standard-of-care method) must be employed for each measurement.  For subjects with plasmacytoma at Baseline and did not progress during treatment, plasmacytoma will no longer be 
required.  During long-term follow-up, plasmacytoma evaluation will also no longer be required. 
q Bone marrow aspirate or biopsy is required at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) to quantitate percent myeloma cell involvement.  Obtain bone marrow aspirate sample for 
fluorescence in situ hybridization (FISH) studies.  A portion of the sample may be used for optional genomic biomarker analysis, for all patients who consent.  If Baseline bone marrow aspirate 
or biopsy were previously obtained and included cytogenetics and FISH (with results available) within 45 days prior to Cycle 1 Day 1 dosing, collection does not need to be repeated unless the 
patient consents to the optional biomarker genomic samples, which include collection of additional bone marrow aspirate(s).  Repeat bone marrow aspirate when appropriate to confirm 
achievement of stringent complete response (sCR) or complete response (CR) within 30 days (+ 5 days) of confirmation assessment.  Bone marrow aspirate will also be collected at disease 
progression if clinically indicated (may be collected at End of Study Treatment/Early Discontinuation due to PD; it will no longer be required during Long-term Follow-up) for subjects who 
consent to optional genomic biomarker analysis.   
r Optional genomic biomarker samples- blood and saliva:  For subjects who consent to participate, blood and saliva samples (in addition to a portion of the bone marrow aspirate obtained for 
FISH analysis; no new sample is required, as applicable) will be collected at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) 
s Sampling times are indicated in Section 11.4 of the protocol, and volumes are provided in the Laboratory Manual.  
t Oprozomib treatment will be administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 during 28-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any 
reason.  On days on which oprozomib and dexamethasone are administered concurrently (i.e., on Days 1, 2, 8, 9, 15, 16, 22, 23 of each cycle), dexamethasone should be taken at least 30 minutes 
prior to oprozomib.  Oprozomib should be taken with food.  On the PK collection days, dosing of oprozomib in relation to the meal intake (within 2 hours before and 1 hour after dose) will be 
recorded.   
u Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle.  
v Pomalidomide will be administered Days 1–21 of each 28-day cycle up to Cycle 24.  Pomalidomide should be taken in the fasted state (i.e., 2 hours before or after a meal). 
 
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Page 118 of 223 
CONFIDENTIAL 
w Record all AEs from time of consent through 30 days after the last dose of study drug or before start of subsequent anticancer treatment (whichever occurs first).  Start to record concomitant 
medications from 30 days prior to Day 1 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 eCRF. 
x All patients will be followed for survival status by telephone contact or other method approximately every 3 months (± 1 week), or as needed, until study closure. 
 
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
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Page 119 of 223 
CONFIDENTIAL 
APPENDIX B1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 5/14 SCHEDULE 
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of 
Study 
Treatment/ 
Early 
Discon.a 
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−4 
Day 
5 
Day 
6−7 
Day 
8  
Day 
9−14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
22−28 
Written Informed 
Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
Previous Treatment 
History 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological 
Assessment 
(BPNS and 
NCI-CTCAE Grading)c  
X 
X 
X 
X 
Patient Questionnairesd: 
BPI-SF 
EORTC QLQ-C30 
EORTC QLQ-MY20 
FACT/GOG-Ntx4 
EQ-5D-5L  
X 
X 
X 
X 
Vital Signse,f
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg (Local)  
X 
X 
X 
X 
X 
Urinalysish
X 
X 
Serum Chemistryi,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsj,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Testsl 
X 
Pregnancy Testm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes are defined on next page 
Approved
Product: 
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Supplemental Clinical Study Report:  20130411
30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
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Page 120 of 223 
CONFIDENTIAL 
APPENDIX B1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 5/14 SCHEDULE (CONT'D)
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−4 
Day 
5 
Day 
6−7 
Day 
8 
Day 
9−14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
16−21 
Day 
22−28 
Day 
1 
Day 
22−28 
End of 
Study 
Treatment/ 
Early 
Discon.a 
SPEP/UPEP/Serum 
FLC Immunofixationn 
X 
X 
(Day -7 
to 1) 
X 
sFLC 
only 
X 
X 
X 
β2 Microglobulin 
X 
Skeletal Surveyo 
X 
X 
Plasmacytoma 
Evaluationp 
X 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
X 
Optional – Genomic 
Biomarker Assessment:  
Bloodr 
X 
Optional − Genomic 
Biomarker Assessment:  
Salivar 
X 
Blood for PKs 
X 
X 
X 
Blood for PDn Assays 
X 
X 
X 
Oprozomib Dosingt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone Dosingu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pomalidomide Dosingv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsw 
Telephone or other 
contact for disease and 
survival statusx 
X 
Footnotes are defined on next page 
Approved
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Date: 
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Supplemental Clinical Study Report:  20130411
30 July 2019
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Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
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Page 121 of 223 
CONFIDENTIAL 
APPENDIX B1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 5/14 SCHEDULE (CONT'D)
AE = adverse event; BPI-SF = Brief Pain Inventory – Short Form; BPNS = Brief Peripheral Neuropathy Screen; C = Cycle; CBC = complete blood count; D = Day; Discon. = discontinuation; 
EBMT = European Group for Blood and Marrow Transplantation; ECG = electrocardiogram; EORTC = European Organization for Research and Treatment; EQ-5D-5L = a new facility for the 
measurement of health-related quality of life; FACT/GOG-Ntx = Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale questionnaire; 
FISH = fluorescence in situ hybridization; FLC = free light chain; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; NCI-CTCAE = National Cancer Institute – 
Common Terminology Criteria for Adverse Events; PDn = pharmacodynamic(s); PK = pharmacokinetic(s); SFLC = serum free light chain; SPEP = serum protein electrophoresis; UPEP = urine 
protein electrophoresis.  
a All End of Study Treatment/Early Discontinuation Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other 
treatment, whichever comes first.   
b Complete physical examinations will be performed during Screening and at the End of Study Treatment/Early Discontinuation visits.  All other physical examinations will be limited physical 
examinations only if clinically indicated.  A complete physical examination will include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief 
neurological examination including an assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern Cooperative Oncology Group (ECOG) performance status 
(assessed only at the time of the Screening and End of Study Treatment/Early Discontinuation physical examination) will be conducted.  A limited physical examination will include an 
examination of the chest (heart and lungs) and abdomen, with additional examinations as clinically indicated or directed by AEs.  Screening Physicals may be used for Cycle 1 Day 1 if done 
within 7 days prior to Day 1.  Physical exams for additional cycles can be conducted within 3 days of Day 1 of the next cycle prior to dosing.  
c Neurological assessments (BPNS and if applicable record AEs with CTCAE grading) will be performed at Screening and on Day 1 of every cycle starting from Cycle 2 if clinically indicated 
and at the End of Study Treatment/Early Discontinuation (See Appendix M).  
d BPI-SF, EORTC QLQ-C30, EORTC QLQ-MY20, FACT/GOG-Ntx4, and EQ-5D-5L to be collected at on Day 1 of every cycle through End of Study Treatment/Early Discontinuation visit.
  
These patient-reported outcome instruments should be administered prior to administration of any study drug. 
e Vital signs:  On Cycle 1 Days 1–5, 8, 15, and 19.  On days when oprozomib is administered measure vitals within 1 hour prior to oprozomib dose and approximately 1 hour after each 
oprozomib dose.  Include measurement of orthostatic blood pressure, pulse, respiration rate, and temperature on every study visit, including Screening and End of Study Treatment/Early 
Discontinuation.  Subject should lie down for 5 minutes and then have blood pressure and pulse measured consistently in either arm.  This should be followed by having the subject stand and 
repeating the blood pressure and pulse at 1 and 3 minutes.  A drop of 20 mmHg systolic, 10 mmHg diastolic, or lightheadedness/dizziness between supine and standing blood pressures would 
indicate orthostatic hypotension.  Usually an increase in pulse of 10 beats/min is associated but not required.  Subject’s dosage and use of antihypertensive agents in the setting of orthostatic 
hypotension should be evaluated and reassessed on an ongoing basis while on study.  Fluid intake should be assessed to confirm the subject is acting in accordance with protocol requirements. 
Re-education should occur if subject is not adhering to protocol requirements.  Fluid status should be repleted to normal levels.  If protocol requirements for oral intake of fluids are already 
being met, additional measures should be taken to increase volume status, and ongoing monitoring is warranted and can be managed per investigator discretion.  At the investigator’s medical 
discretion, vital sign monitoring may be extended beyond the time periods specified above.  For time points where PK and vital signs are to be done together, vital signs should be obtained first 
as the act of phlebotomy may impact vital sign measurement results. 
f For Cycles 2, if clinically indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Days 1, 5, 15, and 19.  For Cycles 3 and higher, if clinically 
indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Day 1. 
g Perform ECG approximately within 1 hour before (predose) and approximately 1 hour after (postdose) administration of oprozomib for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24 and then every 
6 months solely if clinically indicated, until progression or unacceptable toxicity.  Perform standard ECG assessment at Screening and End of Study Treatment/Early Discontinuation visit. 
h Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein analyses. Urine samples and urinalysis, done locally. 
i 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), done locally if clinically indicated.  Calculate or measure creatinine clearance (CrCl).  Screening results may be used for Cycle 1 
Day 1 if obtained within 72 hours of Cycle 1 Day 1.  
 
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CONFIDENTIAL 
APPENDIX B1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 5/14 SCHEDULE (CONT'D)
j CBC and serum chemistry obtained Days 1, 5, 15, and 19 of Cycles 1 and 2, and on Days 3 and 8 of Cycle 1.  Day 1 samples for laboratory analyses can be drawn within 72 hours prior to 
dosing on Day 1 for all subsequent cycles after Cycle 1 only if clinically indicated.  
k Complete blood count (CBC) with differential, done locally, and includes the following:  Hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated 
differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count.  Screening results may be used for 
Cycle 1 Day 1 if obtained within 72 hours of Cycle 1 Day 1.  
l Coagulation tests, done locally if clinically indicated, and includes the following:  Prothrombin time, activated partial thromboplastin time, and international normalized ratio.  
m Screening pregnancy testing, done locally for females of childbearing potential (FCBP) must have a sensitivity of at least 50 mIU/mL with TWO medically supervised tests performed before 
pomalidomide dosing starts.  One test must be obtained within 10–14 days and one test within 24 hours prior to the start of pomalidomide on Cycle 1 Day 1.  A medically supervised, serum 
pregnancy test will be done weekly during Cycle 1 (Days 1, 8, 15, and 22).  Starting with Cycle 2, serum pregnancy tests will be done within 24 hours prior to each cycle of pomalidomide 
dosing in FCBP only.  Pregnancy tests will be repeated on Day 15 of Cycle 2 and beyond if menses are irregular (i.e., not within ± 7 days of a 28-day cycle) or menses are not present in FCBP.  
n Results for SPEP, UPEP, and SFLC, obtained locally, during Screening must be available before starting study drug treatment.  When the subject is on study drug, the disease response 
assessments will be performed at the end of each cycle (Day 22–28 or prior to dosing on Day 1 of the next cycle) for the first 18 months (Cycles 1–18), then every 8 weeks thereafter (starting 
with Cycle 20).  If the subject comes off study for reasons other than progressive disease, then disease response assessments will be performed every 4 weeks through 18 months on study, and 
then every 8 weeks thereafter.  Obtain blood for SPEP (please refer to Section 11.3 for collection times for SPEP Immunofixation, UPEP and UPEP Immunofixation with 24-hr urine, and 
sFLC) within 7 days prior to next Cycle study drug dosing.  If a response assessment indicates PD, confirmation of PD may be obtained any time at or before the next scheduled assessment. 
o Subjects are required to have a skeletal survey at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early Discontinuation.  This does not need to be 
repeated if previously done within 30 days of consent.  If a skeletal survey was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical monitor 
approval.  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.  If present 
at Baseline, bone lesion (s) must be monitored throughout the study only as needed to document response according to the IMWG-URC and modified EBMT criteria or if clinically indicated. 
For subjects who did not progress during treatment with bone lesions present at Baseline, skeletal survey will no longer be required.  During long-term follow-up, skeletal survey evaluation 
will also no longer be required. 
p Subjects are required to have a plasmacytoma evaluation if known or suspected clinically at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment.  This does 
not need to be repeated if previously done within 30 days of consent.  If the assessment was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical 
monitor approval.  If present at Baseline, plasmacytoma evaluation is to be repeated during treatment only to document response according to the IMWG-URC and modified EBMT criteria or if 
clinically indicated.  If clinically indicated due to history of extramedullary disease, the same technique (may include ultrasound, CT scan, MRI, PET, or other standard-of-care method) must be 
employed for each measurement.  For subjects with plasmacytoma at Baseline and did not progress during treatment, plasmacytoma will no longer be required.  During long-term follow-up, 
plasmacytoma evaluation will also no longer be required. 
q Bone marrow aspirate or biopsy is required at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) to quantitate percent myeloma cell involvement.  Obtain bone marrow aspirate sample for 
fluorescence in situ hybridization (FISH) studies.  A portion of the sample may be used for optional genomic biomarker analysis, for all patients who consent.    If Baseline bone marrow 
aspirate or biopsy were previously obtained and included cytogenetics and FISH (with results available) within 45 days prior to Cycle 1 Day 1 dosing, collection does not need to be repeated 
unless the patient consents to the optional biomarker genomic samples, which include collection of additional bone marrow aspirate(s).  Repeat bone marrow aspirate when appropriate to 
confirm achievement of stringent complete response (sCR) or complete response (CR) within 30 days (+ 5 days) of confirmation assessment.  Bone marrow aspirate will also be collected at 
disease progression if clinically indicated (may be collected at End of Study Treatment/Early Discontinuation due to PD; it will no longer be required during Long-term Follow-up) for 
subjects who consent to optional genomic biomarker analysis.   
r Optional genomic biomarker samples- blood and saliva:  For subjects who consent to participate, blood and saliva samples (in addition to a portion of the bone marrow aspirate obtained for 
FISH analysis; no new sample is required, as applicable) will be collected at Baseline (within 45 days prior to Cycle 1 Day 1 dosing). 
s Sampling times are indicated in Section 11.4 of the protocol, and volumes are provided in the Laboratory Manual. 
 
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CONFIDENTIAL 
APPENDIX B1 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 5/14 SCHEDULE (CONT'D)
t Oprozomib treatment will be administered on Days 1–5 and 15–19 during 28-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.  On 
days on which oprozomib and dexamethasone are administered concurrently (i.e., on Days 1, 2, 15, and 16 of each cycle), dexamethasone should be taken at least 30 minutes prior to 
oprozomib.  Oprozomib should be taken with food.  On the PK collection days, dosing of oprozomib in relation to the meal intake (within 2 hours before and 1 hour after dose) will be recorded. 
u Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle.  
v Pomalidomide will be administered Days 1–21 of each 28-day cycle up to Cycle 24.  Pomalidomide should be taken in the fasted state (i.e., 2 hours before or after a meal). 
w Record all AEs from time of consent through 30 days after the last dose of study drug or before start of subsequent anticancer treatment (whichever occurs first).  Start to record concomitant 
medications from 30 days prior to Day 1 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 eCRF. 
x All patients will be followed for survival status by telephone contact or other method approximately every 3 months (± 1 week), or as needed, until study closure. 
 
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CONFIDENTIAL 
APPENDIX B2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 2/7 SCHEDULE 
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early 
Discon.a 
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−7 
Day  
8 
Day 
9−14 
Day  
15 
Day 
16−21 
Day  
22−28 
Day 
1 
Day 
2–14 
Day 
15 
Day 
22−28 
Day 
1 
Day 
22−28 
Written Informed 
Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
Previous Treatment 
History 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Neurological 
Assessment 
(BPNS and 
NCI-CTCAE Grading)c  
X 
X 
X 
X 
Patient Questionnairesd: 
BPI-SF 
EORTC QLQ-C30 
EORTC QLQ-MY20 
FACT-COG-Ntx4 
EQ-5D-5L 
X 
X 
X 
X 
Vital Signse,f
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg (Local)  
X 
X 
X 
X 
X 
Urinalysish
X 
X 
Serum Chemistryi,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff and 
Plateletsj,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Testsl 
X 
Pregnancy Testm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes are defined on the next page 
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CONFIDENTIAL 
APPENDIX B2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 2/7 SCHEDULE (CONT'D) 
Visit 
Screening Baseline 
Cycle 1 
Cycle 2 
Cycle 3 + 
End of Study 
Treatment/ 
Early 
Discon.a
Long-
term 
Follow-
up 
Day 
-28 to -1 
(Pre-
C1D1 
dose) 
Day 
1 
Day 
2 
Day 
3−7 
Day 
8 
Day 
9−14 
Day 
15 
Day 
16−21 
Day  
22−28 
Day 
1 
Day 2–
14 
Day  
15 
Day 
22−28 Day 1 
Day 
22−28 
SPEP/UPEP/ Serum 
FLC Immunofixationn 
X 
X 
(Day -7 
to 1) 
X 
sFLC 
only 
X 
X 
X 
β2 Microglobulin 
X 
Skeletal Surveyo 
X 
X 
Plasmacytoma 
Evaluationp 
X 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
X 
Optional – Genomic 
Biomarker Assessment:  
Bloodr 
X 
Optional − Genomic 
Biomarker Assessment:  
Salivar 
X 
Blood for PKs 
X 
X 
X 
Blood for PDn Assays 
X 
X 
X 
Oprozomib Dosingt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dexamethasone 
Dosingu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pomalidomide Dosingv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and Concomitant 
Medicationsw 
Telephone or other 
contact for disease and 
survival statusx 
X 
Footnotes are defined on next page 
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CONFIDENTIAL 
APPENDIX B2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 2/7 SCHEDULE (CONT'D) 
AE = adverse event; BPI-SF = Brief Pain Inventory – Short Form; BPNS = Brief Peripheral Neuropathy Screen; C = Cycle; CBC = complete blood count; D = Day; Discon. = discontinuation; 
EBMT = European Group for Blood and Marrow Transplantation; ECG = electrocardiogram; EORTC = European Organization for Research and Treatment; EQ-5D-5L = a new facility for the 
measurement of health-related quality of life; FACT/GOG-Ntx = Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale questionnaire; 
FISH = fluorescence in situ hybridization; FLC = free light chain; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; NCI-CTCAE = National Cancer Institute – 
Common Terminology Criteria for Adverse Events; PDn = pharmacodynamic(s); PK = pharmacokinetic(s); SFLC = serum free light chain; SPEP = serum protein electrophoresis; UPEP = urine 
protein electrophoresis.  
a All End of Study Treatment/Early Discontinuation Assessments must be performed within 30 days following the subject’s last administration of study drug and prior to initiation of any other 
treatment, whichever comes first.   
b Complete physical examinations will be performed during Screening and at the End of Study Treatment/Early Discontinuation visits.  All other physical examinations will be limited physical 
examinations only if clinically indicated.  A complete physical examination will include examination of the skin, head and neck, chest (heart and lungs), and abdomen, extremities, and a brief 
neurological examination including an assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern Cooperative Oncology Group (ECOG) performance status 
(assessed only at the time of the Screening and End of Study Treatment/Early Discontinuation physical examination) will be conducted.  A limited physical examination will include an 
examination of the chest (heart and lungs) and abdomen, with additional examinations as clinically indicated or directed by AEs.  Screening Physicals may be used for Cycle 1 Day 1 if done 
within 7 days prior to Day 1.  Physical exams for additional cycles can be conducted within 3 days of Day 1 of the next cycle prior to dosing.  
c Neurological assessments (BPNS and if applicable record AEs with CTCAE grading) will be performed at Screening and on Day 1 of every cycle starting from Cycle 2 if clinically indicated 
and at the End of Study Treatment/Early Discontinuation (See Appendix M).  
d BPI-SF, EORTC QLQ-C30, EORTC QLQ-MY20, FACT/GOG-Ntx4, and EQ-5D-5L to be collected on Day 1 of every cycle  through End of Study Treatment/Early Discontinuation visit.
  
These patient-reported outcome instruments should be administered prior to administration of any study drug.  
e Vital signs:  On Cycle 1 Days 1, 2, 8, 9, 15, 16, 22, and 23.  On days when oprozomib is administered measure vitals within 1 hour prior to oprozomib dose and approximately 1 hour after each 
oprozomib dose.  Include measurement of orthostatic blood pressure, pulse, respiration rate, and temperature on every study visit, including Screening and End of Study Treatment/Early 
Discontinuation.  Subject should lie down for 5  minutes and then have blood pressure and pulse measured consistently in either arm.  This should be followed by having the subject stand and 
repeating the blood pressure and pulse at 1 and 3 minutes.  A drop of 20  mmHg systolic, 10 mmHg diastolic, or lightheadedness/dizziness between supine and standing blood pressure would 
indicate orthostatic hypotension.  Usually an increase in pulse of 10  beats/min is associated but not required.  Subject’s dosage and use of antihypertensive agents in the setting of orthostatic 
hypotension should be evaluated and reassessed on an ongoing basis while on study.  Fluid intake should be assessed to confirm the subject is acting in accordance with protocol requirements. 
Re-education should occur if subject is not adhering to protocol requirements.  Fluid status should be repleted to normal levels.  If protocol requirements for oral intake of fluids are already 
being met, additional measures should be taken to increase volume status and ongoing monitoring is warranted and can be managed per investigator discrection.  At the investigator’s medical 
discretion, vital sign monitoring may be extended beyond the time periods specified above.  For time points where PK and vital signs are to be done together, vital signs should be obtained first 
as the act of phlebotomy may impact vital sign measurement results. 
f For Cycle 2, if clinically indicated, vital signs are required within approximately 1 hour prior to oprozomib administration on Days 1, 2, and 15.  For Cycles 3 and higher, if clinically 
indicated, vital signs are required within approximatley 1 hour prior to oprozomib administration on Day 1. 
g Perform ECG approximately within 1 hour before (predose) and approximately 1 hour after (postdose) administration of oprozomib for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24 and then every 6 months 
solely if clinically indicated, until progression or unacceptable toxicity.  Perform standard ECG assessment at Screening and End of Study Treatment/Early Discontinuation visit.  
h Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein analyses.  Urine samples and urinalysis, done locally. 
i 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), done locally, if clinically indicated.  Calculate or measure creatinine clearance (CrCl).  Screening results may be used for Cycle 1 
Day 1 if obtained within 72 hours of Cycle 1 Day 1.  
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CONFIDENTIAL 
APPENDIX B2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 2/7 SCHEDULE (CONT'D) 
j CBC and serum chemistry obtained Days 1, 2, and 15 of Cycles 1 and 2, and on Days 8, 9, and 16 of Cycle 1.  Day 1 samples for laboratory analyses can be drawn within 72 hours prior to 
dosing on Day 1 for all subsequent cycles after Cycle 1 only if clinically indicated.  
k Complete blood count (CBC) with differential, done locally, and includes the following:  Hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated 
differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count.  Screening results may be used for 
Cycle 1 Day 1 if obtained within 72 hours of Cycle 1 Day 1.  
l Coagulation tests, done locally if clinically indicated, and includes the following:  Prothrombin time, activated partial thromboplastin time, and international normalized ratio.  
m Screening pregnancy testing, done locally, for females of childbearing potential (FCBP) must have a sensitivity of at least 50 mIU/mL with TWO medically supervised tests performed before 
pomalidomide dosing starts.  One test must be obtained within 10–14 days and one test within 24 hours prior to the start of pomalidomide on Cycle 1 Day 1.  A medically supervised, serum 
pregnancy test will be done weekly during Cycle 1 (Days 1, 8, 15, and 22).  Starting with Cycle 2, serum pregnancy tests will be done within 24 hours  prior to each cycle of pomalidomide 
dosing in FCBP only.  Pregnancy tests will be repeated on Day 15 of Cycle 2 and beyond if menses are irregular (i.e., not within ± 7 days of a 28-day cycle) or menses are not present in FCBP.  
n Results for SPEP, UPEP, and SFLC, obtained locally, during Screening must be available before starting study drug treatment.  When the subject is on study drug, the disease response 
assessments will be performed at the end of each cycle (Day 22–28 or prior to dosing on Day 1 of the next cycle) for the first 18 months (Cycles 1–18), then every 8 weeks thereafter (starting 
with Cycle 20).  If the subject comes off study for reasons other than progressive disease, then disease response assessments will be performed every 4 weeks through 18 months on study, and 
then every 8 weeks thereafter.  Obtain blood for SPEP (please refer to Section 11.3 for collection times for SPEP Immunofixation, UPEP and UPEP Immunofixation with 24-hr urine, and sFLC) 
within 7 days prior to next Cycle study drug dosing.  If a response assessment indicates PD, confirmation of PD may be obtained any time at or before the next scheduled assessment. 
o Subjects are required to have a skeletal survey at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early Discontinuation. This does not need to be 
repeated if previously done within 30 days of consent.  If a skeletal survey was done more than 30 days before consent, it may be acceptable with the Sponsor’s study medical monitor approval. 
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.  If present at Baseline, 
bone lesion (s) must be monitored throughout the study only as needed to document response according to the IMWG URC and modified EBMT criteria or if clinically indicated.  For subjects 
who did not progress during treatment with bone lesions present at Baseline, skeletal survey will no longer be required.  During long-term follow-up, skeletal survey evaluation will also no 
longer be required. 
p Subjects are required to have a plasmacytoma evaluation if known or suspected clinically at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) and at End of Study Treatment/Early 
Discontinuation.  This does not need to be repeated if previously done within 30 days of consent.  If the assessment was done more than 30 days before consent, it may be acceptable with the 
Sponsor’s study medical monitor approval.  If present at Baseline, plasmacytoma evaluation is to be repeated during treatment only to document response according to the IMWG-URC and 
modified EBMT criteria or if clinically indicated.  If clinically indicated due to history of extramedullary disease, the same technique (may include ultrasound, CT scan, MRI, PET, or other 
standard of care method) must be employed for each measurement.  For subjects with plasmacytoma at Baseline and did not progress during treatment , plasmacytoma will no longer be 
required.  During long-term follow-up, plasmacytoma evaluation will also no longer be required. 
q Bone marrow aspirate or biopsy is required at Baseline (within 45 days prior to Cycle 1 Day 1 dosing) to quantitate percent myeloma cell involvement.  Obtain bone marrow aspirate sample for 
fluorescence in situ hybridization (FISH) studies.  A portion of the sample may be used for optional genomic biomarker analysis, for all patients who consent.   If Baseline bone marrow aspirate 
or biopsy were previously obtained and included cytogenetics and FISH (with results available) within 45 days prior to Cycle 1 Day 1 dosing, collection does not need to be repeated unless the 
patient consents to the optional biomarker genomic samples, which include collection of additional bone marrow aspirate(s).  Repeat bone marrow aspirate when appropriate to confirm 
achievement of stringent complete response (sCR) or complete response (CR) within 30 days (+ 5 days) of confirmation assessment.  Bone marrow aspirate will also be collected at disease 
progression if clinically indicated (may be collected at End of Study Treatment/Early Discontinuation due to PD; it will no longer be required during Long-term Follow-up) for subjects who 
consent to optional genomic biomarker analysis.   
r Optional genomic biomarker samples- blood and saliva:  For subjects who consent to participate, blood and saliva samples (in addition to a portion of the bone marrow aspirate obtained for 
FISH analysis; no new sample is required, as applicable) will be collected at Baseline (within 45 days prior to Cycle 1 Day 1 dosing). 
s Sampling times are indicated in Section 11.4 of the protocol, and volumes are provided in the Laboratory Manual. 
 
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CONFIDENTIAL 
APPENDIX B2 SCHEDULE OF STUDY ASSESSMENTS – PHASE 1B DOSE EXPANSION 2/7 SCHEDULE (CONT'D) 
t Oprozomib treatment will be administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 during 28-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any 
reason.  On days on which oprozomib and dexamethasone are administered concurrently (i.e., on Days 1, 2, 8, 9, 15, 16, 22, 23 of each cycle), dexamethasone should be taken at least 
30 minutes prior to oprozomib.  Oprozomib should be taken with food.  On the PK collection days, dosing of oprozomib in relation to the meal intake (within 2 hours before and 1 hour after 
dose) will be recorded. 
u Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle.  
v Pomalidomide will be administered Days 1–21 of each 28-day cycle up to Cycle 24.  Pomalidomide should be taken in the fasted state (i.e., 2 hours before or after a meal). 
w Record all AEs from time of consent through 30 days after the last dose of study drug or before start of subsequent anticancer treatment (whichever occurs first).  Start to record concomitant 
medications from 30 days prior to Day 1 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 eCRF. 
x All patients will be followed for survival status by telephone contact or other method approximately every 3 months (± 1 week), or as needed, until study closure. 
 
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CONFIDENTIAL 
APPENDIX C 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
Table D1 
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
o
If the serum and urine M-protein are not measurable, a decrease of > 90% in the
difference between the involved and uninvolved sFLC levels is required in place
of the M-protein criteria
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 present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is
also requiredd, e
Stable 

Not meeting criteria for CR, VGPR, PR, or PD
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 patients without measurable serum and urine M-protein levels:  the
difference between involved and uninvolved FLC levels (absolute increase must be
> 10 mg/dL)

Only in patients without measurable serum and urine M-protein levels and without
measurable disease by FLC levels, bone marrow plasma cell 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 
Footnotes are defined on next page 
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CONFIDENTIAL 
Table D1 Summary of International Myeloma Working Group-Uniform Response 
Criteria (IMWG-URC) (cont’d) 
Response 
Subcategorya 
Response Criteria 
Sources:  Blade 1998; Durie 2006; Rajkumar 2011. 
CR = complete response; sCR = stringent complete response; FLC = 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 progressive disease only needs to be met, and confirmed, in one parameter. 
b All response categories (CR, sCR, VGPR, PR) require two 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. 
c Presence/absence of clonal cells is based on 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 patients 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, patients with measurable disease restricted to 
SPEP will need to be followed only by SPEP.  Correspondingly, patients with measurable disease 
restricted to UPEP will need to be followed only by UPEP. 
e Determination of PD based on based on M-protein, hypercalcemia, or FLC while on study requires two 
consecutive assessments made at any time before classification of progressive disease 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. 
Approved
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Table D2 
Definition of Minimal Response per EBMT Criteria 
Minimal Response  
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 
 
If the serum and urine M-protein are not measurable, a decrease of 25%–49% in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria. 
 
For patients with nonsecretory 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) 
Sources:  Bladé 1998; Kyle 2009. 
EBMT = European Group for Blood and Marrow Transplantation; FLC = free light chain; MR = minimal 
response.  
a The response category MR requires 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. 
 
Approved 
 
 
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APPENDIX D 
EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER (EORTC) CORE MODULE (QLQ-C30) AND 
EORTC MULTIPLE MYELOMA MODULE (QLQ-MY20) 
Subjects should be instructed to fill out the EORTC QLC-C30 (Version 3) and 
EORTC QLC-MY20 questionnaires to the best of their abilities.  The study staff will be 
responsible for confirming that the subject has completed the questionnaires. 
Citations for the EORTC QLQ-C30 and the EORTC QLQ-MY20 are provided in the 
Reference List (Aaronson 1993; Fayers 2001; Cocks 2007). 
Approved 
 
 
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APPENDIX E 
NEUROTOXICITY SUBSCALE OF THE GYNECOLOGIC 
ONCOLOGY GROUP’S FUNCTIONAL ASSESSMENT OF CANCER THERAPY 
(FACT/GOG-NTX4 [VERSION 4]) 
Subjects with neurotoxicities should be instructed to fill out the FACT/GOG-Ntx4 
(Version 4) to the best of their abilities.  The study staff will be responsible for confirming 
that the subject has completed the questionnaire. 
Approved 
 
 
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APPENDIX F 
EQ-5D-5L (V.2) 
Subjects should be instructed to fill out the EQ-5D-5L (v.2) questionnaire to the best of their 
abilities.  The study staff will be responsible for confirming that the subject has completed 
the questionnaire. 
 
Approved 
 
 
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APPENDIX G 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCALE 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 
5 
Death 
Source:  Oken 1982 
 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
Approved 
 
 
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APPENDIX H 
DRUG-DRUG INTERACTION POTENTIAL OF OPROZOMIB 
AND POMALIDOMIDE 
Oprozomib 
Alfentanil 
Diergotamine 
Quinidine 
Astemizolea 
Ergotamine 
Sirolimus 
Cisapridea 
Fentanyl 
Tacrolimus 
Cyclosporine 
Pimozide 
Terfenadinea 
a Not available in the United States. 
Because oprozomib is a P-gp substrate, use of P-gp inhibitors and inducers (see table below) 
should be carefully monitored and such drugs should be substituted for others if necessary. 
Pomalidomide 
In accordance with the Pomalidomide Prescribing Information, use of the following 
concomitant medications is to be carefully monitored and these drugs should be substituted 
for others if necessary.  
Drugs That May Increase Pomalidomide Plasma Concentrations  
CYP3A, CYP1A2, or P-gp inhibitors:  Co-administration of POMALYST with drugs that are 
strong inhibitors of CYP1A2, CYP3A (e.g., ketoconazole) or P-gp could increase exposure 
and should be avoided.  
Drugs That May Decrease Pomalidomide Plasma Concentrations  
CYP3A, CYP1A2, or P-gp inducers:  Co-administration of POMALYST with drugs that are 
strong inducers of CYP1A2, CYP3A (e.g., rifampin) or P-gp could decrease exposure and 
should be avoided.  
Smoking 
Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction.  Subjects 
should be advised that smoking may reduce the efficacy of pomalidomide. 
Approved 
 
 
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The tables below provide lists of the inhibitors and inducers of concern.  
CYP 3A inhibitor 
CYP1A2 inhibitor 
P-gp inhibitor 
Strong: 
Strong: 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir, telithromycin, 
voriconazole 
ciprofloxacin 
enoxacin 
fluvoxamine 
amiodarone 
azithromycin 
captopril 
carvedilol 
clarithromycin 
conivaptan 
cyclosporine 
diltiazem 
dronedarone 
erythromycin 
felodipine 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
quercetin 
quinidine, ranolazine, ticagrelor, 
verapamil 
 
CYP 3A inducer 
CYP1A2 inducer 
P-gp inducer 
Strong: 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St John’s wort 
tipranavir/ritonavir 
 
Approved 
 
 
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APPENDIX I 
POMALIDOMIDE RISKS OF FETAL EXPOSURE, PREGNANCY 
TESTING GUIDELINES, AND ACCEPTABLE BIRTH CONTROL METHODS 
Risks Associated with Pregnancy 
Pomalidomide was found to be teratogenic in a developmental study in rabbits.  
Pomalidomide is an analogue of thalidomide.  Thalidomide is a known human teratogen that 
causes severe life‐threatening human birth defects.  If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to an unborn baby. 
Criteria for Females of Childbearing Potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman 
who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
Counseling 
For an FCBP, pomalidomide is contraindicated unless all of the following are met 
(i.e., FCBP must be counseled concerning the following risks and requirements prior to the 
start of pomalidomide study therapy): 
 She understands the potential teratogenic risk to the unborn child 
 She understands the need for effective contraception, without interruption, 28 days before 
starting study treatment, throughout the entire duration of study treatment, dose 
interruption, and 28 days after the End of Study Treatment 
 She should be capable of complying with effective contraceptive measures 
 She is informed and understands the potential consequences of pregnancy and the need to 
notify her study doctor immediately if there is a risk of pregnancy 
 She understands the need to commence the study treatment as soon as pomalidomide is 
dispensed following a negative pregnancy test 
 She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
 She acknowledges that she understands the hazards and necessary precautions associated 
with the use of pomalidomide 
Approved 
 
 
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The Investigator must ensure that females of childbearing potential: 
 Comply with the conditions for pregnancy risk minimization, including confirmation that 
she has an adequate level of understanding 
 Acknowledge the aforementioned requirements  
For a female NOT of childbearing potential, pomalidomide is contraindicated unless the 
following are met (i.e., all females NOT of childbearing potential must be counseled 
concerning the following risks and requirements prior to the start of pomalidomide study 
therapy): 
 She acknowledges that she understands the hazards and necessary precautions associated 
with the use of pomalidomide 
The effect of pomalidomide on spermatogenesis is not known and has not been studied. 
Therefore, male subjects taking pomalidomide must meet the following conditions (i.e., all 
males must be counseled concerning the following risks and requirements prior to the start of 
pomalidomide study therapy): 
 Understand the potential teratogenic risk if engaged in sexual activity with a woman of 
childbearing potential 
 Understand the need for the use of a condom, even if he has had a vasectomy, if engaged 
in sexual activity with a female of childbearing potential. 
Contraception 
Females of childbearing potential enrolled in this protocol must agree to use 2 reliable forms 
of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study:  1) for at least 28 days 
before starting study drug; 2) while participating in the study; 3) dose interruptions; 
and 4) for at least 28 days after study treatment discontinuation.  
The 2 methods of reliable contraception must include 1 highly effective method and 
1 additional effective (barrier) method.  An FCBP must be referred to a qualified provider of 
contraceptive methods if needed. 
Approved 
 
 
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The following are examples of highly effective and additional effective methods of 
contraception: 
 Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
 Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking pomalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended.  If a subject is currently using combined oral contraception the subject should 
switch to another one of the effective methods listed above.  The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. 
The efficacy of contraceptive steroids may be reduced during co‐treatment with 
dexamethasone. 
Implants and levonorgestrel‐releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding.  Prophylactic 
antibiotics should be considered, particularly in subjects with neutropenia. 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential 
who commit to complete abstinence, as outlined below. 
Approved 
 
 
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Before starting study drug 
Female Subjects 
Females of childbearing potential must have 2 negative pregnancy tests (sensitivity of at least 
50 mIU/mL) prior to starting pomalidomide.  The first pregnancy test must be performed 
within 10-14 days prior to the start of pomalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of pomalidomide.  The subject may not receive 
study drug until the investigator has verified that the results of these pregnancy tests are 
negative. 
Male Subjects 
Must practice complete abstinence or agree to use a condom during sexual contact with 
FCBP while participating in the study, during dose interruptions, and for at least 90 days 
following study drug discontinuation, even if he has undergone a successful vasectomy. 
During study participation and for 28 days following study drug discontinuation 
Female Subjects 
 Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days 
while on study, at study discontinuation, and at Day 28 following study drug 
discontinuation.  If menstrual cycles are irregular, the pregnancy testing must occur 
weekly for the first 28 days and then every 14 days while on study, at study 
discontinuation, and at Days 14 and 28 following study drug discontinuation. 
 At each visit, the investigator must confirm with the FCBP that she is continuing to use 
2 reliable methods of birth control. 
 Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. 
 If pregnancy or a positive pregnancy test does occur in a study subject, pomalidomide 
must be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be 
discontinued during this evaluation. 
 Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after study drug discontinuation. 
Approved 
 
 
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Male Subjects 
 Counseling about the requirement for condom use during sexual contact with FCBP and 
the potential risks of fetal exposure must be conducted at a minimum of every 28 days. 
 If pregnancy or a positive pregnancy test does occur in the partner of a male study subject 
during study participation, the investigator must be notified immediately. 
Additional precautions 
 Subjects should be instructed never to give this medicinal product to another person and 
to return any unused capsules to the investigator at the End-of-Treatment. 
 Subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of pomalidomide. 
 Male subjects should not donate semen or sperm during therapy or for at least 90 days 
following discontinuation of pomalidomide. 
 Only enough pomalidomide for 1 cycle of therapy may be dispensed with each cycle of 
therapy. 
Approved 
 
 
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APPENDIX J 
POMALIDOMIDE EDUCATION AND COUNSELLING 
GUIDANCE DOCUMENT 
Protocol Number:  OPZ007 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
Female 
If female, check one: 
 
FCBP (female of childbearing potential):  Sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at any time during 
the preceding 24 consecutive months) 
 
NOT FCBP 
To be completed prior to each dispensing of pomalidomide 
Do Not Dispense pomalidomide if: 
 The patient is pregnant. 
 No pregnancy tests were conducted for a FCBP. 
 The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual intercourse) [at least 28 days prior while 
taking pomalidomide, during dose interruption, and 28 days after discontinuation of 
pomalidomide]. 
FCBP 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
 Potential fetal harm:  If pomalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby.  Females are advised to avoid pregnancy while 
taking pomalidomide.  The teratogenic potential of pomalidomide in humans cannot be 
ruled out.  Females of childbearing potential must agree not to become pregnant while 
taking pomalidomide. 
Approved 
 
 
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 Using TWO reliable methods of birth control at the same time or complete abstinence 
from heterosexual intercourse [at least 28 days prior, while taking pomalidomide, during 
dose interruption, and 28 days after discontinuation of pomalidomide]. 
 Continuation of TWO reliable methods of birth control or complete abstinence if therapy 
is interrupted. 
 That even if she has amenorrhea she must comply with advice on contraception. 
 Use of one highly effective method and one additional method of birth control AT THE 
SAME TIME.  The following are examples of highly effective and additional effective 
methods of contraception: 
o Highly effective methods: 
– Intrauterine device (IUD) 
– Hormonal (birth control pills, injections, implants) 
– Tubal ligation 
– Partner’s vasectomy 
o Additional effective methods: 
– Male condom 
– Diaphragm 
– Cervical cap 
 Pregnancy tests before and during treatment, even if the patient agrees not to have 
reproductive heterosexual intercourse.  Two pregnancy tests will be performed prior to 
receiving study drug, one within 10–14 days and the second within 24 hours of the start 
of pomalidomide. 
 Frequency of pregnancy tests to be done: 
o Every week during the first 28 days of this study and a pregnancy test every 
28 days during the patient’s participation in this study if menstrual cycles are 
regular or every 14 days if cycles are irregular. 
o If the patient missed a period or has unusual menstrual bleeding. 
o When the patient is discontinued from the study and at Day 28 after study 
drug discontinuation if menstrual cycles are regular.  If menstrual cycles are 
irregular, pregnancy tests will be done at discontinuation from the study and at 
Days 14 and 28 after study drug discontinuation. 
 Stop taking pomalidomide immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible. 
 NEVER share pomalidomide with anyone else. 
Approved 
 
 
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 Do not donate blood while taking pomalidomide and for 28 days after stopping 
pomalidomide. 
 Do not breastfeed a baby while participating in this study and for at least 28 days after 
study drug discontinuation. 
 Do not break, chew, or open pomalidomide capsules. 
 Return unused pomalidomide to the investigator. 
3. Provide Pomalidomide Information Sheet to the patient. 
Female not of childbearing potential (natural menopause for at least 24 consecutive 
months, a hysterectomy, or bilateral oophorectomy): 
1. I counseled the female NOT of childbearing potential regarding the following: 
 Potential fetal harm (Refer to item #2 in FCBP). 
 NEVER share pomalidomide with anyone else. 
 Do not donate blood while taking pomalidomide and for 28 days after stopping 
pomalidomide. 
 Do not break, chew, or open pomalidomide capsules. 
 Return used pomalidomide capsules to the investigator. 
2. Provide Pomalidomide Information Sheet to the patient. 
Male 
1. I counseled the Male patient regarding the following: 
 Potential fetal harm (Refer to item #2 in FCBP). 
 To engage in complete abstinence or use a condom when engaging in sexual intercourse 
(including those who have had a vasectomy) with a FCBP, while taking pomalidomide, 
during dose interruptions, and for 28 days after stopping pomalidomide. 
 Males should notify their study doctor when their female partner becomes pregnant and 
female partners of males taking pomalidomide should be advised to call their healthcare 
provider immediately if they get pregnant. 
 NEVER share pomalidomide with anyone else. 
 Do not donate blood while taking pomalidomide and for 28 days after 
stopping pomalidomide. 
 Do not donate semen or sperm while taking pomalidomide and for 90 days after 
stopping pomalidomide. 
 Do not break, chew, or open pomalidomide capsules. 
Approved 
 
 
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 Return unused pomalidomide capsules to the Investigator. 
2. Provide Pomalidomide Information Sheet to the patient. 
Investigator/Counselor Name (Print): ____________________ 
(circle applicable) 
Investigator/Counselor Signature: _______________________ Date: _____/_____/_____ 
(circle applicable) 
Maintain a copy of the completed Education and Counseling Guidance Document in the 
patient records. 
Approved 
 
 
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APPENDIX K 
POMALIDOMIDE INFORMATION SHEET FOR PATIENTS 
ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Pomalidomide Information Sheet before you start taking pomalidomide and 
each time you get a new supply, since there may be new information.  This 
Pomalidomide Information Sheet does not take the place of an informed consent to 
participate in clinical research or talking to your study doctor or healthcare provider about 
your medical condition or your treatment. 
What is the most important information I should know about pomalidomide? 
Pomalidomide may cause birth defects (deformed babies) or death of an unborn baby.  
Pomalidomide is similar to the medicine thalidomide.  It is known that thalidomide causes 
life-threatening birth defects.  Pomalidomide has not been tested in pregnant women but may 
also cause birth defects.  Pomalidomide was found to cause birth defects when tested in 
pregnant rabbits. 
If you are a female who is able to become pregnant: 
 Do not take pomalidomide if you are pregnant or plan to become pregnant  
o For 28days before starting pomalidomide 
o While taking pomalidomide  
o During dose interruptions of pomalidomide  
o For 28 days after stopping pomalidomide 
 Stop taking pomalidomide if you become pregnant during pomalidomide treatment 
 Do not breastfeed while taking pomalidomide 
 You must have pregnancy testing done at the following times: 
o Within 10–14 days and again 24 hours prior to the first dose of pomalidomide 
o Weekly for the first 28 days 
o Every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
o If you miss your period or have unusual menstrual bleeding 
Approved 
 
 
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o 28 days after the last dose of pomalidomide (14 and 28 days after the last dose 
if menstrual periods are irregular) 
 You must either not have any sexual relations with a man or use 2 reliable, separate 
forms of effective birth control at the same time: 
o For 28 days before starting pomalidomide 
o While taking pomalidomide 
o During dose interruptions of pomalidomide and for 28 days after stopping 
pomalidomide 
o The study doctor will be able to advise you where to get additional advice on 
contraception. 
o If you suspect you are pregnant at any time during the study, you must stop 
pomalidomide immediately and immediately inform your study doctor.  
The study doctor will report all cases of pregnancy to Celgene Corporation 
and to Onyx Therapeutics. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to pomalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a male: 
The effect of pomalidomide on sperm development is not known and has not been studied. 
The risk to the fetus in females of childbearing potential whose male partner is receiving 
pomalidomide is unknown at this time. 
 Male patients (including those who have had a vasectomy) must either not have any 
sexual relations with a female who can become pregnant or a pregnant female or must 
use a condom during sexual intercourse with a pregnant female or a female that can 
become pregnant: 
o While you are taking pomalidomide 
o During dose interruptions of pomalidomide 
o For 90 days after you stop taking pomalidomide 
 Male patients should not donate sperm or semen while taking pomalidomide and for 
90 days after stopping pomalidomide. 
 If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor.  The study doctor will report all cases of 
pregnancy to Celgene Corporation and to Onyx Therapeutics. 
Approved 
 
 
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Pomalidomide restrictions in sharing pomalidomide and donating blood: 
 Do not share pomalidomide with other people.  It must be kept out of the reach of 
children and should never be given to any other person. 
 Do not give blood while you take pomalidomide and for 28 days after stopping 
pomalidomide. 
 Do not break, chew, or open pomalidomide capsules. 
 You will be supplied with no more than 1 cycle of pomalidomide 
 Return unused pomalidomide capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 
Approved 
 
 
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APPENDIX L 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 
Source: NIAID Adult AIDS Clinical Trials Group 
1.  Elicit Subjective Symptoms 
Ask the patient 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." 
Approved 
 
 
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APPENDIX M 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 
(CONT’D) 
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 
 
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 patient'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 patient 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 
R 
L 
 
 
Approved 
 
 
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APPENDIX M 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL 
(CONT’D) 
4. Evaluate Deep Tendon Reflexes 
With the patient seated, the examiner uses one hand to press upward on the ball of the foot, 
dorsiflexing the patient'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 patient 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 
 
From Peripheral Neuropathy 
Primary Care of Veterans with HIV 
Office of Clinical Public Health Programs 
Veterans Health Administration, 2009 
Approved 
 
 
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APPENDIX M 
SAMPLE BRIEF PAIN INVENTORY – SHORT FORM (BPI-SF) 
Source:  Cleeland 2006. 
 
Approved 
 
 
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Approved 
 
 
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APPENDIX N 
EXAMPLE ELECTRONIC SERIOUS ADVERSE EVENT 
CONTINGENCY REPORT FORM 
 
Approved 
 
 
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Approved 
 
 
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Approved 
 
 
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APPENDIX O 
EXAMPLE AMGEN PREGNANCY NOTIFICATION 
WORKSHEET 
 
 
Approved 
 
 
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APPENDIX P 
EXAMPLE AMGEN LACTATION NOTIFICATION 
WORKSHEET 
Approved 
 
 
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APPENDIX O 
SUMMARY OF CHANGES IN STUDY OPZ007 AMENDMENT 2.0 
Study OPZ007 was amended to include the following: 
 Revised inclusion and exclusion criteria to allow subjects with prior carfilzomib 
1.
exposure to be considered for inclusion in the study, if carfilzomib was not withdrawn 
due to toxicity. 
 Revised exclusion criteria to allow subjects with prior pomalidomide exposure to be 
2.
considered for inclusion in the dose-escalation portion of the study, if pomalidomide 
was neither dose-reduced nor withdrawn due to toxicity. 
 Revised alkylator language to specify that only subjects who have been treated with 
3.
adequate alkylator therapy are eligible to be considered for inclusion in the Phase 1b 
dose-escalation portion and Phase 3 portion of the study.  
 An exclusion criterion for previous GI bleed was added, proton-pump inhibitors were 
4.
changed from recommended to required, and additional text has been added to the 
dose modification table for nonhematologic toxicities and guidance to investigators 
because of toxicities observed in Study 2011-001. 
 The planned number of study sites for Part 1 of the study was increased from 20 to 35 
5.
sites, and the number of sites planned for the Dose-Escalation versus Dose-Expansion 
portions were clarified (15 and 20 sites, respectively). 
 The health-related quality of life measurement by Brief Pain Inventory – Short Form 
6.
was added as an exploratory objective and endpoint for the dose-expansion portion of 
the study, and as a secondary objective and endpoint for the Phase 3 portion of the 
study. 
 The text for secondary and exploratory objectives for Part 2 (randomized Phase 3 
7.
portion of the study) was revised for accuracy and consistency within the protocol. 
 The text “at sponsor discretion” was added for Part 1 (Phase 1b dose-escalation and 
8.
dose-expansion portions of the study) for flexibility if MTD cannot be achieved with 
4 mg of pomalidomide. 
 The “>” sign before Grade 3 fatigue in the Dose-Limiting Toxicities sections was 
9.
removed as there is no > Grade 3 fatigue per NCI-CTCAE. 
 The carfilzomib status stratification factors were revised to “carfilzomib 
10.
naïve/sensitive versus carfilzomib-refractory” to reflect allowed enrollment of 
carfilzomib-refractory patients to the study. 
 The sample size justification text was revised for clarity. 
11.
 The 8 hour postdose PK sample timepoint was removed, and a 3 hour postdose PK 
12.
sample timepoint was added to further characterize the PK profile for oprozomib. 
 Genomic measurements language was revised for clarity.  
13.
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 Endpoints language was revised for accuracy and consistency within the protocol. 
14.
 The efficacy and safety analyses sections were revised for clarity. 
15.
 The clinical background information for Study 2009-003 and Study 2011-001 were 
16.
updated per the most recent information. 
 Updated clinical background information was added for Study 2012-001 and OPZ003 
17.
for consistency with other oprozomib protocols. 
 Text that allows for the potential use of blister packs in Phase 3 of the study was 
18.
added to the Study Drug Accountability section. 
 The text “or fosaprepitant” was added for consistency with other oprozomib protocols 
19.
to allow IV administration of this antiemetic if needed. 
 Additional guidance for subjects who may experience orthostatic hypotension was 
20.
added. 
 A new subsection “11.5 Patient-Reported Outcomes Assessments” was added in the 
21.
Study Procedures section to further clarify these assessments in the dose-expansion 
and Phase 3 portions of the study. 
 The term “on study” and additional text was added for clarity on the long-term 
22.
follow-up based on disease progression status. 
 Subgroups of interest were revised for clarity, including potential inclusion of 
23.
subjects with prior carfilzomib exposure in the study. 
 For Appendices A1, A2, B1, B2, C1, and C2, “X”s in the Schedule of Assessment 
24.
tables were removed and added, and the text of footnotes was revised for clarity and 
consistency with the protocol body text. 
 Definition of “Baseline” (within 45 days prior to Cycle 1 Day 1 dosing) versus 
25.
Screening (Days -1 to -28 prior to Cycle 1 Day 1 dosing) was added, and skeletal 
survey, plasmacytoma evaluation, bone marrow aspirate and FISH analyses, and 
optional genomic biomarker assessments on blood and saliva in Appendices A1, A2, 
B1, B2, C1, and C2 were moved from Screening to Baseline to provide clarity on the 
use of the tests.  Screening tests are mandated to confirm eligibility, whereas baseline 
tests are used for disease assessments after patient enrollment. 
 The ACTG Brief Peripheral Neuropathy Screening Tool was added as Appendix M. 
26.
 The Brief Pain Inventory – Short Form was added as Appendix N. 
27.
In addition, administrative updates, editorial changes, and style and formatting revisions have 
been made to improve clarity and consistency throughout the document.  Changes noted in 
specific sections were also made in the protocol synopsis and elsewhere in the document, as 
applicable.  Significant changes are presented in the table below.  Detailed changed text is 
displayed for first major occurrence only.  All affected sections are noted in the “Section(s)” 
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column.  Text that has been deleted is presented in strikethrough format.  Added text is 
presented in bold format. 
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Section(s) 
Changed from 
Changed to 
Rationale 
Cover Page 
Signature Page 
Protocol 
Acceptance Page 
– 
Added:  Amendment 2 and 08 July 2014  
Updated for new 
amendment 
Confidentiality and 
approval statements 
This document is signed with electronic signatures at 
Onyx Therapeutics, Inc. (a wholly owned subsidiary of 
Onyx Pharmaceuticals, Inc.).  
This document is signed with electronic signatures at 
Onyx Therapeutics, Inc. (a wholly owned subsidiary of 
Onyx Pharmaceuticals Inc., an Amgen subsidiary).   
Updated confidentiality and 
approval statements where 
Onyx Therapeutics and 
Onyx Pharmaceuticals are 
listed to be consistent with 
current company name and 
study sponsorship 
Global:  In all 
sections listing 
“Inc.” 
– 
Deleted:  Inc.
Removed all references to 
“Inc.” to be consistent with 
current company name and 
study sponsorship 
Global:  Oprozomib 
tablets (where 
applicable) 
– 
Added:  ER 
In instances where this was 
missing, it was clarified that 
Oprozomib ER Tablets will 
be used 
Global:  Oprozomib 
and dexamethasone 
dosing regimens 
Days 1–2, 8–9, 15–16, and 22–23 
Days 1, 2, 8, 9, 15, 16, 22, and 23 
Oprozomib and 
dexamethasone dosing 
regimens were made 
consistent throughout the 
protocol 
Global:  In all 
instances of “End of 
Study” and “End of 
Treatment” 
“End of Study” or “End of Treatment” 
End of Study Treatment 
Corrected for accuracy and 
consistency throughout the 
protocol, and to distinguish 
between “End of Study” 
and “End of Study 
Treatment” 
Global:  In instances 
where the timing of 
disease response 
Treatment cycles will last 28 days.  Disease response 
assessments will be performed at the end of every 
4-week cycle for the first 18 months on study, and at 
Treatment cycles will last 28 days.  Disease response 
assessments will be performed at the end of every 
4-week cycle for the first 18 months on study, and at 
Added text for clarity 
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Section(s) 
Changed from 
Changed to 
Rationale 
assessments are 
described 
the end of every other cycle (every 8 weeks) thereafter. 
the end of every other cycle (every 8 weeks) thereafter, 
beginning with Month 20.
Global:  In instances 
of “first dose” 
(where applicable) 
“…first dose…” 
“…first dose of study drug...” or “…first dose of 
study treatment…” 
Added “of study drug” or 
“of study treatment” for 
clarity 
Synopsis:  Study 
objectives 
Section 4.1 Part 1:  
Phase 1b 
Dose-Escalation and 
Expansion Portions 
of the Study (by 
Schedule)
Part 1:  Phase 1b Dose Escalation and Expansion 
Portions of the Study  
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by schedule) 
Added text to clarify that 
each individual schedule 
will be assessed 
independently for Part 1 of 
the study  
Synopsis:  Study 
Objectives 
Section 4.1.3 
Exploratory 
Objectives 
Part 1:  Phase 1b Dose Escalation and Expansion 
Portions of the Study 
Exploratory Objectives 

To evaluate quality of life (in the dose expansion 
phase only) on the basis of patient-reported
outcomes tools listed below:
o Global health scale as measured by European 
Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Core Module 
(QLQ-C30) questionnaire
o Health status assessed by the European Quality 
of Life descriptive system
EQ-5D-5L (EuroQol EQ-5D-5L) 
o Disease symptoms subscale as measured by 
EORTC Multiple Myeloma Module (QLQ-
MY20) questionnaire
o Neurotoxicity symptoms as measured by the 
Functional Assessment of Cancer Therapy 
Scale / Gynecological Oncology Group –
Neurotoxicity (FACT/GOG-Ntx4 [(Version 
4]) for patients with neurotoxicity score 
Part 1:  Phase 1b Dose Escalation and Dose-Expansion 
Portions of the Study 
Exploratory Objectives 

To evaluate quality of life (in the dose-expansion 
phase portion only) on the basis of patient-reported 
outcomes (PRO) using the tools listed below:
o Bone pain and the impact of bone pain 
measured with the Brief Pain Inventory -
Short Form (BPI-SF) 
o Health-related quality of life (HRQoL) 
measured by the global health scale
status/QoL scale as measured by of the
European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life 
Core Module (QLQ-C30) questionnaire
o Health status assessed by the European Quality 
of Life descriptive system  EQ-5D-5L 
(EuroQol EQ-5D-5L) 
o Disease symptoms subscale as measured by 
the disease symptoms subscale of the
EORTC Multiple Myeloma Module 
Added Brief Pain Inventory 
– Short Form as a HRQoL 
exploratory objective in the 
dose-expansion portion of 
the study 
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Section(s) 
Changed from 
Changed to 
Rationale 
(QLQ-MY20) questionnaire 
o Neurotoxicity symptoms as measured by the
neurotoxicity subscale of the Functional
Assessment of Cancer Therapy Scale / 
Gynecological Oncology Group –
Neurotoxicity (FACT/GOG-Ntx4 [(Version 4]) 
for patients with neurotoxicity score
questionnaire
Synopsis:  
Secondary 
objectives 
Section 4.2.2 
Secondary 
Objectives 
Part 2:  Randomized Phase 3 Portion of the Study 
To compare the following between subjects treated 
with OPomd and those treated with Pomd:  
… 
Improvement in renal function over time, as defined 
by an increase in glomerular filtration rate (GFR) of 
at least 10 mL/min over baseline
Improvement in hemoglobin over time, as defined 
by an increase of at least 2 g/dL over baseline
Population–based PK parameters of oprozomib in 
the OPomd regimen 
Safety and tolerability 
Health-related quality of life (HRQoL) QLQ-30 
global health status score measured by EORTC 
QLQ-C30 
Disease symptoms as measured by the disease 
symptoms subscale of EORTC QLQ-MY20

Health status as assessed with EuroQol EQ-5D-5L 
Part 2:  Randomized Phase 3 Portion of the Study 

To compare the following between subjects treated 
with OPomd and those treated with Pomd: 
… 
o Incidence of improvement in renal function 
over time, as defined by an increase in
glomerular filtration rate (GFR) of at least 10 
mL/min over baseline at least once after the 
start of treatment
o Incidence of improvement in hemoglobin over 
time, as defined by an increase of at 
least 2 g/dL over baseline at least once after 
the start of treatment
o Population-based PK parameters of oprozomib
in the OPomd regimen  
o Safety and tolerability
o Bone pain and the impact of bone pain 
measured with the BPI-SF
o Health-related quality of life (HRQoL) QLQ-
30 global health status score measured by the
global health status/QoL scale of the EORTC 
QLQ-C30 
o Disease symptoms as measured by the disease 
symptoms subscale of EORTC QLQ-MY20
o Neurotoxicity symptoms as measured by the 
neurotoxicity subscale of the FACT/GOG-
Removed and added text for 
accuracy of secondary 
objectives for Part 2 of the 
study 
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Section(s) 
Changed from 
Changed to 
Rationale 
Ntx4 (Version 4) 
o Health status as assessed with EuroQol EQ-
5D-5L 

To evaluate population-based PK parameters of 
oprozomib in the OPomd regimen 
Synopsis:  Study 
objectives 
Section 4.2.3 
Exploratory 
Objectives 
Part 2:  Randomized Phase 3 Portion of the Study 
… 
Exploratory Objectives 
To compare the following between subjects treated 
with OPomd and those treated with Pomd:  
PFS and ORR as determined by the investigator
Duration of response (DOR), defined as the time 
from the first evidence of confirmed PR or better to
disease progression or death due to any cause as 
determined by the investigator according to the 
IMWG-URC and modified EBMT criteria
Clinical benefit rate (CBR) as determined by the 
investigator according to the modified EBMT 
criteria
Duration of clinical benefit (DOCB), defined as the 
time from first evidence of ≥ MR as determined by 
ORCA and the investigator according to the
modified EBMT criteria
Genomic biomarkers that may correlate with 
antitumor activity and resistance following 
treatment with proteasome inhibitors
The incidence of neuropathy events (defined as 
Grade 2 or higher peripheral neuropathy incidence)
The number of neuropathy events (defined as 
Grade 2 or higher peripheral neuropathy incidence, 
and neurotoxicity symptoms scores assessed by 
FACT/GOG-Ntx4 [Version 4]) 
Health status assessed with subscale scores of 
Part 2:  Randomized Phase 3 Portion of the Study 
… 
Exploratory Objectives 
To compare the following between subjects treated 
with OPomd and those treated with Pomd:  
PFS and ORR as determined by the investigator
according to the IMWG-URC
Duration of response (DOR), defined as the time 
from the first evidence of confirmed PR or better to
disease progression or death due to any cause as 
determined by the investigator according to the 
IMWG-URC and modified EBMT criteria
Clinical benefit rate (CBR) as determined by the 
investigator according to the IMWG-URC and the 
modified EBMT criteria
Duration of clinical benefit (DOCB), defined as the 
time from first evidence of ≥ MR or better to 
disease progression or death due to any cause, as 
determined by ORCA and the investigator 
according to the IMWG-URC and the modified
EBMT criteria 
Genomic biomarkers that may be correlated with 
antitumor activity and resistance following 
treatment with proteasome inhibitors
The incidence of neuropathy events (defined as 
Grade 2 or higher peripheral neuropathy incidence) 
The number of neuropathy events (defined as 
Grade 2 or higher peripheral neuropathy incidence, 
and neurotoxicity symptoms scores assessed by 
Revised text for corrections 
and for consistency within 
the protocol 
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Section(s) 
Changed from 
Changed to 
Rationale 
EORTC QLQ-C30 (excluding global health status 
scale) and EORTC QLQ-MY20 (excluding disease 
symptom subscale) 
FACT/GOG-Ntx4 [Version 4])  
Health status HRQoL assessed with subscale
scores of EORTC QLQ-C30 (excluding global 
health status scale) and EORTC QLQ-MY20
(excluding disease symptom subscale)
Synopsis:  Study 
design 
Synopsis:  Study 
population 
Section 5 Study 
design 
This study will include subjects with primary 
refractory or relapsed and refractory multiple 
myeloma, i.e., those who have demonstrated disease 
progression on or within 60 days of their last therapy, 
and who have received at least 2 prior lines of therapy 
including bortezomib and lenalidomide or thalidomide 
and adequate alkylator therapy.   
This study will include subjects with primary refractory 
or relapsed and refractory multiple myeloma, i.e., those 
who have demonstrated disease progression on or 
within 60 days of their last therapy, and who have 
received at least 2 prior lines of therapy (including 
bortezomib and lenalidomide and/or thalidomide, and 
in the dose-expansion and Phase 3 portions of the 
study only, been treated with adequate alkylator 
therapy). 
Revised alkylator language 
to specify that only subjects 
who have been treated with 
adequate alkylator therapy 
are eligible to be considered 
for inclusion in the Phase 
1b dose-escalation portion 
and Phase 3 portion of the 
study 
Synopsis:  Study 
design 
Part 1:  Phase 1b Dose Escalation and Expansion 
Portions of the Study 
… 
If the starting dose of oprozomib cannot be safely 
administered with the labeled pomalidomide dose, then 
up to 2 possible alternative paths for oprozomib with 
lower pomalidomide doses will be explored.  (See 
tables below for primary and alternative 
dose-escalation paths.)  Dose escalation will continue 
until ≥ 2 DLTs occur in a cohort, which will be 
declared the maximal administered dose for that dose 
level of pomalidomide (if more than 1 dose level is 
explored).  The prior cohort will be expanded to at 
least 6 subjects if not previously done to establish that 
dose as the MTD.  There may be more than 1 MTD for 
oprozomib if more than 1 dose level of pomalidomide 
is studied.  The MTD of oprozomib associated with 
each dose level of pomalidomide assessed will be the 
dose level where < 2 DLTs in 6 subjects are observed.   
There will be no planned maximum dose of oprozomib 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
… 
If the starting dose of oprozomib cannot be safely 
administered with the labeled pomalidomide dose, or 
at sponsor discretion, after the MTD with 4 mg of 
pomalidomide is determined, then up to 2 possible 
alternative paths for oprozomib with lower 
pomalidomide doses will be explored.  (See tables 
below for primary and alternative dose-escalation 
paths.)  Dose escalation will continue until sponsor 
discretion, the maximum planned dose of 
pomalidomide is reached, or ≥ 2 DLTs occur in a 
cohort, whoever occurs firstwhich will be declared the 
maximal administered dose for that dose level of 
pomalidomide (if more than 1 dose level is explored).  
The prior cohort will be expanded to at least 6 subjects 
if not previously done to establish that dose as the 
MTD.  There may be more than 1 MTD for oprozomib 
if more than 1 dose level of pomalidomide is studied.  
Added text for flexibility if 
MTD cannot be achieved 
with 4 mg of pomalidomide 
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Section(s) 
Changed from 
Changed to 
Rationale 
to be studied as it is being added to the FDA approved 
regimen of pomalidomide/dexamethasone.  The 
starting dose of oprozomib for the 5/14 schedule is 
150 mg, 3 dose levels below the established 5/14 
single-agent MTD of 240 mg.   
… 
The MTD of oprozomib associated with each dose 
level of pomalidomide assessed will be the dose level 
where < 2 DLTs in 6 subjects are observed.    
There will be is no planned maximum dose of 
oprozomib to be studied as it is being added to the FDA 
approved regimen of pomalidomide/dexamethasone, 
however, this could be imposed at any time during 
the course of the study, based on sponsor discretion.
The starting dose of oprozomib for the 5/14 schedule is 
150 mg, 3 dose levels below the established 5/14 
single-agent MTD of 240 mg.   
…
Synopsis:  Study 
design 
Section 5.1.1 Dose 
Escalation Schema 
for the 5/14 
Oprozomib Dosing 
Schedule 
The starting dose for the 5/14 schedule will be 150 mg 
of oprozomib and 4 mg of pomalidomide.  The 5/14 
primary and alternate paths are summarized below. 
5/14 Schedule Study Dose-Escalation Paths* 
*
There is no predefined maximum dose level of 
oprozomib being studied.
The starting dose for the 5/14 schedule will be 150 mg 
of oprozomib and 4 mg of pomalidomide.  The 5/14 
primary and alternate paths are summarized below; 
these are examples, and are not inclusive of all 
possible dose-escalation paths.
5/14 Schedule Primary Study Dose-Escalation Paths*a 
5/14 = Dosing on Days 1–5 and 15–19; Dex = 
dexamethasone; OPZ = oprozomib; Pom = pomalidomide. 
* a There is no predefined maximum dose level of 
oprozomib being studied. 
Added text to clarify that 
the dose-escalation paths 
are examples, and not 
inclusive of all possible 
dose-escalation paths. 
Revised in schema “Dex 
20 mg Days 1, 2, 8, 9…” 
for consistency with the rest 
of the protocol  
Synopsis Study 
Table 3  Primary Dose-Escalation Path for Oprozomib 
Table 3  Primary Dose-Escalation Path for Oprozomib 
Revised titles and notes for 
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Design 
Section 5.1.1 Dose 
Escalation Schema 
for the 5/14 
Oprozomib Dosing 
Schedule 
Section 5.1.2 Dose 
Escalation Schema 
for the 2/7 
Oprozomib Dosing 
Schedule 
and Pomalidomide on 5/14 Schedule in Phase 1b 
… 
Note:  This is an example of the primary dose-
escalation cohort and dose-escalation will continue in 
30 mg increments of oprozomib until the MTD is 
identified. 
Table 6  Primary Dose-Escalation Path for Oprozomib 
and Pomalidomide on the 2/7 Schedule in Phase 1b 
… 
Note:  This is an example of the primary dose-
escalation cohort and dose-escalation will continue in 
30 mg increments of oprozomib until the MTD is 
identified. 
and Pomalidomide on 5/14 Schedule with 
Pomalidomide 4 mg in Phase 1b 
… 
Note:  This is an example of the primary 
dose-escalation cohort and dose-escalation will 
continue in 30-mg increments of oprozomib at sponsor 
discretion or until the MTD is identified. 
Table 6  Primary Dose-Escalation Path for Oprozomib 
and Pomalidomide on the 2/7 Schedule with 
Pomalidomide 4 mg in Phase 1b 
… 
Note:  This is an example of the primary 
dose-escalation cohort and dose-escalation will 
continue in 30-mg increments of oprozomib at sponsor 
discretion or until the MTD is identified. 
Table 3 and Table 6 for 
clarity. 
Synopsis:  Study 
design 
Section 5.1.1 Dose 
Escalation Schema 
for the 5/14 
Oprozomib Dosing 
Schedule 
Section 5.1.2 Dose 
Escalation Schema 
for the 2/7 
Oprozomib Dosing 
Schedule 
Table 4 Alternative Dose-Escalation Path 1 for 
Oprozomib andPomalidomide 
on 5/14 Schedule in Phase 1b if Cohort 1a Exceeds the 
MTD 
Table 5 Alternative Dose-Escalation Path 2 for 
Oprozomib and Pomalidomide in Phase 1b if Cohort 
1b Exceeds the MTD 
Table 7 Alternative Dose-Escalation Path 1 for 
Oprozomib and Pomalidomide 
on 2/7 Schedule in Phase 1b if Cohort 101a Exceeds 
the MTD 
Table 8 Alternative Dose-Escalation Path 2 for 
Oprozomib and Pomalidomide on 2/7 Schedule 
in Phase 1b if Cohort 101b Exceeds the MTD 
Table 4 Alternative Dose-Escalation Path 1 for 
Oprozomib and Pomalidomide 
on 5/14 Schedule with Pomalidomide in Phase 1b if 
Cohort 1a Exceeds the MTD, or at Sponsor 
Discretion
Table 5 Alternative Dose-Escalation Path 2 for 
Oprozomib and Pomalidomide on 5/14 Schedule with 
Pomalidomide in Phase 1b if Cohort 1b Exceeds the 
MTD, or at Sponsor Discretion
Table 7 Alternative Dose-Escalation Path 1 for 
Oprozomib and Pomalidomide 
on 2/7 Schedule with Pomalidomide in Phase 1b if 
Cohort 101a Exceeds the MTD or at Sponsor 
Discretion
Table 8 Alternative Dose-Escalation Path 2 for 
Added “or at Sponsor 
Discretion” to Table 4, 
Table 5, Table 7, and Table 
8 titles match earlier added 
text, and revised titles for 
clarity 
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Date: 
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Oprozomib and Pomalidomide on 2/7 Schedule with 
Pomalidomide in Phase 1b if Cohort 101b Exceeds the 
MTD or at Sponsor Discretion
Synopsis:  Study 
design 
Section 5.1.2 Dose 
Escalation Schema 
for the 2/7 
Oprozomib Dosing 
Schedule 
The starting doses for the 2/7 oprozomib dosing 
schedule will be 210 mg of oprozomib and 4 mg of 
pomalidomide.  The 2/7 primary and alternate paths 
are summarized below. 
2/7 Schedule Study Dose-Escalation Paths  
The starting doses for the 2/7 oprozomib dosing 
schedule will be 210 mg of oprozomib and 4 mg of 
pomalidomide.  The 2/7 primary and alternate paths are 
summarized below; these are examples, and are not 
inclusive of all possible dose-escalation paths.
2/7 Schedule Primary Study Dose-Escalation Pathsa  
2/7 = Dosing on Days 1, 2, 8, 9, 15, 16, 22, and 23; Dex = 
dexamethasone; OPZ = oprozomib; Pom = pomalidomide. 
a There is no predefined maximum dose level of 
oprozomib being studied. 
Added text to clarify that 
the dose-escalation paths 
are examples, and not 
inclusive of all possible 
dose-escalation paths. 
Revised in schema “Dex 
20 mg Days 1, 2, 8, 9…” 
for consistency with the rest 
of the protocol. 
Added note below figure 
for consistency with the 
figure of 5/14 Schedule 
Study Dose-Escalation 
Paths. 
Synopsis:  Study 
design 
At the sponsor’s discretion, once the MTD for 
oprozomib is reached on 1 or both schedules, 
additional dose escalation with oprozomib may 
continue with lower doses of pomalidomide down to 
the 2 mg dose level. 
The sponsor, with input from the Cohort Safety 
Review Committee ([CSRC] consisting of 
investigators, sponsor’s medical monitor, and 
sponsor’s Drug Safety representative), will determine 
which single dose combination to use for the dose 
expansion (i.e., the RP3D) portion of the study.  The 
At the sponsor’s discretion, once the MTD for 
oprozomib is reached on 1 or both schedules, or if the 
initial cohort exceeds the MTD, additional dose 
escalation with oprozomib may continue with lower 
doses of pomalidomide down to the 2-mg dose level. 
The sponsor, with input from the Cohort Safety Review 
Committee ([CSRC] consisting of investigators, 
sponsor’s medical monitor, and sponsor’s drug safety 
representative, will determine which single dose 
combination dose and schedule of oprozomib in 
combination with Pomd to use for the dose-expansion 
Revised text for consistency 
within the protocol 
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RP3D may differ from the MTD, but will not be higher 
than the MTD, and will be selected based upon the 
assessment of the safety, tolerability, PK, PDn, 
preliminary activity, and other variables to be observed 
across multiple cycles of combination therapy.   
(i.e., the RP3D) portion of the study.  The sponsor has 
the option of expanding 1 or both schedules in order 
to establish the RP3D and schedule.  The RP3D may 
differ from the MTD, but will not be higher than the 
MTD, and will be selected based upon the assessment 
of the safety, tolerability, PK, PDn, preliminary 
activity, and other variables to be observed across 
multiple cycles of combination therapy.   
Synopsis:  Study 
Design 
Section 10.5 
Definition of 
Dose-Limiting 
Toxicity 
Dose-Limiting Toxicities 
… 
o > Grade 3 fatigue lasting < 14 days is not considered 
a DLT
… 
Dose-Limiting Toxicities 
… 
o > Grade 3 fatigue lasting < 14 days is not considered 
a DLT
… 
Removed “>” sign for 
accuracy as there is no 
> Grade 3 fatigue per 
NCI-CTCAE 
Synopsis:  Study 
Design 
Section 5.1.4 
Subject 
Replacement 
In the Phase 1b portion of the study, subjects must 
meet the following criteria to be considered evaluable 
for MTD determination during the 4-week DLT 
evaluation period unless a study drug-related DLT 
occurs before the subject receives all planned doses of 
oprozomib for both the 5/14 and 2/7 dosing schedules: 
… 
In the Phase 1b portion of the study, subjects must meet 
the following criteria to be considered evaluable for 
MTD determination during the 4-week DLT evaluation 
period unless a study drug-related DLT occurs before 
the subject receives all planned doses of oprozomib for 
both the 5/14 and 2/7 dosing schedules: 
… 
Deleted text for clarity 
Synopsis:  Study 
Design 
Section 5.1.5 Dose 
Expansion 
Section 5.2 Part 2:  
Randomized Phase 
3 Portion of the 
Study 
Dose Expansion 
The criteria for selecting the RP3D for 1 or both 
schedules of oprozomib at the sponsor’s discretion will 
include assessment of the safety, tolerability, and 
preliminary activity observed across multiple cycles of 
therapy.  In addition, both PK and PDn assessments to 
demonstrate adequate exposure and proteasome 
inhibition will be a key factor.  Therefore, the RP3D 
may differ from the MTD.  Once the MTD(s) has been 
determined and the RP3D has been selected, a 
minimum of 20 additional subjects for 1 or both 
schedules of oprozomib at the sponsor’s discretion will 
be enrolled in the dose-expansion portion of Part 1in 
order to continue the evaluation of the safety and 
Dose Expansion 
The criteria for selecting the RP3D for 1 or both 
schedules of oprozomib at the sponsor’s discretion will 
include assessment of the safety, tolerability, and 
preliminary activity observed across multiple cycles of 
therapy.  In addition, both PK and PDn assessments to 
demonstrate adequate exposure and proteasome 
inhibition will be a key factor.  Therefore, the RP3D 
may differ from the MTD.  Once the MTD(s) has been 
determined and the RP3D recommended dose for the 
expansion phase has been selected, a minimum of 
20 additional subjects for 1 or both schedules of 
oprozomib at the sponsor’s discretion will be enrolled 
in the dose-expansion portion of Part 1in order to 
Revised text for clarity 
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Date: 
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efficacy of the regimen as a prelude to initiation of the 
Phase 3 portion of the study.  The safety of subjects in 
the Dose Expansion will be monitored on an ongoing 
basis by the CSRC during bimonthly calls.  Enrollment 
to the Phase 3 portion will not commence until the 
CSRC has evaluated all available safety information 
from a minimum of 10 subjects who have completed 
≥ 2 cycles of therapy at the R3PD and enrollment of 
the remaining 10 subjects in Dose Expansion has 
occurred in 1 or both schedules if both were opened.   
continue the evaluation of the safety and efficacy of the 
regimen as a prelude to initiation of the Phase 3 portion 
of the study.  The safety of subjects in the Dose 
Expansion will be monitored on an ongoing basis by 
the CSRC during bimonthly regularly scheduled calls.  
Enrollment to the Phase 3 portion will not commence 
until the CSRC has evaluated all available safety 
information from a minimum of 10 subjects who have 
completed ≥ 2 cycles of therapy at the R3PD and 
enrollment of the remaining 10 subjects in Dose 
Expansion has occurred in 1 or both schedules if both 
were opened.  This information will inform the 
selection of a RP3D and schedule by the sponsor 
and CSRC.
Synopsis:  Study 
design 
Section 5.4.1 
Randomization 
Section 14.5.2.2 
Part 2 Randomized 
Phase 3 Portion of 
the Study 
Part 2:  Randomized Phase 3 Portion of the Study 
Randomization 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus oprozomib 
placebo, respectively.  Central randomization will be 
implemented in this part of the study through the use of 
an interactive voice response system / interactive web 
response system (IVRS/IWRS).  Eligible subjects will 
be stratified by: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more 

Carfilzomib status:  Carfilzomib naïve versus
carfilzomib sensitive 
Within each stratum, treatment assignment will be 
made using a random permuted blocked randomization 
scheme. 
Part 2:  Randomized Phase 3 Portion of the Study 
Randomization 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus oprozomib 
placebo, respectively.  Central randomization will be 
implemented in this part of the study through the use of 
an Interactive Voice Response System / Interactive 
Web Response System (IVRS/IWRS).  Eligible 
subjects will be stratified by: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  Carfilzomib-naïve/sensitive
versus carfilzomib-refractory sensitive.
Carfilzomib-sensitive multiple myeloma 
patients are defined as having had previously 
achieved a PR or greater with therapy that 
includes carfilzomib (or carfilzomib 
monotherapy), and did not experience PD 
until more than 60 days after their last dose 
of carfilzomib.  Carfilzomib-refractory 
Correction made to remove 
“oprozomib” before 
“placebo” 
Revised carfilzomib status 
stratification factors to 
reflect potential inclusion of 
subjects with prior 
carfilzomib exposure in the 
study 
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Date: 
Oprozomib
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multiple myeloma is defined as disease that is 
nonresponsive while on primary or salvage 
therapy that includes carfilzomib, or that 
progresses on or within 60 days of last 
therapy.
Within each stratum, treatment assignment will be 
made using a random permuted blocked randomization 
scheme.       
Synopsis:  Number 
of investigational 
sites 
Section 5 Study 
Design 
Up to 20 study sites will participate in Part 1 of the 
study (Phase 1b Dose-Escalation and Dose-Expansion 
portion of the study). 
Approximately 70 sites will participate in Part 2 of the 
study (Phase 3 portion of the study).
Approximately Up to 35 20 study sites will participate 
in Part 1 of the study (15 sites for the Phase 1b 
dose-escalation and 20 sites for the dose-expansion 
portions of the study). 
An additional 35 sites, for a total of approximately 
70 sites will participate in Part 2 of the study (Phase 3 
portion of the study).
Increased the planned 
number of study sites for 
Part 1 of the study, and 
clarified how many sites are 
planned for the 
Dose-Escalation versus 
Dose-Expansion portions 
Synopsis:  Planned 
number of subjects 
Section 14.7 
Determination of 
Sample Size 
Part 1:  Phase 1b (Dose Escalation and Expansion 
Portions of the Study) 
A total enrollment of approximately 82 subjects is 
planned for Part 1 of the study.  During the Phase 1b 
Dose Escalation portion of Part 1, up to 21 subjects 
will be enrolled for each schedule.   
… 
Part 2:  Randomized Phase 3 Portion of the Study 
During Part 2, the planned enrollment is approximately 
270 subjects.   
Therefore, a total enrollment of approximately 352 
subjects is planned. 
Part 1:  Phase 1b (Dose-Escalation and 
Dose-Expansion Portions of the Study) 
A total enrollment of up to approximately 82 subjects 
is planned for Part 1 of the study.  During the Phase 1b 
dose-escalation portion of Part 1, approximately 
21 subjects will be enrolled for each schedule. 
… 
Part 2:  Randomized Phase 3 Portion of the Study 
During Part 2, the planned enrollment is approximately 
270 subjects.   
Therefore, a the total planned enrollment of will be 
approximately 352 subjects is planned. 
Revised text for flexibility 
and for clarity 
Synopsis:  Sample 
size justification 
Part 2:  Randomized Phase 3 Portion of the Study 
The estimated sample size for the Phase 3 portion of 
the study is based on comparison of PFS (death or 
disease progression events) distributions for subjects 
treated with Pomd plus placebo versus those treated 
with OPomd based on the log-rank test statistic.  It is 
assumed that the risk of a PFS event for subjects 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, 157 PFS events 
are required to detect a 45.7% reduction in the risk 
of PFS (HR=0.543) with 95% power and a 1-sided 
significance level of 0.025.  Enrollment of 
270 subjects (2:1 OPomd versus Pomd, respectively) 
is consistent with reaching the required 157 events 
Revised text for clarity 
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Date: 
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randomized to OPomd will be 45.7% lower than for 
subjects randomized to Pomd.  Therefore, the target 
hazard ratio (HR) is 0.543.  The statistical hypothesis 
being tested is as follows: 
H0:  PFS (Pomd) = PFS (OPomd) 
Ha:  PFS (Pomd) < PFS(OPomd) 
For a 1-sided α = 0.025 level of significance and 95% 
power, 157 PFS events are required.   
… 
in approximately 14 months, assuming an 
enrollment rate of approximately 22 subjects per 
month, a drop-out rate of 5% at 18 months, and a 
median PFS of 3.8 and 7 months for Pomd and 
OPomd, respectively.  The estimated sample size for 
the Phase 3 portion of the study is based on comparison 
of PFS (death or disease progression events) 
distributions for subjects treated with Pomd plus 
placebo versus those treated with OPomd based on the 
log-rank test statistic.  It is assumed that the risk of a 
PFS event for subjects randomized to OPomd will be 
45.7% lower than for subjects randomized to Pomd.  
Therefore, the target hazard ratio (HR) is 0.543.  
The statistical hypothesis being tested is as follows: 
H0:  PFS (Pomd) = PFS (OPomd) 
Ha:  PFS (Pomd) < PFS(OPomd) 
For a 1-sided α = 0.025 level of significance and 95% 
power, 157 PFS events are required.  
Synopsis:  Study 
population 
The study population will consist of subjects with 
primary refractory or relapsed and refractory, 
symptomatic multiple myeloma that have been treated 
with at least 2 prior lines of therapy including 
lenalidomide and bortezomib or thalidomide and been 
treated with adequate alkylator therapy, who have 
progressed on or within 60 days of their last therapy, 
and who are considered to be appropriate for this 
clinical study by their treating physicians. 
The study population will consist of subjects with 
primary refractory or relapsed and refractory, 
symptomatic multiple myeloma that had been treated 
with, i.e., those who have demonstrated disease 
progression on or within 60 days of their last 
therapy, and who have received at least 2 prior lines 
of therapy (including lenalidomide and bortezomib and 
lenalidomide and/or thalidomide, and in the 
dose-expansion and Phase 3 portions of the study 
only, been treated with adequate alkylator), and who 
have progressed on or within 60 days of their last 
therapy, and who are considered to be appropriate for 
this clinical study by their treating physicians. 
Revised text for consistency 
within the protocol 
Synopsis:  Inclusion 
Criteria 
Section 6.1 
Inclusion Criteria 
1.
Multiple myeloma that is primary refractory or 
relapsed and refractory after at least 2 lines of 
standard therapy for multiple myeloma including:
a. ≥ 2 consecutive cycles of both bortezomib 
1.
Multiple myeloma that is primary refractory, or 
relapsed and refractory, or intolerant after at
least 2 lines of standard therapy for multiple 
myeloma including:
Revised alkylator language 
to specify that only subjects 
who have been treated with 
adequate alkylator therapy 
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and lenalidomide or thalidomide (alone or in 
combination) 
i.
Patients who received bortezomib as their 
last therapy who were not refractory but 
developed bortezomib intolerance, as 
defined by the development of Grade 2 
peripheral neuropathy with pain or 
≥ Grade 3 peripheral neuropathy after 
≥ 2 consecutive cycles, are eligible 
b. Adequate alkylator therapy defined as: 
i.
High-dose melphalan or other alkylating
agent as conditioning for autologous or
allogeneic stem cell transplant (SCT), or 
ii.
≥ 6 cycles of induction therapy, or 
iii. Progressive disease after ≥ 2 cycles
a. ≥ 2 consecutive cycles of both bortezomib 
and lenalidomide or thalidomide (alone or in 
combination)
i.
Patients who received bortezomib as their 
last therapy who were not refractory but 
developed bortezomib intolerance, as 
defined by the development of Grade 2 
peripheral neuropathy with pain or 
≥ Grade 3 peripheral neuropathy after 
≥ 2 consecutive cycles, are eligible 
b. In the dose-expansion and Phase 3 portions 
of the study only:  In addition to the above, 
treatment with adequate alkylator therapy 
defined as:
i.
High-dose melphalan or other alkylating
agent as conditioning for autologous or
allogeneic stem cell transplant (SCT), or
ii.
≥ 6 cycles of induction therapy, or
iii. Progressive disease after ≥ 2 cycles
are eligible to be considered 
for inclusion in the Phase 
1b dose-escalation portion 
and Phase 3 portion of the 
study 
Moved definition of 
bortezomib intolerance 
from Inclusion Criterion 1 
to Inclusion Criterion 3 for 
clarity 
Synopsis:  Inclusion 
Criteria 
Section 6.1 
Inclusion Criteria 
2.
Measurable disease as indicated by 1 or more of 
the following:
d. Serum M-protein ≥ 500 mg/dL 
e. Urine M-protein ≥ 200 mg/24 h 
f.
For subjects without measurable M-protein 
by serum protein electrophoresis (SPEP) or 
urine protein electrophoresis (UPEP), 
involved free light chain (FLC) 
concentration ≥ 10 mg/dL provided serum 
free light chain (SFLC) ratio is abnormal
2.
Measurable disease as indicated by 1 or more of 
the following:
a. Serum M-protein ≥ 500 mg/dL 
b. Urine M-protein ≥ 200 mg/24 h 
c. Only for subjects without measurable M-
protein by serum protein electrophoresis 
(SPEP) or and urine protein electrophoresis 
(UPEP), involved free light chain (FLC) 
concentration ≥ 10 mg/dL provided serum free 
light chain (SFLC) ratio is abnormal
Added “only” and added 
“and” for clarity 
Synopsis:  Inclusion 
Criteria 
Section 6.1 
Inclusion Criteria
3. Disease progression on or within 60 days of
completion of the last therapy as long as the last 
treatment was not carfilzomib.
3. Disease progression on or within 60 days of
completion of the last therapy, or intolerance to 
bortezomib if received as their last therapy as 
long as the last treatment was not carfilzomib.
a. Patients who received bortezomib as their 
last therapy who were not refractory but 
Revised to allow subjects 
with prior carfilzomib 
exposure to be considered 
for inclusion in the study  
Moved definition of 
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Date: 
Oprozomib
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developed bortezomib intolerance, as defined 
by the development of Grade 2 peripheral 
neuropathy with pain or ≥ Grade 3 
peripheral neuropathy after ≥ 2 consecutive 
cycles, are eligible   
bortezomib intolerance 
from Inclusion Criterion 1 
to Inclusion Criterion 3 for 
clarity 
Synopsis:  Inclusion 
Criteria 
Section 6.1 
Inclusion Criteria 
4. Prior carfilzomib is not required but is allowed if a 
subject 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 subject: 
a. Had at least a PR to prior carfilzomib therapy
b. Was not removed from carfilzomib therapy due 
to toxicity 
c. Was not removed from carfilzomib therapy for 
progressive disease nor experienced 
progressive disease within 6 months of any 
prior carfilzomib therapy.
4.
Prior carfilzomib is not required but is allowed if 
a subject was not removed from carfilzomib 
therapy due to toxicity, unless approved by the 
Onyx study medical monitor 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 
subject:  
a. Had at least a PR to prior carfilzomib therapy
b. Was not removed from carfilzomib therapy 
due to toxicity 
c. Was not removed from carfilzomib therapy 
for progressive disease nor experienced 
progressive disease within 6 months of any 
prior carfilzomib therapy. 
Revised to allow subjects 
with prior carfilzomib 
exposure to be considered 
for inclusion in the study, if 
carfilzomib was not 
withdrawn due to toxicity 
Synopsis:  
Exclusion Criteria 
Section 6.2 
Exclusion Criteria 
7. Prior treatment of any duration with 
pomalidomide
7.
Prior  treatment of any duration with
pomalidomide exposure
a. For the dose-escalation portion of the 
study:  Subjects requiring pomalidomide 
dose reduction or removal due to toxicity
b. For the dose-expansion portion and Part 2 
of the study:  Prior pomalidomide 
treatment of any duration
Revised to allow subjects 
with prior pomalidomide 
exposure to be considered 
for inclusion in the 
dose-escalation portion of 
the study, if pomalidomide 
was neither dose-reduced 
nor withdrawn due to 
toxicity 
Synopsis:  
Exclusion Criteria 
Section 6.2 
Exclusion Criteria 
11. Primary refractory or relapsed and refractory to
carfilzomib alone or in combination with at least 2
cycles at a dose of at least 20/27 mg/m2
11. Primary refractory or relapsed and refractory to 
carfilzomib alone or in combination with at least 2 
cycles at a dose of at least 20/27 mg/m2  
Revised to allow subjects 
with prior carfilzomib 
exposure to be considered 
for inclusion in the study; 
subsequent Exclusion 
Criteria were renumbered 
accordingly 
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Date: 
Oprozomib
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Changed to 
Rationale 
Synopsis:  
Exclusion Criteria 
Section 6.2 
Exclusion Criteria 
_ 
14. History of previous clinically significant GI 
bleed in the 6 months prior to first dose of 
study drug
Added an Exclusion 
Criterion for previous GI 
bleed to potentially reduce 
the risk for GI hemorrhage; 
subsequent Exclusion 
Criteria were renumbered 
accordingly 
Synopsis:  Criteria 
for evaluation:  
Other  
Section 11.4.1.1. 
Phase 1b Dose 
Escalation and 
Expansion 
Section 14.5.5 
Pharmacokinetic 
Analyses 
Pharmacokinetics 
In the Phase 1b Dose Escalation and Expansion 
portions of the study, blood samples will be collected 
from all subjects for determination of plasma 
concentrations of oprozomib at 1 predose time point 
and up to 7 postdose time points on Day 1 of Cycle 1 
and Cycle 2 (0.25, 0.5, 1, 2, 4, 6, and 8 hours postdose) 
and 1 predose time point on Day 2 of Cycle 1 for both 
schedules. 
In the Phase 3 portion of the study, PK samples will be 
collected from all randomized subjects at Cycle 1 Day 
1 and Cycle 3 Day 1 and will be analyzed for 
oprozomib concentrations. 
Pharmacokinetics 
In the Phase 1b dose-escalation and dose-expansion 
portions of the study, blood samples will be collected 
from all subjects for determination of plasma 
concentrations of oprozomib at 1 predose time point 
and up to 7 postdose time points on Day 1 of Cycle 1 
and Cycle 2 (0.25, 0.5, 1, 3, 2, 4, and 6, and 8 hours 
postdose) and 1 predose time point on Day 2 of Cycle 1 
for both schedules. 
In the Phase 3 portion of the study, PK samples will be 
collected from all randomized subjects at Cycle 1 Day 
1 and Cycle 3 Day 1 and will be analyzed for 
oprozomib concentrations in OPomd subjects. 
Removed 8 hour postdose 
PK sample timepoint and 
added 3 hour postdose PK 
sample timepoint to further 
characterize the PK profile 
for oprozomib 
Added text for clarity 
Synopsis:  Criteria 
for evaluation:  
Other  
Section 11.4.3 
Genomic 
Measurements
Genomics 
Analysis of genomic biomarkers that may predict 
response and resistance following treatment with 
proteasome inhibitors will be conducted for all subjects 
from all phases of the study who consent to optional 
genomic biomarker analysis.  These analyses will be 
performed on Screening bone marrow aspirate (a 
portion of the bone marrow aspirate sample obtained at 
Screening will be used; no additional sample is 
required), blood, and saliva.  Additional bone marrow 
samples for biomarkers may be collected at the time of 
progression or at the End of Treatment visit from all 
subjects who consent. 
Genomics 
Analysis of genomic biomarkers that may predict 
response and resistance following treatment with 
proteasome inhibitors will be conducted for all subjects 
receiving oprozomib from all phases of the study who 
consent to optional genomic biomarker analysis.  These 
analyses will be performed on Screening a bone 
marrow aspirate (obtained at Baseline (within 45
days prior to Cycle 1 Day 1 dosing, only after all 
other eligibility criteria have been met (a portion of 
the bone marrow aspirate obtained at Screening 
Baseline will be used; no additional sample is 
required), as well as a sample of blood, and saliva, 
also collected at Baseline.  Bone marrow aspirate or 
Revised text for clarity; 
definition of “Baseline”  
added 
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biopsy collection does not need to be repeated if 
previously completed within 45 days prior to Cycle 
1 Day 1 dosing, and for Phase 3 only, if it was 
processed at the central laboratory.  Additional bone 
marrow samples for biomarkers may be collected at the 
time of disease progression or at the (End of Study 
Treatment visit due to progressive disease [PD], or 
Long-term Follow-up) from all subjects who consent.
Synopsis:  
Statistical methods 
and analyses 
Section 14.1 Study 
Endpoints  
Endpoints 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion Portions of the Study 
Primary Endpoints-Part 1 

Nature of DLTs

Nature and severity of AEs Adverse events and select laboratory abnormalities graded according to 
NCI-CTCAE, v Version 4.03

Changes from baseline in Vital signs and select clinical laboratory results during and following study drug 
administration 
Secondary Endpoints-Part 1 

Overall response rate of OPomd defined as the proportion of subjects with best response of sCR, CR, 
VGPR, or PR as determined by investigator and defined by according to the IMWG-URC

Clinical benefit rate of OPomd, defined as the proportion of subjects with overall best response of MR or 
better as determined by investigator according to the IMWG-URC and modified EBMT criteria

Pharmacokinetics parameters, including maximum plasma concentration (Cmax), time to maximum 
concentration (Tmax), area under the plasma concentration time curve from time 0 to last time point 
(AUC0-), and area under the plasma concentration time curve from time 0 to time infinity (AUC0-) using
noncompartmental methods 
Exploratory Endpoints-Part 1 

Pharmacodynamic biomarkers that may be correlated with antitumor activity and resistance following 
treatment with proteasome inhibitors 

Genomic biomarkers that may be correlated with antitumor activity

Change over time in bone pain and the impact of bone pain measured with the BPI-SF (Dose Expansion 
only) 

Change over time in the global health scale status/QoL scale of the EORTC QLQ-C30 (Dose Expansion 
Revised for accuracy and 
consistency within the 
protocol 
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only) 

Change over time in health status assessed by EuroQol EQ-5D-5L 
(Dose Expansion only) 

Change over time in the disease symptoms subscale of the EORTC QLQ-MY20 (Dose Expansion only)

Change over time in neurotoxicity symptoms measured by the FACT/GOG-Ntx4 score (Version 4) (Dose 
Expansion only)
Part 2:  Randomized Phase 3 Portion of the Study 
Primary Endpoint-Part 2 

Progression-free survival, defined as time from randomization to the earlier of disease progression 
determined by ORCA according to the IMWG-URC, or death due to any cause, according to ORCA 
and according to the IMWG-URC and modified EBMT criteria
Secondary Endpoints-Part 2 

Overall survival, defined as time from randomization to death due to any cause

Overall response, defined as an overall the best response of sCR, CR, VGPR, or PR as determined by 
ORCA and defined by  according to the IMWG-URC 

Clinical benefit, defined as an overall  the best response of MR or better, as determined by ORCA
according to the IMWG-URC and modified EBMT criteria, as determined by ORCA

Duration of response, defined as the time from the first evidence of confirmed PR or better to disease 
progression as determined by ORCA according to the IMWG-URC or death due to any cause as 
determined by ORCA

Improvement in renal function over time, as defined by an increase in GFR of at least 10 mL/min 

Improvement in hemoglobin over time, as defined by an increase of at least  2 g/dL 

Duration of response, defined as the time from the first evidence of confirmed PR or better to disease 
progression or death due to any cause as determined by ORCA

Population–based PK parameters including, but not limited to, area under the curve  (AUC) and Cmax, will 
be determined from OPomd subjects 

Adverse events and select laboratory abnormalities graded according to NCI-CTCAE, v Version 4.03 over 
time

Vital signs and select clinical laboratory results during and following study drug administration over time

Change over time in bone pain and the impact of bone pain measured with the BPI-SF 

Change over time in the global health scale status/QoL scale of the EORTC QLQ-C30
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
Change over time in the disease symptoms subscale of the EORTC QLQ-MY20 

Change over time in health status assessed by EuroQol EQ-5D-5L 

Population–based PK parameters including, but not limited to, area under the plasma 
concentration-time curve  (AUC) and Cmax, will be determined from OPomd subjects
Exploratory Endpoints-Part 2 

Progression-free survival and ORR overall response, as determined by the investigator according to the 
IMWG-URC

Duration of response, defined as the time from the first evidence of confirmed PR or better to disease
progression as determined by the investigator according to the IMWG-URC or death due to any cause 
as determined by the investigator according to the IMWG-URC and modified EBMT criteria

Clinical benefit rate as determined by the investigator according to the IMWG-URC and modified 
EBMT criteria 

Duration of clinical benefit (DOCB), defined as the time from first evidence of ≥ MR or better to disease 
progression or death due to any cause, as determined by ORCA and the investigator according to the
IMWG-URC and modified EBMT criteria

Genomic biomarkers that may be correlated with antitumor activity and resistance following treatment
with proteasome inhibitors 

Neuropathy events (defined as Grade 2 or higher peripheral neuropathy incidence) 

Change in the neurotoxicity symptoms as measured by FACT/GOG-Ntx4 score (Version 4) 

Change over time in all  domains of the EORTC QLQ-C30 and EORTC 
QLQ-MY20 (excluding the global health scale and disease symptoms subscale, respectively)
Synopsis:  
Statistical methods 
and analyses 
Efficacy Analyses 
Part 1:  Phase 1b Dose Escalation and Dose-Expansion Portions of the Study
Response assessment data, PFS, Progression-free survival and duration of response will be listed for all subjects 
by dose level and schedule.  Overall response rate and clinical benefit rate will be estimated for all subjects 
treated at the RP3D along with the associated 95% exact binomial confidence intervals (CIs).
Part 2:  Randomized Phase 3 Portion of the Study 
Median PFS will be estimated for each treatment arm using Kaplan-Meier estimates.  The 95% confidence 
interval (CI) for the median PFS will be constructed using the method of Brookmeyer (1982) primary analysis 
of PFS and other efficacy endpoints will be based on the ITT population, defined as all subjects 
randomized.  The primary inferential comparison for PFS between treatment groups will be based on use the 
stratified log-rank test using stratified by the randomization stratification factors.  The hazard ratio between the 
Revised text for clarity 
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2 treatment arms HR will be estimated using a stratified Cox proportional hazards model using randomization 
stratification factors.  Duration of follow-up for PFS will be estimated by reverse The distribution of PFS, 
including medians, will be summarized descriptively using the Kaplan-Meier method for each treatment 
group. Overall survival will be analyzed using the same method as for PFS.  Duration of response and 
DOCB will be summarized for each treatment group by Kaplan-Meier method (Schemper 1996); however. 
Statistical methods for analyses of OS will be identical to those used for PFS.  The Kaplan-Meier methodology 
will also be used for estimating median DOR.  no formal inferential comparisons of DOR will be made, as 
responders constitute a nonrandom subset of the ITT population. 
Point estimates and 95% exact binomial CIs will be calculated for the ORR and CBR for each treatment group.  
Inferential comparison between treatment groups for this endpoint these endpoints will be made using the 
Cochran-Mantel Haenszel chi-square test, stratified by the randomization stratification factors. 
Inferential testing of the primary efficacy endpoint and selected secondary endpoints will be assessed (OS, ORR,
CBR, improvement in renal function, improvement in hemoglobin, change over time in QLQ-MY20 total 
scale, and change over time in QLQ-C30 total scale) against an overall 1-sided significance level of 0.025 in 
accordance with a closed testing procedure.   
Safety Analyses 
Part 1:  Phase 1b Dose Escalation and Dose-Expansion Portions of the Study 
For the Phase 1b portion of the study, safety will be assessed through summaries of DLTs, AEs, changes in select 
laboratory test results, ECGs, vital signs, and oprozomib, pomalidomide, and dexamethasone exposure.  All AE 
data collected will be listed by study site, cohort, subject number, and cycle study day. 
Section 3.1 
Introduction 
_ 
This is a Phase 1b/Phase 3 clinical trial of the oral 
proteasome inhibitor, oprozomib, in subjects with 
primary refractory or relapsed and refractory 
multiple myeloma.  See Section 5 for a complete 
description of the study design.   
The protocol has been amended with changes to the 
study design as new data became available from 
other ongoing oprozomib studies, and based on 
review of safety results from these studies.  A 
summary of changes for each amendment is 
included in the appendix of each version of the 
protocol.  The main purposes for each amendment 
are summarized below. 
Amendment 1: 
Added text in a new 
subsection “Introduction” 
to provide a top level 
summary of the 
amendments thus far.  All 
subsequent headings in this 
section were renumbered 
accordingly    
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Added an  alternative oprozomib dosing 
1.
schedule consisting of 2 consecutive days 
every 7 days (2/7), as preliminary data 
suggest that a 2/7 schedule has single-agent 
activity, and may be better tolerated than 
the existing schedule of 5 consecutive days 
every 14 days (5/14 schedule).
Clarified that plasmapheresis is not 
2.
permitted at any time during the study.
The starting dose of oprozomib was
3.
changed from 210 mg to 150 mg to provide 
increased margin of safety for subjects 
participating in this study.  This dose 
(150 mg) is 3 dose levels below the 
single-agent MTD and was selected due to 
the overlapping toxicities of oprozomib 
with pomalidomide. 
Additional dose modification text was 
4.
added to the dose modification table for 
nonhematologic toxicities and guidance to 
investigators to mitigate Grade 4 
gastrointestinal (GI) hemorrhage. 
Amendment 2:  
To allow subjects with prior carfilzomib 
1.
exposure to be considered for inclusion in 
the study, if carfilzomib was not withdrawn 
due to toxicity. 
To allow subjects with prior pomalidomide 
2.
exposure to be considered for inclusion in 
the dose-escalation portion of the study, if 
pomalidomide was neither dose-reduced 
nor withdrawn due to toxicity.
To specify that only subjects who have been 
3.
treated with adequate alkylator therapy are 
eligible to be considered for inclusion in the 
Phase 1b dose-escalation portion and Phase 
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3 portion of the study.  
Additional safety guidance regarding 
4.
Grade 3 or 4 GI hemorrhage (see Section 
10.4.2.1.2), mandatory proton-pump 
inhibitors (see Section 10.6.1.5), and the 
addition of an exclusion criterion for 
patients with prior clinically significant 
bleed in the 6 months prior to first dose of 
study treatment, because of toxicities 
observed in Study 2011-001.
Revisions in synopsis, statistical sections, 
5.
objectives, and endpoints for accuracy,
clarity, and consistency within the protocol.
Section 3.2 Multiple 
Myeloma 
Background 
Median OS from diagnosis was reported at 3 years for 
high-risk patients, 4 to 5 years for intermediate-risk 
patients, and 8 to 20 years for standard-risk patients 
(Mikhael 2013). 
Median OS from diagnosis was reported at 3 years for 
high-risk patients, 4 to 5 years for intermediate-risk 
patients, and 8 to 10 20 years for standard-risk patients 
(Mikhael 2013). 
Corrected text 
Section 3.4 
Oprozomib 
Background 
Oprozomib is a tripeptide epoxyketone proteasome 
inhibitor and structural analogue of carfilzomib 
(Kyprolis) that primarily targets the chymotrypsin-like 
activity of the 20S proteasome.  Carfilzomib is a 
tetrapeptide epoxyketone proteasome inhibitor 
approved in the US for the treatment of relapsed and 
refractory multiple myeloma.  Similar to carfilzomib, 
oprozomib is a potent, selective, and irreversible 
inhibitor of the CT-L activity of the constitutive 
proteasome (the form of proteasome found in most cell 
types) and the immunoproteasome (the form of 
proteasome found in many hematopoietic cells) 
(Zhou 2009).  In addition, when measured against a 
broad panel of proteases containing metallo-, aspartyl, 
cysteine, and serine proteases, oprozomib 
demonstrated minimal reactivity against 
nonproteasomal proteases. 
Oprozomib (formerly ONX 0912) is a tripeptide 
epoxyketone proteasome inhibitor and structural 
analogue of carfilzomib (Kyprolis) that primarily 
targets the CT-L chymotrypsin-like activity of the 20S 
proteasome.  Carfilzomib received accelerated 
approval in the 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]).  Carfilzomib is a tetrapeptide epoxyketone 
proteasome inhibitor approved in the US for the 
treatment of relapsed and refractory multiple myeloma.  
Similar to carfilzomib, oprozomib is a potent, selective, 
and irreversible inhibitor of the CT-L activity of the 
constitutive proteasome (the form of proteasome found 
in most cell types) and the immunoproteasome (the 
Updated text to provide 
missing information on 
carfilzomib label, and for 
consistency with other 
oprozomib protocols. 
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form of proteasome found in many hematopoietic cells) 
(Zhou 2009).  In addition, when measured against a 
broad panel of proteases containing metallo-, aspartyl, 
cysteine, and serine proteases, oprozomib demonstrated 
minimal reactivity against nonproteasomal proteases. 
Section 3.4.2 
Relevant Clinical 
Background 
3.3.2.1 Study 2009-003:  Solid Tumors 
Efficacy 
In Study 2009-003, oprozomib, dosed as powder in capsule, was studied in solid tumor subjects.  In the 
Phase 1 study in refractory solid tumors (n = 44), no subject achieved an objective response.  Stable disease 
(SD) was observed in 6 subjects (30%) in the once daily dosing group and 4 subjects (23.5%) in the split 
daily dosing group. 
Safety 
The majority of adverse events (AEs) were Grade 1 and 2, manageable, and there were no apparent 
cumulative toxicities.  The most common AEs were in the GI system organ class.  This was consistent with 
preclinical animal studies with oprozomib.  Dose-limiting toxicities for the once daily dose group in Study 
2009-003 included Grade 3 dehydration/vomiting and Grade 3 hypophosphatemia in the 180 mg cohort.  
The maximum tolerated dose (MTD) for the once daily x5 days dose group is 150 mg.  Dose-limiting 
toxicities for the split daily x5 days dosing group in Study 2009-003 included Grade 3 hypophosphatemia at 
180 mg and Grade 5 upper GI hemorrhage and Grade 3 hallucinations at 210 mg.  The MTD for the split 
dosing is 180 mg. 
The first-in-human clinical trial (2009-003) of oprozomib was initiated in May 2010 and completed the last 
subject visit in November 2012 in 44 subjects with advanced solid tumors; the database was closed 
19 March 2013.  This was an open-label, Phase 1 study in which subjects initially received Oprozomib in 
Capsules orally, once daily, on a 5 consecutive day, bimonthly treatment schedule, with cycles repeated every 
14 days.  The primary objectives of the study were to evaluate the safety, tolerability, and maximum tolerated 
dose (MTD) of oprozomib in this patient population.  Samples for pharmacokinetics (PK) and PDn evaluations 
were collected at various time points during Cycles 1 and 2.  For subjects enrolled under 2009-003 Protocol 
Amendment 4, oprozomib was administered as a split dose (doses administered 4 to 6 hours apart) to mitigate 
gastrointestinal (GI) toxicity and to support additional dose escalation after reaching the MTD with single daily 
dosing.  Differences in PDn and tolerability between fasted (Cycle 1) and fed (Cycle 2) states were also explored 
for subjects enrolled under Protocol Amendment 4. 
Efficacy Powder in Capsule 
The Efficacy Evaluable (EE) population comprised 21 of 25 subjects (84.0%) in the once-daily dosing group and 
17 of 19 subjects (89.5%) in the twice-daily dosing group who had measureable disease at baseline, completed 
Updated clinical 
background information for 
Study 2009-003 per most 
recent information 
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the first 4 treatment cycles, and either had at least 1 post-treatment response assessment or discontinued treatment 
due to progressive disease (PD) prior to the first scheduled disease assessment.  In the EE population, no subject 
achieved a partial response (PR).  Stable disease (SD) was the best response achieved by 6 subjects (28.6%) in 
the once-daily dosing group and 4 subjects (23.5%) in the twice-daily dosing group.  The median time to 
progression was 43 days for the once daily group and 57 days for the twice-daily group.  The clinical benefit rate 
(CBR; best response ≥ minimal response [MR]) was 28.6% in the once-daily dosing group and 23.5% in the 
twice-daily dosing group. 
Safety 
Once-Daily Group Powder in Capsule 
All 25 subjects who received a once-daily dose of Oprozomib in Capsules were included in the safety population.  
All subjects are off study; reasons for study discontinuation included PD (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 
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 GI 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 AE (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. 
Twice Daily Group Powder in Capsule 
The safety population comprised all 19 enrolled subjects who received at least 1 dose of Oprozomib in Capsules.  
All subjects are off study; reasons for study discontinuation included PD (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 
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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 GI hemorrhage and 1 subject with Grade 3 
hallucinations.  The MTD for the twice-daily dosing group was determined to be 180 mg. 
Nineteen subjects (100.0%) experienced at least 1 treatment-emergent AE.  The most frequent AEs 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 (7 subjects each, 36.8%); and pyrexia, dysguesia, and anemia (5 
subjects each, 26.3%). 
The most frequent AEs were GI and Grade 1 and 2 in severity.  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 AEs occurred in the twice-daily dosing group.  One subject in the 210-mg cohort died 
within 30 days of discontinuing study drug due to a GI bleed. 
Further details are provided in the Oprozomib IB. 
Section 3.4.2 
Relevant Clinical 
Background 
3.3.2.2. Study 2011-001:  Hematologic Malignancies 
Efficacy 
As of 21 January 2014, the Phase 1b portion of Study 2011-001 has completed enrollment; 61 response-
evaluable subjects with hematologic malignancies have 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.  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, respectively.  
Table 1 Phase 1 Response Rates for Subjects with Multiple Myeloma, by Schedule and Formulation 
Formulation/Schedule (n) 
Dose Range (mg) 
ORR 
Clinical Benefit Rate 
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) 
ORRa 
Major Responseb 
Updated clinical 
background information for 
Study 2011-001 per most 
recent information 
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Tablets 5/14 (11) 
150–270 
63.6% 
54.5% 
Tablets 2/7 (7) 
150–330 
42.9% 
14.3% 
MR = minimal response; ORR = overall response rate; PR = partial response. 
a ORR is defined as ≥ MR. 
b Major response is defined as ≥ PR. 
The Phase 2 portion of Study 2011-001 is ongoing.  Eight (8) response-evaluable subjects have received 
Oprozomib Tablets on the 5/14 schedule with once daily dosing in Phase 2; 7 subjects had SD, and 
1 subject was off study prior to any disease response assessment. 
Safety 
In the Phase 1 portion of the study (as of 21 January, 2014):  
Thirty-two (32) subjects have been enrolled on the 5/14 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 initially selected for the 
Phase 2 portion 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 2/7 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.  With the opening of Amendment 6, 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 Phase 2 portion 
for the 2/7 schedule.
In 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 (19) 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 IB (Version 6).  There were 2 cases of renal failure.  
There were also 2 Grade 5 GI hemorrhages at the 240 mg dose level on the 5/14 schedule. 
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The second clinical trial (2011-001) was initiated in September 2011 in subjects with hematologic malignancies.  
This is an ongoing, open-label, Phase 1b/2, multicenter study of oprozomib with 37 subjects treated as of 
March 2013.  The primary objectives for the Phase 1b escalation are to evaluate the safety, tolerability, and MTD 
of oprozomib in this patient population.  Differences in oprozomib tolerability and PDn in subjects treated in a 
fasted and fed state are also being explored.  The study was initiated with Oprozomib in Capsules administered 
orally, twice daily (doses separated by 4 to 6 hours), on a 5 consecutive day, bimonthly (Days 1 to 5 of a 14-day 
cycle) treatment schedule.  For subjects enrolled under 2011-001 Protocol Amendment 2, subjects received 
Oprozomib Tablets, once daily, either on a 5 consecutive day, bimonthly schedule or a 2 consecutive day, weekly 
schedule (Days 1, 2, 8, and 9 of a 14-day cycle).  Under Protocol Amendment 3, a cohort of subjects with 
carfilzomib-refractory multiple myeloma (n = 20) will be enrolled in the Phase 2 portion of the study to evaluate 
the efficacy and safety of oprozomib in this patient population.  Subjects with carfilzomib-refractory multiple 
myeloma will be treated using the 5 consecutive day, bimonthly schedule only. 
Efficacy 
Twice Daily × 5 Bimonthly Powder in Capsule 
As of 25 March 2013, 13 subjects have received Oprozomib in Capsules on a 5 consecutive day, bimonthly 
schedule with split daily dosing.  Twelve subjects are evaluable for response assessment and 1 has withdrawn 
from the study.  Among the subjects with multiple myeloma, 3 had a PR, 2 had a MR, 4 had SD, and 2 had PD as 
their best response.  In addition, 1 subject on study with chronic lymphocytic leukemia (CLL) had a PR as best 
response. 
Once Daily × 5 Bimonthly Powder in Capsule 
Thirteen multiple myeloma and 5 Waldenström macroglobulinemia (WM) subjects on the once-daily×5 
bimonthly schedule were included in the response evaluation.  The clinical benefit rates (CBR) were 23.1% 
(multiple myeloma) and 80.0% (WM).  In subjects with multiple myeloma, 1 (150 mg/d) had a very good partial 
response (VGPR), 2 (210 mg/d) had a PR, 6 (150–240 mg/d) had SD, 1 (150 mg/d) had PD, and 3 were not 
evaluable for response.  In WM subjects, 4 (150–210 mg/d) had a PR and 1 (180 mg/d) had SD.  
Safety 
Twice Daily × 5 Bimonthly Powder in Capsule 
As of 25 March 2013, 13 subjects (5 males, 8 females) with a median age of 62.0 years (range:  52 to 81 years) 
have received Oprozomib in Capsules on a 5 consecutive day, bimonthly schedule with twice-daily dosing.  All 
13 subjects received at least 1 dose of study drug and were evaluable for safety.  No DLTs were observed at doses 
up to 210 mg/day.  At study entry, 11 subjects had relapsed multiple myeloma and 2 subjects had CLL. 
At least 1 treatment-emergent AE has been recorded in all 13 subjects.  Treatment-emergent AEs seen in ≥ 25% 
of subjects were nausea (11 subjects), diarrhea (9 subjects), vomiting (9 subjects), fatigue (8 subjects), anemia (6 
subjects), thrombocytopenia (4 subjects), and decreased appetite (4 subjects). 
Seven subjects had at least 1 treatment-emergent Grade 3 AE according to National Cancer Institute-Common 
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Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, which were diarrhea (3 subjects), anemia 
and nausea (2 subjects each), and thrombocytopenia, abdominal pain, fatigue, Herpes zoster ophthalmic, 
neutropenia, pneumonia, back pain, and vomiting (1 subject each).  Three subjects had at least 1 treatment-
emergent Grade 4 AE (thrombocytopenia in all 3 subjects).  No Grade 5 AEs were reported within 30 days of the 
last dose of study drug.  One death due to PD occurred, 71 days after the last dose of study drug. 
Three subjects experienced at least 1 treatment-emergent SAE, including pneumonia (1 subject in the 120-mg 
cohort), Herpes zoster ophthalmic (1 subject in the 120-mg cohort), and nausea (1 subject in the 150-mg cohort).  
The pneumonia resolved after 2 days without oprozomib dose modification.  The Herpes zoster event resolved 
after 2 days and required the subject’s oprozomib dose to be held or delayed. The nausea event resolved after 2 
days and required dose reduction and concomitant mediation. 
Once Daily × 5 Bimonthly Tablet and Once Daily × 2 Tablet 
As of 01 July 2013, median treatment duration was 11.3 cycles and 8.7 cycles for the once daily×5 bimonthly 
schedule and once daily × 2 weekly schedule, respectively.  There were 2 DLTs, both of which occurred on the 
once daily × 5 bimonthly schedule:  renal failure on a dose of 180 mg/day and tumor lysis syndrome (TLS) on a 
dose of 240 mg/day.  The most common Grade 1–2 adverse events are summarized below in Table 1. 
Table 1 Grade 1-2 Adverse Events in > 25% of Subjects 
Grade 1-2 Adverse Events 
Number of Subjects 
Nausea 
28 
Diarrhea 
20 
Fatigue 
20 
Vomiting 
14 
Constipation 
11 
The most common Grade 3-4 AEs (≥ 2 subjects) are summarized in Table 2.  
Table 2 Grade 3-4 Adverse Events (≥ 2 Subjects) 
Grade 1-2 Adverse Events 
Number of Subjects 
Diarrhea 
9 
Anemia 
4 
Nausea 
4 
Neutropenia 
4 
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Hypophosphatemia 
3 
Thrombocytopenia 
3 
Vomiting 
3 
Dehydration 
2 
Fatigue 
2 
Further details are provided in the Oprozomib IB. 
Section 3.4.2 
Relevant Clinical 
Background 
– 
3.3.2.3 Study 2012-001:  Oprozomib in Combination 
with Dexamethasone in Multiple Myeloma 
Efficacy 
For the 2012-001 Phase 1b/2 study, as of 31 March 
2014, 5 response-evaluable relapsed and/or 
refractory multiple myeloma subjects received 
Oprozomib Tablets on a 5 consecutive day 
bimonthly (5/14) schedule with daily dosing in 
combination with dexamethasone; 1 subject had 
MR and 4 subjects had SD as their best response.  
As of 31 March 2014, 8 response-evaluable subjects 
have received Oprozomib Tablets administered 
orally, once daily, on Days 1, 2, 8, and 9 of a 14-day 
cycle (2/7) in combination with 20 mg of 
dexamethasone; 1 subject had a VGPR 
(unconfirmed), 2 subjects had a partial response 
([PR] confirmed or unconfirmed), 1 subject had a 
MR, and 4 subjects had SD as the best response.  
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 (3) subjects have 
Added updated clinical 
background information for 
Study 2012-001 for 
consistency with other 
oprozomib protocols. 
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experienced DLTs at the 210 mg dose, including 
1 subject with a subarachnoid hemorrhage 
(SAH), 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).  Data 
suggest that the 180-mg dose level will be the 
tolerable dose in combination with 
dexamethasone.  This dose level exceeds the 
starting dose for the combination of oprozomib, 
pomalidomide, and dexamethasone (OPomd). 

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.  Dose escalation is ongoing at the 
300-mg dose level, suggesting that doses lower 
than 300 mg in combination with
dexamethasone are tolerable.   Current doses 
explored in this schedule exceed the starting
dose for the combination of OPomd.
As of 31 March 31 2014, ten (10) subjects 
experienced serious adverse events (SAEs) across 
both schedules.  The 3 treatment-related SAEs were 
1 subject with a SAH, hypertension, and headache, 
1 subject with thrombocytopenia, pneumonia, and 
sepsis, and 1 subject with delirium.  
Thrombocytopenia and infection were expected 
events based on the Oprozomib IB (Version 6), but 
the SAH, hypertension, headache, and delirum were 
not.  
Section 3.4.2 
Relevant Clinical 
Background 
_ 
3.3.2.4 Study OPZ003:  Oprozomib in Combination 
with Lenalidomide and Dexamethasone in Multiple 
Myeloma 
Efficacy 
Added updated clinical 
background information for 
Study OPZ003 for 
consistency with other 
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No efficacy data are available at this time. 
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, 3 
subjects have been enrolled.  Two (2) subjects 
remain on study.  One subject, a
year old
 
experienced a treatment-related SAE of Grade 3 
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. 
oprozomib protocols. 
Section 3.5.3 
Pomalidomide 
Deleted Section 3.5 Clinical Background Pomalidomide; added text to Section 3.5.3 Pomalidomide as shown: 
Pomalidomide (Pomalyst), a thalidomide analogue, is an IMiD that displays similar antiangiogenic activity 
but far greater antiproliferative and immunomodulatory activity compared with the parent drug (Bartlett 
2007; Payvandi 2004).  Pomalidomide has also been shown to stimulate antibody‐dependent cytotoxic 
T-cell activity (ADCC) (Bartlett 2007). 
Pomalidomide received accelerated approval in the EU in August 2013 and in the US in February 2013.  
The European Commission has granted approval for pomalidomide in combination with dexamethasone, 
for the treatment of relapsed and refractory multiple myeloma who received at least two prior therapies 
and have demonstrated disease progression on the last drug taken and the US FDA granted accelerated 
approval for patients with multiple myeloma with 2 prior therapies including both bortezomib and 
lenalidomide and who are refractory to their last therapy or progressed within 60 days.  The approved 
dose of pomalidomide is 4 mg given 21 days of a 28-day cycle until progressive disease (PD). 
Approval was based on Study MM002, a randomized Phase 2 comparison of pomalidomide in combination 
with low-dose therapeutic dexamethasone (POM + LoDex) to pomalidomide alone (Jagannath 2012).  
The overall response rate (ORR) was 34%, with a median PFS of 4.6 months and median OS of 
16.5 months.  Grade 3 or 4 AEs reported in > 5% of subjects were neutropenia (41%), anemia (22%), 
pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain 
Reorganized sections for 
clarity and to reduce 
redundancy 
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(10%), and urinary tract infection (9%).  Grade 3 or 4 neutropenia occurred in 46% of subjects aged ≤ 65 
years and in 35% of subjects aged > 65 years.  Febrile neutropenia was observed in only 1 subject in each 
age group (2%).  Overall, 78% of subjects who developed Grade 3 or 4 neutropenia were treated with 
granulocyte-colony stimulating factor (G-CSF) during study treatment.  There was no Grade 3 or 4 
peripheral neuropathy (PN) reported, although Grade 1 or 2 PN occurred in 7% of subjects treated with 
POM + LoDex.  Deep vein thrombosis (DVT) occurred in 2 subjects (2%).  Pomalidomide appears to 
provide an efficacious option with a manageable toxicity profile for subjects with refractory or relapsed 
and refractory multiple myeloma. 
The approved dose of pomalidomide is 4 mg given 21 days of a 28-day cycle until PD. 
The MM003 study assessed relapsed and/or refractory subjects with multiple myeloma who had been previously 
treated with bortezomib and lenalidomide or thalidomide and progressed on or within 60 days of the last therapy.  
A regimen of pomalidomide and dexamethasone was compared to high-dose dexamethasone. 
Subjects were randomized 2:1 to receive 28-day cycles of pomalidomide 4 mg on Days 1–21 + dexamethasone 
40 mg (20 mg for subjects more than 75 years old) weekly or dexamethasone 40 mg (20 mg for subjects more 
than 75 years old) on Days1–4, 9–12, and 17–20.  Treatment continued until PD or unacceptable toxicity.  
The primary endpoint was PFS.  Secondary endpoints included OS, overall response rate (ORR (≥ PR), and 
safety.  Analyses were based on intent to treat.  A total of 455 subjects were randomized to pomalidomide + low-
dose dexamethasone (n = 302) or high-dose dexamethasone (n = 153).  The median number of prior therapies was 
5 (range:  1–17).  Seventy-two percent (72%) of subjects were refractory to lenalidomide and bortezomib.  
Median follow-up was 4 months.  Pomalidomide + low-dose dexamethasone significantly extended median PFS 
(3.6 versus 1.8 months, hazard ratio [HR] = 0.45, p < 0.001) and OS (not reached versus 7.8 months, HR = 0.53, 
p < 0.001) compared with high-dose dexamethasone.  The OS benefit was observed despite 29% of high-dose 
dexamethasone subjects receiving pomalidomide after PD (Jagannath 2012).  With updated data, the ORR was 
21% for pomalidomide + low-dose dexamethasone versus 3% for high-dose dexamethasone (p < 0.001) and 24% 
versus 3% for subjects randomized ≥ 6 months after enrollment (p < 0.001).  Median OS overall survival was 
12.7 months for pomalidomide and 8.1 months for high-dose dexamethasone; HR = 0.74 (p = 0.28).  The most 
frequent Grade 3/4 AEs for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone were 
neutropenia (42% versus 15%), anemia (27% versus 29%), and infection (24% versus 23%).  Discontinuation due 
to AEs was infrequent (7% versus 6%) (San Miguel 2013). 
…
Section 3.5 Dose 
Rationale 
3.5.1 Oprozomib 
Early development of oprozomib focused on the 5 
consecutive day bimonthly (either once or twice daily) 
(5/14) and 2 consecutive days weekly (2/7) schedules, 
3.5.1 Oprozomib 
Early development of oprozomib focused on the 5 
consecutive day bimonthly (either once or twice daily) 
(5/14) and 2 consecutive days weekly (2/7) schedules, 
Text was rearranged and 
revised for clarity 
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both on 14-day treatment cycles.  The maximum 
administered dose for Oprozomib Tablets administered 
once daily on a 5 consecutive day bimonthly schedule 
has been reached with a total daily dose of up to 
270 mg in subjects with hematologic malignancies, 
with 1 DLT of TLS and one Grade 3 vomiting out of 6 
subjects.  At the 240 mg dose, 6 subjects were dosed 
with 1 DLT of TLS, therefore 240 mg was the declared 
as the MTD.  The starting dose of 150 mg of 
oprozomib will be added to the FDA approved regimen 
of pomalidomide/dexamethasone, 3 dose levels below 
the MTD in the 5/14 schedule in the single-agent 
study.   The starting dose for the 2/7 schedule will be 
210 mg, 3 dose levels below the single agent MTD of 
300 mg.  One DLT of grade 3 orthostatic hypotension 
was reported in this cohort.  The maximum 
administered dose was reached with a total daily dose 
of 330 mg with 1 DLT of Grade 3 diarrhea and 1 DLT 
of Grade 4 thrombocytopenia. 
The most significant AEs noted are GI toxicities.  This 
study will assess both schedules in Part 1 of the study, 
as oprozomib has demonstrated preliminary activity in 
subjects with hematologic malignancies on both 
schedules. (Kaufman 2013). 
both on 14-day treatment cycles.  The maximum 
administered dose MAD for Oprozomib Tablets 
administered once daily on a 5 consecutive day 
bimonthly schedule has been reached with a total daily 
dose of up to 270 mg in subjects with hematologic 
malignancies, with 1 dose-limiting toxicity (DLT) of 
TLS and 1 one Grade 3 vomiting out of 6 subjects.  At 
the 240-mg dose, 6 subjects were dosed with 1 DLT of 
TLS, therefore 240 mg was the declared as the MTD.  
For the 5/14 schedule, the starting dose of 150 mg of 
oprozomib will be added to the Food and Drug
Administration (FDA)-approved regimen of 
pomalidomide/dexamethasone, 3 dose levels below the 
MTD in the single-agent study in the 5/14 schedule in 
the single-agent study.  The starting dose for the 
2/7 schedule will be 210 mg, 3 dose levels below the 
single agent MTD of 300 mg.  One DLT of grade 3 
orthostatic hypotension was reported in this cohort.  
The maximum administered dose was reached with a 
total daily dose of 330 mg with 1 DLT of Grade 3 
diarrhea and 1 DLT of Grade 4 thrombocytopenia. 
For the 2/7 schedule, the MAD was reached with a 
total daily dose of 330 mg with 1 DLT of Grade 3 
diarrhea and 1 DLT of Grade 4 thrombocytopenia.  
One DLT of Grade 3 orthostatic hypotension was 
reported in the 300-mg cohort, therefore 300 mg 
was declared the MTD.  The starting dose for the 
2/7 schedule will be 210 mg, 3 dose levels below the 
single agent MTD of 300 mg.   
The most significant AEs noted are GI toxicities.  This 
study will assess both schedules in Part 1 of the study, 
as oprozomib has demonstrated preliminary activity in 
subjects with hematologic malignancies on both 
schedules (Kaufman 2013). 
Section 3.5 Dose 
Rationale 
Dexamethasone will be administered in this study 
based on data from the SUMMIT trial (Richardson 
Dexamethasone will be administered in this study 
based on data from the SUMMIT trial (Richardson 
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2003) and an expanded access trial (Mikhael 2009), in 
which dexamethasone was shown to have improved 
efficacy when administered 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 
AEs temporally associated with single-agent 
oprozomib. 
2003) and an expanded access trial (Mikhael 2009), in 
which dexamethasone was shown to have improved 
efficacy when administered 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 AEs temporally 
associated with single-agent oprozomib. 
added clinical background 
information for Study 
2012-001 
Section 3.6 Study 
Rationale 
… 
Carfilzomib (Kyprolis) 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 
CT-L 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). 
… 
Data collected in these 2 trials 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 dose and schedule and have provided 
data indicating both tolerability and efficacy in 
advanced stage, heavily pretreated multiple myeloma 
subjects.  
… 
Carfilzomib (Kyprolis) is an irreversible inhibitor of 
the epoxyketone class (proteasome) that received 
accelerated approval in the 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]).  Carfilzomib 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 CT-L 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). 
… 
Data collected in these 2 trials suggested that the 
2 consecutive day weekly schedule was better tolerated 
and demonstrated clinically meaningful response rates.  
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Subsequent Phase 2 and Phase 3 carfilzomib studies 
have utilized this dose and schedule and have provided 
data indicating both tolerability and efficacy in 
advanced stage, heavily pretreated multiple myeloma 
subjects.  Both schedules will be assessed with 
oprozomib to determine which schedule provides 
an advantage in tolerability and efficacy. 
Section 5 Study 
Design 
During Part 2 of the study, subjects will be randomized 
to oprozomib or placebo (subjects in the Pomd arm) at 
the RP3D and schedule determined during Part 1 of the 
study. 
Up to 20 study sites will participate in Part 1 of the 
study (Phase 1b Dose Escalation and Expansion 
portions of the study).  Approximately 70 sites will 
participate in Part 2 of the study (Phase 3 portion of the 
study). 
During Part 2 of the study, subjects will be randomized 
to oprozomib in combination with pomalidomide 
and dexamethasone (OPomd) or placebo (subjects in 
the Pomd arm) at the RP3D and schedule determined 
during Part 1 of the study or placebo in combination 
with pomalidomide and dexamethasone (Pomd).
Approximately 35 study sites will participate in Part 1 
of the study (15 sites for the Phase 1b dose-escalation 
and 20 additional sites for the dose-expansion portions 
of the study).  An additional 35 sites, for a total of 
approximately 70 sites will participate in Part 2 of the 
study (Phase 3 portion of the study).
Revised text for clarity. 
Section 5 Study 
Design 
Moved from: 
5.1.2 Dose-Escalation Schema for the 2/7 Oprozomib 
Dosing Schedule 
Treatment cycles for both parts of the study will last 
28 days.  Disease assessments will be performed every 
4 weeks for subjects in both arms for 18 months.  
Further disease assessments will be conducted every 
8 weeks after this period.  Details of the study 
assessments required for this study are provided in 
Appendices A1 and A2. 
Moved to: 
(End of) 5 Study Design 
Treatment cycles are 28 days in duration.  Two (2) 
oprozomib dosing schedules will be assessed during 
dose-escalation.  Subjects will receive oprozomib 
once daily either on Days 1–5 and 15–19, referred to 
hereafter as the 5/14 schedule, or an alternate 
schedule of once daily on Days 1, 2, 8, 9, 15, 16, 22, 
and 23, referred to hereafter as the 2/7 schedule.  
Pomalidomide will be given on Days 1–21 and 
dexamethasone will be given on Days 1, 2, 8, 9, 15, 
16, 22, and 23 of every 28-day cycle. 
Revised text for clarity and 
moved text to the 
appropriate location in the 
protocol 
Section 5.1 Part 1: 
Phase 1b Dose-
Escalation and 
Dose-Expansion 
… 
The safety of subjects in the Dose Expansion will be 
monitored on an ongoing basis by the CSRC during 
bimonthly calls.  Enrollment to the Phase 3 portion will 
… 
The safety of subjects in the Dose Expansion will be 
monitored on an ongoing basis by the CSRC during 
bimonthly calls.  Enrollment to the Phase 3 portion will 
Deleted text as it is 
redundant with the text in 
the following section (5.2 
Part 2:  Randomized Phase 
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Portions of the 
Study 
not commence until the CSRC has evaluated all 
available safety information from a minimum of 
10 subjects who have completed ≥ 2 cycles of therapy 
at the RP3D and enrollment of the remaining 10 
subjects in Dose Expansion has occurred in 1 or both 
schedules if both were opened.   
not commence until the CSRC has evaluated all 
available safety information from a minimum of 
10 subjects who have completed ≥ 2 cycles of therapy 
at the RP3D and enrollment of the remaining 10 
subjects in Dose Expansion has occurred in 1 or both 
schedules if both were opened.   
3 Postion of the Study) 
Section 5.1.3 
Dose-Limiting 
Toxicities 
Deleted text from Section 5.1.4 Subject Replacement and added it to this section as shown:  
Subjects in both dosing schedules will be evaluated for DLTs according to the NCI-CTCAE, version 4.03 during 
the 28-day period of Cycle 1 combination therapy.  Intrasubject dose escalation to the RP3D may be permitted 
once that dose has been determined and after a discussion has occurred between the treating physician and Onyx 
study medical monitor.  The decision to escalate to the next higher dose of oprozomib in the Phase 1b portion of 
the study will be based on an assessment of study drug-related DLTs during Cycle 1 by the CSRC.  The CSRC 
consists of investigators, the Onyx medical monitor, and Onyx Drug Safety representative.  Each subject in 
the cohort under review will be discussed and assessed.  Once all data have been presented, the CSRC will 
decide on the most appropriate course of action regarding dose escalation based on guidance in Section 5.1. 
Study drug is defined as the combination of oprozo
alidomide, and dexamethasone.  Study 
drug-related is defined as a reasonable likelihood of clinical causality based on time of event, biology, 
dechallenge improvement and that the AE was not likely explained by the subject’s clinical state, underlying 
disease, concomitant medication, or study/nonstudy procedure.  Definition of DLTs and additional details are 
provided in Section 10.5. 
Reorganized text so that it 
is in the appropriate 
location in the protocol.  
Added definition of “study 
drug” 
Section 5.2 
Randomized Phase 
3 (Part 2) Portion of 
the Study 
Part 2 will consist of a placebo-controlled, 
double-blind RP3D component.  
Part 2 will consist of a placebo-controlled, 
double-blind RP3D randomized Phase 3 component.  
Corrected text 
Section 5.3 
Estimated Study 
Duration and Study 
Closure 
The total study duration is expected to be 
approximately 32-33 months.   

The Phase 1b portion of the study will take 
approximately 7–8 months to complete.

Approximately 5 months will be required to
enroll and evaluate response status of subjects 
in the dose expansion portion of the study.

Approximately 13 additional months will be 
required to enroll subjects in the Phase 3 
portion of the study. 
The total study duration is expected to be 
approximately 32–33 months.   

The Phase 1b portion of the study will take 
approximately 7–8 months to complete

Approximately 5 months will be required to
enroll and evaluate response status of subjects 
in the dose-expansion portion of the study 

Approximately 13 additional months will be 
required to enroll subjects in the Phase 3 
portion of the study
Deleted redundant text 
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
Assuming an enrollment rate of 22 subjects 
per month, it is estimated that the final 
analysis of PFS will occur approximately 17 
months after the first subject is enrolled in the 
Phase 3 portion of the study.
Prior to initiating the Phase 3 portion of the study, an 
assessment of the safety and efficacy data from a 
minimum of 10 subjects treated during the expansion 
portion of the study and the enrollment of the 
remaining 10 subjects in the expansion cohort will be 
completed in 1 or both schedules if each will be 
opened per the sponsor’s discretion.  

Assuming an enrollment rate of 22 subjects 
per month, it is estimated that the final 
analysis of PFS will occur approximately
17 months after the first subject is enrolled in 
the Phase 3 portion of the study
Prior to initiating the Phase 3 portion of the study, an 
assessment of the safety and efficacy data from a 
minimum of 10 subjects treated during the expansion 
portion of the study and the enrollment of the 
remaining 10 subjects in the expansion cohort will be 
completed in 1 or both schedules if each will be 
opened per the sponsor’s discretion. 
Section 5.4.2 
Blinding 
For Phase 3 only, an independent, external Data 
Monitoring Committee (DMC) will monitor the 
conduct of the study and undertake periodic unblinded 
assessments of safety data to optimize the safety of 
study subjects and ensure integrity of the study. 
For Phase 3 only, an independent, external Data 
Monitoring Committee (DMC) will monitor the 
conduct of the study and undertake periodic unblinded 
assessments of safety data to protect optimize the 
safety of study subjects and ensure integrity of the 
study. 
Revised text for accuracy. 
Section 9.4 Study 
Drug Accountability 
Onyx (or designee) and the investigator will maintain 
records of each shipment of investigational product 
(IP).  Upon receipt of IP, the designated recipient at the 
study site will inspect the shipment, verify the number 
and condition of the vials, and prepare an inventory or 
drug accountability record.  The records will document 
shipment dates, method of shipment, batch numbers, 
product presentation, quantity of bottles contained in 
the shipment, and dispensation to individual subjects 
using the subject identification number. 
Onyx (or designee) and the investigator will maintain 
records of each shipment of investigational product 
(IP).  Upon receipt of IP, the designated recipient at the 
study site will inspect the shipment, verify the number 
and condition of the bottles or blister packs vials, and 
prepare an inventory or drug accountability record.  
The records will document shipment dates, method of 
shipment, batch numbers, product presentation, 
quantity of bottles or blister packs contained in the 
shipment, and dispensation to individual subjects using 
the subject identification number. 
Corrected text and added 
text to allow for the 
potential use of blister 
packs in Phase 3 of the 
study 
Section 10.1 
Oprozomib 
Treatment 
Administration  
It is recommended that oprozomib not be taken on an 
empty stomach.  Subjects will be instructed to take the 
oprozomib doses after eating with approximately 
8 ounces of water.   
It is recommended that oprozomib not be taken on an 
empty stomach.  Subjects will be instructed to take the 
oprozomib doses after eating with approximately 
8 ounces of water.  On the PK collection days, dosing 
of oprozomib in relation to the meal intake (within 2 
hours before and 1 hour after dose) will be 
Added text for consistency 
with other oprozomib 
protocols 
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recorded.
Section 10.3 Dose 
Modification 
Guidelines  
This section provides dose reduction and other 
modification guidelines for oprozomib, pomalidomide, 
and dexamethasone to manage possible toxicity.  
Administration of oprozomib or pomalidomide will be 
discontinued in the event of a treatment-related toxicity 
that, in the opinion of the investigator, warrants 
permanent discontinuation. 
Monotherapy with dexamethasone is not allowed in the 
Phase 1b Dose-Escalation and Expansion portions of 
the study.  In the event that oprozomib or 
pomalidomide is permanently discontinued in Phase 3 
only, dexamethasone may be continued.   
This section provides dose reduction and other 
modification guidelines for oprozomib, pomalidomide, 
and dexamethasone to manage possible toxicity.  
Administration of oprozomib or pomalidomide will be 
discontinued in the event of a treatment-related toxicity 
that, in the opinion of the investigator, warrants 
permanent discontinuation. 
Monotherapy with dexamethasone is not allowed in the 
Phase 1b dose-escalation and dose-expansion portions 
of the study.  In the event that oprozomib or 
pomalidomide is permanently discontinued in Phase 
3 only, dexamethasone may be continued.  
Added text for clarity 
Section 10.4.1 Dose 
Reductions 
… 
Modifications of the dose of oprozomib/placebo will 
occur in up to three 30-mg decrements down to a 
minimum of 150 mg.  Additional reductions will be 
managed by schedule change.   
… 
Treatment guidelines for specific hematologic 
toxicities are outlined in Section 10.4.2.1.1 and 
nonhematologic toxicities in Section 10.4.2.1.2.  In 
addition to dose reductions, administration of 
oprozomib, and pomalidomide may be temporarily 
interrupted for a maximum of 4 weeks in the event of a 
treatment-related toxicity.   
… 
If dexamethasone dosing is permanently stopped due 
to toxicity in accordance with the dose modification 
guidelines described in Table 15, the subject should 
stay on oprozomib and/or pomalidomide, depending on 
the arm to which they are randomized, and continue to 
follow protocol required therapy, procedures, and 
assessments.  In the event oprozomib or pomalidomide 
is permanently discontinued in Phase 3 only, 
… 
Modifications of the dose of oprozomib/placebo will 
occur in up to three 30-mg decrements down to a 
minimum dose of 150 mg.  Additional reductions will 
be managed by schedule change.   
… 
Treatment guidelines for specific hematologic toxicities 
are outlined in Section 10.4.2.1.1 and nonhematologic 
toxicities in Section 10.4.2.1.2.  In addition to dose 
reductions, administration of oprozomib, and 
pomalidomide, and dexamethasone may be 
temporarily interrupted for a maximum of 4 weeks in 
the event of a treatment-related toxicity.   
… 
If dexamethasone dosing is permanently stopped due to 
toxicity in accordance with the dose modification 
guidelines described in Table 15, the subject should 
stay on oprozomib and/or pomalidomide, depending on 
the arm to which they are randomized, and continue to 
follow protocol required therapy, procedures, and 
assessments.  Subjects may continue to take 
antiemetic doses of dexamethasone (4 mg) on days 
Corrected text and 
rearranged text for clarity 
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dexamethasone may be continued.  Subjects may 
continue to take antiemetic doses of dexamethasone 
(4 mg) on days of oprozomib dosing at the 
investigator’s discretion.
of oprozomib dosing, if tolerated, at the 
investigator’s discretion.  In the event oprozomib or 
pomalidomide is permanently discontinued in Phase 3 
only, dexamethasone may be continued.  Subjects may 
continue to take antiemetic doses of dexamethasone 
(4 mg) on days of oprozomib dosing at the 
investigator’s discretion. 
Section 10.4.2.1.1 
Hematologic 
Toxicities 
Additional guidance regarding hematologic toxicities 
and dosing actions is as follows: 
To initiate a new cycle of pomalidomide, the
neutrophil count must be at least 500 per mcL and 
the platelet count must be at least 50,000 per mcL.
If toxicities occur after dose reductions to 1 mg, then
discontinue pomalidomide.
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 
after discussion with the Onyx study medical
monitor.  No more than 3 dose reductions down to a 
minimum of 150 mg will be permitted for an 
individual subject on study and additional reductions 
will be managed by schedule change.  If toxicity
continues, oprozomib should be discontinued. 
Additional guidance regarding hematologic toxicities 
and dosing actions is as follows: 
To initiate a new cycle of pomalidomide, the
neutrophil count must be at least 500 per mcL and 
the platelet count must be at least 50,000 per mcL.
If toxicities continue to occur after dose reductions 
to down 1 mg, then discontinue pomalidomide.
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 of oprozomib may be 
permitted after discussion with the Onyx study 
medical monitor.  No more than 3 dose reductions 
down to a minimum of 150 mg will be permitted for
an individual subject on study and additional
reductions will be managed by schedule change.  If 
toxicity continues, oprozomib should be 
discontinued. 
Added text for clarity 
Section 10.4.2.1.2 
Nonhematologic 
Toxicities – Table 
14 
Symptom:  Grade 4 GI Hemorrhage 
Added the following to the table: 
Symptom:  Grade 1 or 2 GI hemorrhage 
Findings:  Assessed as oprozomib-related 
Oprozomib Dosing Action: 

DELAY until Grade 0

DECREASE one dose level for Grade 2
Pomalidomide Dosing Action:  Full dose at 
Additional text has been 
added to the dose 
modification table for 
nonhematologic toxicities 
and guidance to 
investigators to potentially 
reduce the risk for GI 
hemorrhage 
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physician discretion 
Changed to: 
Symptom:  Grade 3 or 4 GI Hemorrhage 
Section 10.4.2.1.2 
Nonhematologic 
Toxicities
Additional guidance regarding nonhematologic 
toxicities and dosing actions is as follows: 

Nontreatment-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 the subject tolerates the reduced dose for 1 cycle, 
the subject’s dose may be re-escalated to the dose 
being taken prior to the dose reduction.

If required by continued or recurrent toxicity, a 
second or third dose reduction may be permitted 
after discussion with the Onyx study medical
monitor.  No more than 3 dose reductions down to 
a minimum of 150 mg will be permitted for an 
individual subject on study and additional 
reductions will be managed by schedule change.  If 
toxicity continues, oprozomib should be 
discontinued.

Subjects who develop Grade 4 GI hemorrhage 
should not be rechallenged with oprozomib. 
Oprozomib should be permanently discontinued.
Additional guidance regarding nonhematologic 
toxicities and dosing actions is as follows: 

Nontreatment-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 the subject tolerates the reduced dose for 1 cycle, 
the subject’s dose may be re-escalated to the dose 
being taken prior to the dose reduction

If required by continued or recurrent toxicity, a 
second or third dose reduction of oprozomib may 
be permitted after discussion with the Onyx study 
medical monitor.  No more than 3 dose reductions 
down to a minimum of 150 mg will be permitted 
for an individual subject on study and additional
reductions will be managed by schedule change.  If 
toxicity continues, oprozomib should be 
discontinued.

Subjects who develop Grade 3 or 4 GI hemorrhage 
should not be rechallenged with oprozomib. 
Oprozomib should be permanently discontinued.
Endoscopy should be strongly considered for any 
subject with GI hemorrhage.
Added text for clarity and 
to reflect change in dose 
modification guidelines for 
GI hemorrhage 
Section 10.6.1.2 
Antinausea and 
Antiemetics 
It is strongly recommended that subjects be 
premedicated with a 5-HT3 inhibitor, such as 
ondansetron or granisetron, prior to administration of 
the first dose of oprozomib each day and throughout 
the day as needed to prevent nausea and vomiting.  If 
nausea/vomiting at any grade persists, aprepitant is 
recommended if needed.  Additional antiemetics may 
It is strongly recommended that subjects be 
premedicated with a 5-HT3 inhibitor, such as 
ondansetron or granisetron, prior to administration of 
the first dose of oprozomib each day and throughout 
the day as needed to prevent nausea and vomiting.  If 
nausea/vomiting at any grade persists, aprepitant or 
fosaprepitant is recommended.  Additional 
Added “or fosaprepitant” 
for consistency with other 
oprozomib protocols to 
allow IV administration of 
this antiemetic if needed 
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be used if needed per investigator discretion. 
antiemetics may be used per investigator discretion. 
Section 10.6.1.5 
Acid-related 
Medications 
Lansoprazole or another oral proton-pump inhibitor is 
recommended for the duration of treatment to prevent 
peptic disease or other GI disorders. 
Lansoprazole or another oral proton-pump inhibitor is
recommended required (unless subject has
intolerance or hypersensitivity) for the duration of 
treatment to prevent peptic disease or other GI 
toxicities. 
Revised text for consistency 
with other oprozomib 
protocols and to potentially 
reduce the risk for GI 
hemorrhage 
Section 10.6.1.7 
Tumor Lysis 
Syndrome 
Tumor Lysis Syndrome Laboratory Abnormalities 
Subjects with laboratory abnormalities prior to dosing 
that are consistent with lysis of tumor cells (e.g., as 
defined by increases in at least 3 of the following 
4 categories:  [1] a 2-fold increase of lactate 
dehydrogenase above the ULN; [2] increases in serum 
creatinine, uric acid, or phosphorus > 50% over 
baseline; [3] potassium > 30% above the ULN; or 
[4] calcium decreases from baseline of > 20% in the 
absence of concomitant bisphosphonate therapy) 
(Sezer 2006) should not receive the scheduled dose 
prior to institution of the aforementioned preventive 
measures.   
Tumor Lysis Syndrome Laboratory Abnormalities 
Subjects with laboratory abnormalities prior to dosing 
that are consistent with lysis of tumor cells (e.g., as 
defined by abnormalities increases in at least 3 of the 
following 4 categories:  [1] a 2-fold increase of lactate 
dehydrogenase above the ULN; [2] increases in serum 
creatinine, uric acid, or phosphorus > 50% over 
baseline; [3] potassium > 30% above the ULN; or 
[4] calcium decreases from baseline of > 20% in the 
absence of concomitant bisphosphonate therapy) (Sezer 
2006).  Subjects should must not receive the scheduled 
dose prior to institution of the aforementioned 
preventive measures.   
Revised as corrections and 
for consistency with other 
oprozomib protocols 
Section 10.6.1.8 
Orthostatic 
Hypotension 
_ 
10.6.1.8 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.  An 
etiology should be sought for the orthostatic 
hypotension to determine its cause is neurogenic, 
non-neurogenic or iatrogenic.  Dose modifications 
should be taken in accordance with Table 13 and 
Table 14. 
For those subjects with orthostatic hypotension 
who are taking antihypertensives, 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 
Added additional guidance 
for subjects who may 
experience orthostatic 
hypotension. 
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subject is getting appropriate hydration in 
accordance with protocol requirements of 6–8 
eight ounce glasses of fluids in the 24−48 hours 
prior to dosing and on every day 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 per 
investigator discretion, such as increased oral 
intake, florinef or midodrine, others depending 
on the etiology.  Holding the dose and dose 
reduction upon resolution may be a 
consideration. 
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 (Appendices A1, A2,
B1, B2, C1, and C2) 
Section 10.6.2 
Optional and 
Allowed 
Concomitant 
Medications 
Additional antiemetics that are not required may be 
used as well as antidiarrheal agents as necessary
Additional antiemetics that are not required may be 
used as well as antidiarrheal agents, and/or 
laxatives as necessary 
Removed extraneous text, 
and added “and/or 
laxatives” for consistency 
with other oprozomib 
protocols 
Section 10.6.3 
Excluded 
Concomitant 
Medications 
Other antimyeloma agents are not permitted prior to 
the subject developing confirmed progressive disease. 
Other antimyeloma or investigational agents are not 
permitted prior to the subject developing confirmed 
progressive disease. 
Added text for clarity 
Section 11.1.1 Vital 
Signs 
Vital signs will include measurement of orthostatic 
blood pressure, pulse rate, and temperature.  Subjects 
should lie down for 5 minutes and then have blood 
All vital signs assessments will include measurement 
of orthostatic blood pressure, pulse rate, respiration
rate, and temperature.  Subjects should lie down for 
Revised text for consistency 
with other oprozomib 
protocols 
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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 mmHg systolic, 10 mmHg diastolic or 
lightheadedness/dizziness between supine and standing 
blood pressures would indicate orthostatic 
hypotension.  Usually an increase in pulse of 
10 beats/min is associated with but not required for 
identification of orthostatic hypotension.  Subject’s 
dosage and use of antihypertensive agents in the setting 
of orthostatic hypotension should be evaluated and 
reassessed on an ongoing basis while on study.  Fluid 
intake should be assessed to confirm the subject is 
acting in accordance with protocol requirements.  Re-
education should occur if subject is not adhering to 
protocol requirements.  Fluid status should be repleted 
to normal levels.  If protocol requirements for oral 
intake of fluids are already being met, additional 
measure should be taken to increase volume status per 
investigator discretion.  Ongoing monitoring of fluid 
status is warranted and should also be managed per 
investigator discretion.  In addition, vital signs 
monitoring may be extended beyond the time periods 
specified in the Schedules of Assessments (Appendices 
A1, A2, B1, B2, C1, and C2) as needed. 
5 minutes and then have blood pressure and pulse 
measured consistently in either arm.  Following the
supine blood pressure/pulse reading, This should be 
followed by having the subject should stand and the 
blood pressure and pulse should be repeated after at 1 
and 3 minutes.  Any drop of 20 mmHg systolic, 
10 mmHg diastolic or lightheadedness/dizziness 
between supine and standing blood pressures would 
indicate orthostatic hypotension.  Usually an increase 
in pulse of 10 beats/min is associated with but not 
required for identification of orthostatic hypotension.  
For time points where PK and vital signs are to be 
done together, vital signs should be obtained first as 
the act of phlebotomy may impact vital sign 
measurement results.  Subject’s dosage and use of 
antihypertensive agents in the setting of orthostatic 
hypotension should be evaluated and reassessed on an 
ongoing basis while on study.  Fluid intake should be 
assessed to confirm the subject is acting in accordance 
with protocol requirements.  Re-education should occur 
if subject is not adhering to protocol requirements.  
Fluid status should be repleted to normal levels.  If 
protocol requirements for oral intake of fluids are 
already being met, additional measure should be taken 
to increase volume status per investigator discretion.  
Ongoing monitoring of fluid status is warranted and 
should also be managed per investigator discretion.  In 
addition, vital signs monitoring may be extended 
beyond the time periods specified in the Schedules of 
Assessments (Appendices A1, A2, B1, B2, C1, and C2) 
as needed. 
Section 11.3 
Disease Response 
Assessments 
… 
Disease response and progression assessments include:  

Serum protein electrophoresis (SPEP)

Urine protein electrophoresis (UPEP)

Serum immunofixation, serum free light chain 
… 
Disease response and progression assessments include:  

Serum protein electrophoresis (SPEP)

Urine protein electrophoresis (UPEP)

Serum immunofixation, serum free light chain 
Separated bullet points for 
clarity; revised text to 
reflect updated Schedules 
of Assessment 
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(SFLC) 

Urine immunofixation

Serum calcium, bone marrow sample as 
clinically indicated to confirm CR

Radiographic assessments including 
plasmacytoma evaluation if baseline 
assessments were positive and as clinically 
indicated per the response criteria

Skeletal survey if baseline assessments were 
positive and as clinically indicated per the 
response criteria
Serum protein electrophoresis and immunofixation 
assessments will be conducted according to the 
schedule outlined in Appendices A1, A2, B1, B2, C1, 
and C2, Schedule of Assessments.  Immunofixation 
will only be required after Screening and End of Study 
Treatment, if results of the previous SPEP are 
zero/undetectable.  
Urine protein electrophoresis and immunofixation will 
be performed on a 24-hour urine specimen collected 
from all subjects during the Screening period and at the 
End of Study Treatment visit.  The UPEP with 24-hour 
urine collection will be conducted according to the 
schedule outlined in Appendices A1, A2, B1, B2, C1, 
and C2, Schedule of Assessments, and is required:  1) 
only if Screening UPEP was ≥ 200 mg/24 hours, and 
2) to confirm a disease response or disease 
progression.  If the Screening UPEP was negative, spot 
urine is required at each time point.  If positive for 
paraprotein, a 24-hour urine collection with UPEP 
must be done at the next assessment and at each 
subsequent assessment unless the UPEP shows an 
absence of paraprotein.  
Serum free light chain assay and kappa:lambda (/) 
ratio will be conducted according to the schedule 
(SFLC) 

Urine immunofixation

Serum calcium, bone marrow sample as 
clinically indicated to confirm CR

Bone marrow sample as clinically indicated 
to confirm CR 

Radiographic assessments including 
plasmacytoma evaluation if baseline 
assessments were positive and as clinically 
indicated per the response criteria

Skeletal survey if baseline assessments were 
positive and as clinically indicated per the 
response criteria
Serum protein electrophoresis and immunofixation 
assessments will be conducted according to the 
schedule outlined in Appendices A1, A2, B1, B2, C1, 
and C2, Schedule of Assessments.  Immunofixation 
will only be required after Screening, Baseline (Day -7 
to 1), and End of Study Treatment, if results of the 
previous SPEP are zero/undetectable.  
Urine protein electrophoresis and immunofixation will 
be performed on a 24-hour urine specimen collected 
from all subjects during the Screening period, Baseline 
(Day -7 to 1), and at the End of Study Treatment visit.  
The UPEP with 24-hour urine collection will be 
conducted according to the schedule outlined in 
Appendices A1, A2, B1, B2, C1, and C2, Schedule of 
Assessments, and is required:  1) only if Screening 
Baseline UPEP was ≥ 200 mg/24 hours, and 2) to 
confirm a disease response or disease progression.  If 
the Screening Baseline UPEP was negative, spot urine 
is required at each time point.  If positive for 
paraprotein, a 24-hour urine collection with UPEP must 
be done at the next assessment and at each subsequent 
assessment unless the UPEP shows an absence of 
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outlined in the Schedule of Assessments, Appendices 
A1, A2, B1, B2, C1, and C2.  Only in subjects without 
measurable serum and urine M-protein levels (serum 
M-protein < 0.5 g/dL or urine M-protein < 200 mg/24 
hours) at Screening will SFLC assays be used to 
determine eligibility and response.  In subjects with 
measurable SPEP and/or UPEP, SFLC may be used in 
conjunction with those assessments to determine 
response per disease response criteria but only SPEP 
and/or UPEP will be used to determine eligibility. 
paraprotein.  
Serum free light chain assay and kappa:lambda (/) 
ratio will be conducted according to the schedule 
outlined in the Schedule of Assessments, Appendices 
A1, A2, B1, B2, C1, and C2.  Only in subjects without 
measurable serum and urine M-protein levels (serum 
M-protein < 0.5 g/dL or urine M-protein < 200 mg/24 
hours) at Screening Baseline will SFLC assays be used 
to determine eligibility and response.  In subjects with 
measurable SPEP and/or UPEP, SFLC may be used in 
conjunction with those assessments to determine 
response per disease response criteria but only SPEP 
and/or UPEP will be used to determine eligibility.   
Section 11.3 
Disease Response 
Assessments 
… 
All response categories (CR, sCR, VGPR, PR, MR, 
PD) 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.  All subjects will be followed until disease 
progression (confirmed by 2 consecutive 
measurements that are also verified by the Onyx 
medical monitor prior to treatment discontinuation), 
unacceptable toxicity, or withdrawal of consent, 
whichever occurs first.   
Disease progression will be determined using the 
IMWG-URC (Appendices A1, A2, B1, B2, C1, and 
C2).  Serum M component increases of ≥ 1.0 g/dL are 
sufficient to define progression if the starting 
component is ≥ 0.5 g/dL according to these criteria.  
However, it is understood from these criteria that a 
single measurement is adequate in cases of clear 
increased bone marrow plasma cell percentage, 
development of new or worsened bone lesions from a 
skeletal survey, or development of new or worsened 
soft tissue plasmacytomas. 
… 
All response categories (CR, sCR, VGPR, PR, MR, 
PD) 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.  All subjects will be followed until disease 
progression (confirmed by 2 consecutive measurements 
that are also verified by the Onyx medical monitor 
prior to treatment discontinuation), unacceptable 
toxicity, or withdrawal of consent, whichever occurs 
first.   
Disease progression will be determined and 
confirmed with the medical monitor by two 
consecutive assessments using the IMWG-URC 
(Appendices A1, A2, B1, B2, C1, and C2).  Serum M 
component increases of ≥ 1.0 g/dL are sufficient to 
define progression if the starting component is ≥ 0.5 
g/dL according to these criteria.  However, it is 
understood from these criteria that a single 
measurement is adequate in cases of clear increased 
bone marrow plasma cell percentage, development of 
new or worsened bone lesions from a skeletal survey, 
or development of new or worsened soft tissue 
Revised text for 
clarification of the 
requirements for the 
assessment of disease 
disease progression  
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plasmacytomas. 
Section 11.4.3 
Genomic 
Measurements 
Whole genome sequencing (WGS), whole exome 
sequencing (WES), and/or whole transcriptome 
sequencing will be conducted on isolated tumor 
(CD138+) cells from bone marrow samples taken at 
Screening and disease progression.  In addition, WGS 
or WES will be performed on a normal tissue sample 
(e.g., saliva, CD3+ T-cells, or isolated PBMCs) in order 
to determine the presence of somatic mutations in 
tumor cell samples.  Data will be analyzed to examine 
specific hypotheses about 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 cell (NF-κB) transcription 
factors as well as genes involved in immunoglobulin 
production and plasma cell protein homeostasis.  These 
data will also be used to derive new hypotheses about 
mechanisms of drug response, resistance, and safety. 
Whole genome sequencing (WGS), whole exome 
sequencing (WES), and/or 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 
Screening and disease progression.  In addition, WGS 
or WES will be performed on a normal tissue sample 
(e.g., saliva or peripheral blood, CD3+ T-cells, or 
isolated PBMCs) in order to determine the presence of 
somatic mutations in tumor cell samples.  Data will be 
analyzed to examine specific hypotheses about 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 cell (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 enzyme-linked 
immmunosorbent assay (ELISA) and/or other 
protein quantification methods. These data will also 
be used to derive new hypotheses about mechanisms of 
drug response, resistance, and safety. 
Added text for clarity and 
consistency with other 
oprozomib protocols 
Section 11.5 Quality 
of Life Assessments 
- 
Added subsection: 
11.5 Patient-Reported Outcomes Assessments 
Beginning with Cycle 1, HRQoL/PRO assessments 
are to be completed at the beginning of every cycle 
prior to drug administration through End of Study 
Treatment/Early Discontinuation visit during the 
dose-expansion portion of the trial, and at the 
beginning of every cycle prior to drug 
administration through End of Study 
Treatment/Early Discontinuation visit and then 
every 12 weeks during the long-term follow-up in 
the Phase 3 portion of the study.  The HRQoL/PRO 
Added subsection to further 
clarify the quality of life 
assessments to be 
performed in the 
dose-expansion and Phase 3 
portions of the study 
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assessments include:  

BPI-SF (see Appendix N for a sample Brief Pain 
Inventory – Short Form) 

EORTC QLQ-C30 (Appendix E) 

EORTC QLQ-MY20 (Appendix E)

Neurotoxicity subscale of the FACT/GOG-Ntx4
(Appendix F)

EQ-5D-5L (Appendix G)
Section 12 Study 
and Study 
Treatment 
Discontinuation 
… 
An individual subject who discontinues study 
treatment for PD is considered to have completed the 
study after the safety follow-up visit.   
… 
… 
An individual subject who discontinues study treatment 
for PD will be followed for OS in long-term 
follow-up is considered to have completed the study 
after the safety follow-up visit.   
…
Revised text for clarity 
Section 12.1 Study 
Treatment 
Discontinuation 
… 
Subjects who discontinue from study treatment will be 
monitored for AEs for 30 days after the last dose of 
oprozomib or before the start of subsequent anticancer 
treatment (whichever occurs first).  Treatment 
discontinuation due to progression should be recorded 
on the Treatment/Discontinuation eCRF as “Disease 
Progression.” 
Onyx Therapeutics, or designee must be notified 
within 24 hours if a subject is withdrawn from 
treatment for any reason (i.e., disease progression, 
toxicity, etc.).  Disease progression must be confirmed 
by the medical monitor before any subject is 
discontinued from study treatment. 
… 
Subjects who discontinue from study treatment will be 
monitored for AEs for 30 days after the last dose of 
oprozomib or immediately before the start of 
subsequent anticancer treatment (whichever occurs 
first).  Treatment discontinuation due to progression 
should be recorded on the Study Drug Completion 
Treatment/Discontinuation eCRF as “Disease 
Progression.” 
Onyx Therapeutics, or designee must be notified within 
24 hours if a subject is withdrawn from treatment for 
any reason (i.e., disease progression, toxicity, etc.).  
Disease progression with 2 consecutive disease 
assessments must be confirmed by the medical monitor 
before any subject is discontinued from study 
treatment. 
Corrected text and revised 
text for clarification of the 
requirements for the 
duration of AE collection  
Section 12.2 Study 
Discontinuation 
The sponsor, Onyx Therapeutics, Inc., may elect to 
discontinue the study at any time.  Each subject will be 
followed until death or study closure.  The reason for 
The sponsor, Onyx Therapeutics, Inc., may elect to 
discontinue the study at any time.  Each subject will be 
followed until death or study closure.  The reason for 
Deleted text as it was in the 
inappropritate location in 
the protocol 
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discontinuation from the study will be documented on 
the eCRF. 
… 
discontinuation from the study will be documented on 
the eCRF. 
… 
Section 12 Study 
and Study 
Treatment 
Discontinuation 
Section 12.3 Long-
Term Follow-up 
Long-Term Follow-up 
After completion of the post treatment visit, subjects 
will be followed for disease and survival status by 
telephone contact or other method every 3 months in 
addition to disease assessments.  Long-term follow-up 
will continue until the subject has withdrawn consent 
for further participation, is lost to follow-up, has died, 
or the sponsor makes a decision to close the study.  For 
any subject who is lost to follow-up, the study site will 
attempt to ascertain survival information via public 
database search.  Informed consent to obtain these data 
will be obtained from subjects at the time of 
enrollment. 
Long-Term Follow-up 
After completion of the post treatment End of Study 
Treatment visit, subjects will be followed for disease 
progression, OS, and quality of life (QOL). and 
survival status by telephone contact or other method 
every 3 months in addition to disease assessments.  
Subjects will be followed based on their disease 
progression status at End of Study Treatment. 
Progression and Overall Survival 
For subjects who have not progressed at end of
study treatment, disease response assessments 
will be performed every 4 weeks through 18 
months on study, and then every 8 weeks 
thereafter, beginning with Month 20, until 
progression or initiation of next therapy
Subjects who progressed at end of study 
treatment or long-term follow-up will be followed 
for survival status approximately every 3 months, 
or as needed 
Quality of Life  
For Phase 3 only, in long-term follow-up, QOL 
questionnaires will be collected from subjects 
(regardless of disease status) every 12 weeks.   
Long-term follow-up will continue until the subject has 
withdrawn consent for further participation, is lost to 
follow-up, has died, or the sponsor makes a decision to 
close the study.  For any subject who is lost to follow-
up, the study site will attempt to ascertain survival 
information via public database search.  Informed 
consent to obtain these data will be obtained from 
subjects at the time of enrollment. 
Added “on study” and 
additional text for clarity on 
the long-term follow-up 
based on disease 
progression status 
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Section 12.4 Study 
Termination  
Onyx has the right to terminate this study or a study 
site from participating in a study at any time. 
… 
Onyx has the right to terminate this study, either 
schedule, or a study site from participating in a study at 
any time. 
… 
Added text to provide 
flexibility in terminating 
either schedule 
Section 14.2 
Analysis of the 
Conduct of the 
Study 
Enrollment, subject disposition, study treatment 
administration, and discontinuation from the study will 
be summarized.  Eligibility exceptions and major 
protocol deviations will be summarized. 
Enrollment, subject disposition, study treatment 
administration, and discontinuation from the study will 
be summarized.  Eligibility exceptions and major
important protocol deviations will be summarized. 
Revised to match ICH E3 
Guidance 
Section 14.3 Data 
Monitoring 
Committee 
In Part 1 of the study, safety will be monitored by a CSRC for both the Phase 1b dose-escalation and 
dose-expansion portions of the study.  
In the Phase 3 portion of the study, no formal efficacy interim analyses are planned for the PFS primary endpoint.  
An interim analysis of OS,—the key secondary endpoint,—is planned at the time of primary analysis of PFS. 
Details of the monitoring plan for OS are described in Section 14.5.2.2.
Overall survival may also be evaluated without penalty by the DMC in their ongoing safety review of benefit-
risk during the course of the study.  Details of the monitoring plan for OS are described in Section 14.5.2.2. As 
the objective of this evaluation is not to declare OS efficacy before the planned efficacy interim and final 
analyses of OS, alpha level will not be adjusted for these reviews. 
An independent DMC will be convened for this the Phase 3 portion of the study and will act in an advisory 
capacity to the sponsor with respect to safeguarding the interests of study subjects, assessing interim safety and 
efficacy (OS secondary only) data, and for monitoring the overall conduct of the study.  To enhance the integrity 
of the study, the DMC may also formulate recommendations relating to the selection, recruitment, and retention 
of subjects, management of subjects, improving adherence to protocol treatment, and the procedures for data 
management and quality control.  
The DMC will meet to review safety data on a periodic basis, but no less frequently than approximately every 6 
months.  The initial meeting should occur within 3 months after approximately 30 subjects are enrolled in the 
Phase 3 part portion of the study.  Unplanned safety review meetings of the DMC may be called at any time by 
the sponsor or the DMC Chair if additional review of safety data is warranted. 
The membership criteria and other details of the DMC will be described in the DMC Charter. 
Revised text for clarity 
Section 14.4 
Analysis of 
Treatment Group 
Comparability 
Descriptive statistics will be used to summarize 
baseline subject characteristics, treatment 
administration, efficacy, and safety outcomes.  
Summaries of discrete data will include number of 
subjects and incidence as a frequency and as a 
percentage.  Summaries of continuous data will include 
Descriptive statistics will be used to summarize 
baseline subject characteristics, treatment 
administration, efficacy, and safety outcomes.  
Summaries of discrete data will include number of 
subjects and incidence as a frequency and as a 
percentage.  Summaries of continuous data will include 
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mean, standard deviation, median, minimum, 
maximum, and sample size. 
mean, standard deviation, median, minimum, 
maximum, and sample size. 
Section 14.4.1 
Treatment Exposure 
and Medication 
Compliance 
… 
The average relative dose intensity for each treatment 
group will be calculated by summarizing the average 
relative dose intensity for individual subjects.  These 
results will be provided to determine the presence of 
any major differences between the treatment groups for 
the planned versus actual dose and schedule of 
pomalidomide and dexamethasone administered. 
For each subject, a compliance measure will be 
calculated based on the information provided in the 
CRFs.  Compliance will be defined as the percentage 
of the actual number of days with treatment intake over 
the expected number of days with treatment intake.  
Summary statistics will be provided on percent 
compliance by treatment group. 
… 
The average relative dose intensity for each treatment 
group will be calculated by summarizing the average 
relative dose intensity for individual subjects.  These 
The results for pomalidomide and dexamethasone 
will be provided to determine the presence of any 
major differences between the treatment groups for the 
planned versus actual dose and schedule of 
pomalidomide and dexamethasone administered these 
two (2) study medications.
For each subject, a compliance measure will be 
calculated based on the information provided in the 
CRFs.  Compliance will be defined as the percentage 
of the actual number of days with treatment intake over 
the expected number of days with treatment intake.  
Summary statistics will be provided on percent 
compliance by treatment group. 
Revised text for clarity and 
as corrections 
Section 14.5.1.1 
Safety Population 
All subjects receiving any amount of study treatment 
(oprozomib, pomalidomide, or dexamethasone) will be 
included in safety analyses.   
All subjects receiving any amount of study treatment 
(oprozomib, placebo, pomalidomide, or 
dexamethasone) will be included in safety analyses.   
Corrected text by adding 
“placebo” 
Section 14.5.2 
Efficacy Analyses 
All efficacy analyses will be presented separately for Part 1 and Part 2 of the study. 
Part 1:  Phase 1b Dose Escalation and Dose-Expansion Portions of the Study 
Overall response rate is defined as the proportion of subjects with a best overall response of sCR, CR, VGPR, or 
PR as determined by investigator according to the IMWG-URC. 
Clinical benefit rate (CBR) is defined as a the proportion of subjects with a best response of PR or better 
according to IMWG-URC or a best response of MR according to the EBMT criteria, as determined by the 
investigator.  A point estimate and 95% exact binomial confidence interval (CI) will be calculated for both ORR 
and CBR for all subjects treated at the RP3D (during dose escalation and expansion for each schedule).  A 
descriptive summary of ORR and responses will also be provided by dose cohort. 
Response assessment data  Progression-free survival and DOR will be listed for all subjects in the efficacy 
population by dose cohort level and schedule. 
Part 2:  Randomized Phase 3 Portion of the Study 
Revised for clarity and as 
corrections 
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Unless otherwise noted, all primary and secondary efficacy analyses will include all randomized subjects 
analyzed according to the ITT analysis principle (Section 14.5.1), i.e., subjects will be grouped analyzed by the 
treatment assigned at randomization. 
Primary Efficacy Analysis 
The primary efficacy endpoint for the Phase 3 portion of the study is PFS, defined as the time from randomization 
to the earlier of disease progression or death due to any cause.  Disease progression will be determined using the 
IMWG-URC (Appendix D).  Response and disease progression will be determined using a validated computer 
algorithm (ORCA) as well as by local investigators.  The primary analysis of PFS will be based on ORCA-
assessed outcomes.  The PFS outcomes assessed by the investigators will serve as a supportive analysis of the 
primary analysis of PFS. 
For purposes of calculating PFS, the start date for PD is the date at which progression is first observed.  
The duration of PFS will be right-censored according to the conventions described in Table 18 
Table 18 Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of randomization 
Censored 
No postbaseline disease assessments  
and alive 
Date of randomization + 1 day 
Censored 
New anticancer treatment started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of a new anticancer treatment 
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 primary analysis of PFS will be conducted after approximately when 157 PFS events have occurred.  
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The hypothesis to be tested is as given below: 
H0:  PFS (Pomd) = PFS (OPomd) 
Ha:  PFS (Pomd) < PFS (OPomd) 
The primary inferential comparison between treatment groups for PFS will be based on the stratified log-rank 
test at an overall 0.025 (1-sided) significance level using randomization stratification factors as strata: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more 

Carfilzomib status:  carfilzomib-naïve/sensitive versus carfilzomib-sensitive refractory
The hazard ratio between the 2 treatment arms will be estimated using a stratified Cox proportional hazards 
model.   
The distribution of PFS times, including medians, will be summarized descriptively using the Kaplan-Meier 
method.  Median PFS will be estimated for each treatment group from the 50th percentile of the corresponding 
Kaplan-Meier estimates.  The 95% CIs for median and other quartiles of PFS will be constructed using the 
method of Brookmeyer and Crowley (1982).  Duration of follow-up for PFS will be estimated by the reverse 
Kaplan-Meier method of Schemper (1996). 
Secondary Efficacy Analyses 
At the time of the primary PFS analysis, the first of 2 interim analyses that are planned for the key secondary 
endpoint of OS will also be conducted.  Overall survival is defined as the time from randomization to death due 
to any cause.  Subjects who are alive or lost to  
follow-up as of the data analysis cutoff date will be right censored.  The censoring date will be determined from 
the subject’s last known date alive of last contact or data analysis cutoff date, whichever event occurs first.  
Determination of the required number of events and timing of analyses for comparison of OS for subjects 
randomized to treatment with Pomd plus placebo versus those randomized to treatment with OPomd is based 
upon the following assumptions: 
The risk of death in subjects randomized to OPomd is 32% lower than that of subjects randomized to Pomd; i.e., 
the target hazard ratio is 0.68 
The hypothesis test of interest is: 
Ho:  OS (Pomd) = OS (OPomd) 
Ha:  OS (Pomd) < OS (OPomd) 
Inference will be made using the log-rank testing procedure. 

1-sided 0.025 level of significance 

75% power 

1 interim and 1 final analysis (30%, 100%)
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
mOS (Pomd) = 16 months and mOS (OPomd) = 23.5 months

Duration of OS is exponentially distributed 

10% Lost to Follow-Up at 60 months 
Final analysis of OS will be performed when 211 deaths have occurred.  Two hundred and eleven (211) A 
total of 211 deaths will provide 75% power to detect a 32% decrease in the risk of 46.9% increase in median OS 
for OPomd versus Pomd (16 vs. 23.5 months HR = 0.68) at the 1-sided 0.025 level of significance.  Under 
exponential distribution, 23.5 months versus 16 months is assumed for median OS for the OPomd and 
Pomd arms, respectively.  The assumed median OS of 16 months for the Pomd group is based on a Phase 2 
study of pomalidomide/dexamethasone (Jagannath 2012).  Under these assumptions, and assuming 10% lost
to follow-up for OS at 60 months, 211 deaths are expected to occur approximately 56 months after the 
study starts.
The interim analysis for OS will occur at the time of the primary analysis of PFS.  The primary analysis of PFS is 
anticipated to occur approximately 14 months after the first subject is randomized.  Approximately 30% of the 
total number of death events is expected at the time of the primary PFS analysis.  The interim and final analysis 
of OS will be performed using an O’Brien-Fleming group sequential monitoring plan.  The monitoring plan will 
include an upper boundary for benefit constructed using a false-positive error rate of 0.025 (Table 19).  The Lan-
Demets alpha spending function approach will be used to adjust the O’Brien-Fleming boundary if the actual 
interim analysis does not correspond to the projected information time. 
Table 19 O’Brien-Fleming Monitoring Boundary for Benefit 
Information 
Fraction 
Death Events 
Study Month 
Boundary 
(Reject Ho) 
1-Sided 
Significance 
Level 
Alpha Spent 
30% 
63 
14 
3.929 
0.000042 
0.000 
100% 
211 
56 
1.96 
0.025 
0.025 
Statistical analyses conducted for OS will be identical to those described for PFS.  In addition to the key 
secondary endpoint of OS, secondary efficacy analyses inferential testing will be conducted for ORR, CBR, 
time to improvement in renal function, time to improvement in hemoglobin, change from baseline over time in 
QLQ-MY20 total scale, and change from baseline over time in QLQ-C30 total scale. 
Inferential testing of primary and selected secondary endpoints will be assessed performed against an overall 
1-sided significance level of 0.025 in accordance with a closed testing procedure (CTP).  The CTP will be used to 
account for inflation of the overall type 1 error rate due to hypothesis testing of multiple secondary endpoints. 
The CTP will be structured as follows:  If the null hypothesis for the primary efficacy endpoint of PFS is rejected 
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at the 1-sided 0.025 level of significance, then testing of the aforementioned secondary endpoints will proceed in 
a sequential step-down manner.  The nominal level of significance at interim analysis will be as presented above 
in Table 19, consistent with the monitoring plan for the key secondary endpoint of OS. 
Testing of selected secondary efficacy endpoints will continue, provided the null hypothesis for each previously 
tested endpoint is rejected.  Otherwise, no further testing will be done. The sequential order in which secondary 
efficacy endpoints will be tested is as follows:  

PFS 

OS 

ORR 

CBR 

Time to Improvement in renal function 

Time to Improvement in hemoglobin

Change from baseline over time in QLQ-C30 global health scale

Change from baseline over time in QLQ-MY20 disease symptoms subscale
Overall response rate will be estimated based on the proportion of subjects in each treatment group who achieve 
sCR, CR, VGPR, or PR as their best response across the entire treatment duration.  The inferential comparison 
between treatment groups for this endpoint will be made using the Cochran-Mantel Haenszel chi-square test, 
stratified by the randomization stratification factors.  Approximate 95% CIs will be calculated by treatment group 
for the true ORR.  An estimate of the common odds ratio for the odds of overall response will be provided as a 
measure of the relative treatment effect.  The odds ratio (and 95% CI) will be estimated using the 
Mantel-Haenszel method.  The Pomd plus placebo arm group will serve as the reference treatment group in the 
calculation of the odds ratio.  Homogeneity of the odds ratio across randomization strata will be examined at a 
significance level of 0.05 by the Breslow-Day test. 
Clinical benefit rate (CBR) will be estimated based on the proportion of subjects in each group who achieve sCR, 
CR, VGPR, PR, or MR and will be analyzed in the same manner as described previously for ORR. 
Improvement in renal function is defined as an increase in glomerular filtration rate (GFR) of at least 
≥ 10 mL/min.  
Improvement in hemoglobin is defined as an increase of ≥ 2g/dL.  
Inferences for time to Incidence of improvement in renal function and improvement in hemoglobin will parallel 
those for the other time-to-event outcomes of PFS and OS. be analyzed in the same manner as described 
previously for ORR.
The Kaplan-Meier methodology Duration of response and DOCB will also be used for estimating median 
DOR.  be summarized for each treatment group by Kaplan-Meier method; however no formal inferential 
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comparisons of DOR will be made, as responders constitute a nonrandom subset of the ITT population.… 
Section 14.5.3 
Safety Analyses 
The safety population will be used in all safety analyses (see Section 14.5.1.1).  Results of safety analyses will be 
presented separately for Part 1 and Part 2 of the study. 
Part 1:  Phase 1b Dose Escalation and Dose-Expansion Portions of the Study 
For the Phase 1b portion of the study, safety data will be summarized for each cohort and for the pooled
cohorts. Safety will be assessed through summaries of DLTs, AEs, changes in laboratory test results, ECGs, vital 
signs, and oprozomib, pomalidomide, and dexamethasone exposure.  All AE data collected will be listed by study 
site, cohort, subject number, and cycle day.    
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, safety data will be summarized grouped according to treatment actually 
received. 
For both Part 1 and Part 2 of the study, safety analyses will include all AEs occurring on or after treatment on 
Cycle 1 Day 1.  Summaries of AEs will include number and percentage of subjects experiencing 1 or more AEs, 
relationship to study drug, and severity.  Treatment-emergent AEs are defined as AEs that start on or after the 
first day study treatment is administered and within 30 days of the last administration of study treatment or before 
start of subsequent anticancer treatment (whichever occurs first).  Treatment-emergent AEs Adverse events will 
be summarized by the number and percentage of subjects who experienced the event, according to system organ 
class and preferred term.  A subject experiencing multiple instances of the same AE will be counted once within 
each system organ class and similarly counted once within each preferred term.  These conventions will be 
appropriately modified to calculate AE incidence rates separately for each cycle that study therapy is 
administered.  Adverse event incidence rates may also be calculated based on other measures of subject exposure 
(e.g., total number of treatment cycles administered).  Adverse events will also be summarized by NCI-CTCAE 
Version 4.03 severity grade and by relationship to each study drug.  For AEs not adequately addressed by 
NCI-CTCAE version 4.03, the severity grading described in Table 17 may be used.  Additional summaries may 
also be provided for SAEs and events resulting in the permanent discontinuation of therapy.  All AEs will be 
included in individual subject listings.  
Incidence, severity, and duration of specific signs and symptoms indicative of neuropathy and other 
neurotoxicities will be assessed.  The appropriate terms in these categories will be codified and analyses 
performed to provide a subject incidence of those with the relevant events.   
Laboratory parameters will be summarized using descriptive statistics, by postdose shifts in toxicity grades of 
select laboratory parameters relative to baseline, changes from baseline, and data listings of clinically 
significant abnormalities.  The changes in hematology, chemistry, and other laboratory values will be 
summarized descriptively for each scheduled and unscheduled protocol assessment time point.  Changes will be 
calculated relative to the values collected at baseline and on the first day of each cycle of treatment.  
The incidence of Grade 3 and 4 hematological toxicities (including neutropenia, thrombocytopenia, and anemia) 
Revised for clarity and as 
corrections 
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Section(s) 
Changed from 
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Rationale 
will be provided by treatment cycle and across all treatment cycles.  The use of blood transfusions (platelets, 
RBC) and/or growth factor support will be summarized reported in the Concomitant Medications section.  
Similar analyses will be done for selected chemistry tests (including liver and renal function tests).  Subject 
listings of all laboratory data collected during the study will be presented.  Laboratory values outside normal 
limits will be identified in the subject listings and will include flags for high and low values. 
Vital sign results (systolic and diastolic blood pressure, pulse, respiration, and temperature) and ECGs will be 
summarized descriptively for each scheduled and unscheduled protocol time point.  Changes will be calculated 
relative to the assessments at baseline and on the first day of each cycle of therapy.  
Section 14.5.4 
Subgroup Analyses 
and Effects of 
Baseline Factors 
To determine whether the treatment effect is consistent across various subgroups, the estimate of the hazard ratio 
(or odds ratio) for treatment group (with 95% CI) will be provided for the primary and selected secondary 
efficacy endpoints and plotted within each of the following baseline variables, provided there is a reasonable 
sample size in the subgroups of interest: 

Refractory status:  primary refractory versus relapsed, and refractory versus bortezomib intolerant 

Number of prior therapies:  2 versus 3 or more (stratification factor)

Age (< 75 years versus ≥ 75 years) (stratification factor) 

Prior carfilzomib (naïve/sensitive versus sensitive refractory) (stratification factor) 

Refractory status:  Primary refractory versus relapsed-refractory, and refractory versus 
bortezomib-intolerant

Refractory to lenalidomide

Refractory to bortezomib (refractory to lenalidomide and bortezomib)

Double refractory 

FISH risk status:  High-risk group versus standard-risk group.  The high-risk group consists of the 
genetic subtypes t(4; 14), t(14;16), and deletion 17p.  The standard-risk group consists of all other
reported subtypes. 

No prior transplant versus prior transplant

Bone marrow infiltration by plasma cells ≤ 50% versus > 50% at baseline 

Renal function ≤ 60 mL/min versus > 60 mL/min at baseline

Age (< 65 years versus ≥ 65 years) 

Race (Caucasian versus all others)

Sex (male versus female)

Study center 
Revised text for clarity, 
including the potential 
inclusion of subjects with 
prior carfilzomib exposure 
in the study 
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Section 14.7 
Determination of 
Sample Size 
The CSRC will review the data and provide guidance 
in selection of the RP3D.  Therefore the RP3D may 
differ from the MTD.   
The CSRC will review the data and provide guidance 
in selection of the RP3D.  Therefore the RP3D may 
differ from the MTD, but will not be higher than the 
MTD.   
Added text for clarity and 
for consistency within the 
protocol 
Section 14.7 
Determination of 
Sample Size 
Part 2:  Randomized Phase 3 Portion of the Study 
The estimated sample size For the Phase 3 portion of the study is based on comparison of the PFS (death or 
disease progression events) distributions for subjects treated with Pomd plus placebo versus those treated with 
OPomd based upon the log-rank test statistic.  It is assumed that the PFS risk for subjects randomized to OPomd 
will be 45.7% lower than for subjects randomized to Pomd.  Therefore, the target HR of interest is 0.543.  In 
order to have 95% power with 157 PFS events are required to detect a 45.7% reduction in the risk of PFS 
(HR = 0.543) with 95% power and a 1-sided α = 0.025 level of significance level of 0.025. for testing no 
difference in PFS risk versus a 45.7% reduction in risk between the 2 treatments, 157 PFS events are required.  
Enrollment of 270 subjects (2:1 OPomd versus Pomd, respectively) is consistent with reaching the required 157 
events in approximately 14 months, assuming an enrollment rate of approximately 22 subjects per month, a 5% 
drop-out rate at 18 months, and a median PFS of 3.8 and 7 months for Pomd and OPomd, respectively. 
Therefore, a the total planned enrollment of will be approximately 352 subjects is planned for the entire study. 
Revised text for clarity 
Section 16 
References 
_ 
Cleeland CS. The measurement of pain from 
metastatic bone disease: capturing the patient's 
experience.  Clin Cancer Res. 2006;12(20 Pt 
2):6236s–42s. 
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. 
Added references 
Appendix A1, A2, 
B1, B2, C1, and C2 
Appendices updated per body of protocol.  See updated appendices for further details. 
Removed and added “X”s 
in the Schedule of 
Assessment tables and 
revised text of footnotes for 
clarity and consistency with 
the protocol body text 
Appendix D 
Response Criteria for Multiple Myeloma 
Revised text for minor 
corrections 
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Appendix M 
– 
Added: 
Appendix M ACTG Brief Peripheral Neuropathy 
Screening Tool 
Added ACTG Brief 
Peripheral Neuropathy 
Screening Tool as 
Appendix M 
Appendix N 
– 
Added: 
Appendix N  Sample Brief Pain Inventory – Short 
Form 
Added Sample Brief Pain 
Inventory – Short Form as 
Appendix N 
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6XSHUVHGHG
UserName:
Title:  Senior Vice President, Development 
Date: Tuesday, 08 July 2014, 07:31 PM   Pacific Daylight Time 
Meaning: I have reviewed and approved this document. 
================================================
Document Title:
protocol-OPZ007-a2.docx
Workflow Number:
14118445
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APPENDIX Q 
SUMMARY OF CHANGES IN STUDY OPZ007 AMENDMENT 3.0 
Study OPZ007 was amended to include the following: 

The Phase 3 portion of the study was never executed; therefore, all text pertaining to the
Phase 3 portion of the study was removed.

Study visits are less frequent with data collection (eg, labs) being pared down to instances
of clinical need or adverse event reporting 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.  Changes noted in 
specific sections were also made in the protocol synopsis and elsewhere in the document, as 
applicable.  Significant changes are presented in the table below.  Detailed changed text is 
displayed for first major occurrence only.  All affected sections are noted in the “Section(s)” 
column.  Text that has been deleted is presented in strikethrough format.  Added text is 
presented in bold format. 
Onyx Therapeutics 
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Section(s) 
Changed from 
Changed to 
Rationale 
Global 
Phase 1b/3 
Phase 1b/3 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Global 
International Conference on Harmonisation (ICH) 
International Council for Harmonisation (ICH) 
Change in 
regulatory 
body name 
Global 
Onyx Drug Safety 
Amgen Global Patient Safety 
New 
sponsor 
protocol 
standard 
operating 
procedure 
(SOP) 
Global 
Onyx 
Sponsor 
New 
sponsor 
protocol 
SOP 
Title page 
New text added 
NCT Number:  NCT01999335 
New 
protocol 
SOP 
Title page 
Onyx Therapeutics 
249 East Grand Ave. 
South San Francisco, CA 94080 
Onyx Therapeutics, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone:  (805) 447-1000 
Change in 
sponsor title 
and contact 
information 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
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Section(s) 
Changed from 
Changed to 
Rationale 
Title page 
Study Medical Monitor: 
 MD 
249 East Grand Avenue 
Phone:
Email: 
Study Medical Monitor: 
 MD 
Medical Director, Early Development 
1120 Veterans Blvd 
South San Francisco, CA 94080 USA 
Phone:
Email: 
Change in 
responsibilit
ies 
Title page 
New text added 
Amendment 3.0:  07 March 2018 
New 
amendment 
identifiers 
[Protocol 
Approval 
Signature Page] 
Protocol Approval Signature Page 
[page removed] 
New 
sponsor 
protocol 
SOP 
Protocol 
Acceptance 
Page 
Issue/Date:  OPZ007 (08 July 2014) 
Issue/Date:  OPZ007 (07 March 2018) 
New 
amendment 
identifiers 
Synopsis 
(Study 
objectives) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by Schedule) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by Schedule) 
Study is no 
longer 
divided into 
2 parts 
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CONFIDENTIAL 
Synopsis 
(Study 
objectives) 
Section 4.2 
(Part 2:  
Randomized 
Phase 3 Portion 
of the Study) – 
Whole Section 
deleted 
Part 2:  Randomized Phase 3 Portion of the Study 
Phase 3 objectives involve comparison of key outcome 
measures for subjects with primary refractory or relapsed 
and refractory multiple myeloma who are randomized to 
either oprozomib or placebo, in combination with 
pomalidomide and dexamethasone, hereafter denoted by 
OPomd or Pomd, respectively. 
Primary Objective 

To compare progression free survival (PFS), as
determined by Onyx Response Computational
Assessment (ORCA) according to the IMWG-URC,
between subjects treated with OPomd and those
treated with Pomd
Secondary Objectives 

To compare the following between subjects treated
with OPomd and those treated with Pomd:
o Overall survival (OS)
o Overall response rate (ORR), the clinical benefit
rate (CBR), and duration of response (DOR) as 
determined by ORCA according to the IMWG-URC 
and modified EBMT criteria 
o Incidence of improvement in renal function, as
defined by an increase in glomerular filtration rate 
(GFR) of at least 10 mL/min over baseline at least 
once after the start of treatment 
o Incidence of improvement in hemoglobin, as
defined by an increase of at least 2 g/dL over baseline 
at least once after the start of treatment 
o Safety and tolerability
o Bone pain and the impact of bone pain measured
with the BPI-SF 
o Health-related quality of life (HRQoL) measured by
the global health status/QoL scale of the EORTC 
QLQ-C30 
Part 2:  Randomized Phase 3 Portion of the Study 
Phase 3 objectives involve comparison of key outcome 
measures for subjects with primary refractory or relapsed 
and refractory multiple myeloma who are randomized to 
either oprozomib or placebo, in combination with 
pomalidomide and dexamethasone, hereafter denoted by 
OPomd or Pomd, respectively. 
Primary Objective 

To compare progression free survival (PFS), as
determined by Onyx Response Computational 
Assessment (ORCA) according to the IMWG-URC, 
between subjects treated with OPomd and those 
treated with Pomd 
Secondary Objectives 

To compare the following between subjects treated
with OPomd and those treated with Pomd: 
o Overall survival (OS)
o Overall response rate (ORR), the clinical benefit
rate (CBR), and duration of response (DOR) as 
determined by ORCA according to the IMWG-URC 
and modified EBMT criteria 
o Incidence of improvement in renal function, as
defined by an increase in glomerular filtration rate 
(GFR) of at least 10 mL/min over baseline at least 
once after the start of treatment 
o Incidence of improvement in hemoglobin, as
defined by an increase of at least 2 g/dL over baseline 
at least once after the start of treatment 
o Safety and tolerability
o Bone pain and the impact of bone pain measured
with the BPI-SF 
o Health-related quality of life (HRQoL) measured by
the global health status/QoL scale of the EORTC 
QLQ-C30 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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o Disease symptoms as measured by the disease
symptoms subscale of EORTC QLQ-MY20 
o Neurotoxicity symptoms as measured by the
neurotoxicity subscale of the FACT/GOG-Ntx4 
(Version 4) 
o Health status assessed with EQ-5D-5L

To evaluate population-based PK parameters of
oprozomib in the OPomd regimen.
Exploratory Objectives 
To compare the following between subjects treated with 
OPomd and those treated with Pomd:  

PFS and ORR as determined by the investigator
according to the IMWG-URC

Duration of response (DOR), defined as the time from
the first evidence of confirmed PR or better to disease
progression or death due to any cause as determined
by the investigator according to the IMWG-URC

Clinical benefit rate (CBR) as determined by the
investigator according to the IMWG-URC and
modified EBMT criteria

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease
progression or death due to any cause, as determined
by ORCA and the investigator according to the
IMWG-URC and modified EBMT criteria

Genomic biomarkers that may correlate with
antitumor activity and resistance following treatment
with proteasome inhibitors

The incidence of neuropathy (events are defined as
Grade 2 or higher peripheral neuropathy)

HRQoL assessed with subscale scores of EORTC
QLQ-C30 (excluding global health status scale) and
EORTC QLQ-MY20 (excluding disease symptom
subscale)
o Disease symptoms as measured by the disease
symptoms subscale of EORTC QLQ-MY20 
o Neurotoxicity symptoms as measured by the
neurotoxicity subscale of the FACT/GOG-Ntx4 
(Version 4) 
o Health status assessed with EQ-5D-5L

To evaluate population-based PK parameters of
oprozomib in the OPomd regimen. 
Exploratory Objectives 
To compare the following between subjects treated with 
OPomd and those treated with Pomd: 

PFS and ORR as determined by the investigator
according to the IMWG-URC 

Duration of response (DOR), defined as the time from
the first evidence of confirmed PR or better to disease 
progression or death due to any cause as determined 
by the investigator according to the IMWG-URC 

Clinical benefit rate (CBR) as determined by the
investigator according to the IMWG-URC and 
modified EBMT criteria 

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease 
progression or death due to any cause, as determined 
by ORCA and the investigator according to the 
IMWG-URC and modified EBMT criteria 

Genomic biomarkers that may correlate with
antitumor activity and resistance following treatment 
with proteasome inhibitors 

The incidence of neuropathy (events are defined as
Grade 2 or higher peripheral neuropathy) 
HRQoL assessed with subscale scores of EORTC QLQ-C30 
(excluding global health status scale) and EORTC 
QLQ-MY20 (excluding disease symptom subscale) 
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Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Study design) 
There are 2 parts to this study.  Part 1 includes an 
open-label, Phase 1b, dose-escalation and dose-expansion 
portion (equivalent to a small Phase 2), during which the 
RP3D will be identified. 
This study includes an open-label, Phase 1b, dose-escalation 
and dose-expansion portion (equivalent to a small Phase 2), 
during which the RP3D will be identified. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
During the Phase 1b portion of the study, subjects will 
receive Oprozomib extended release (ER) Tablets according 
to their assigned dose cohort.   
During this study, subjects will receive Oprozomib extended 
release (ER) Tablets according to their assigned dose cohort.  
Study is no 
longer 
divided into 
2 Parts. 
Synopsis 
(Study design) 
Part 2 will consist of a placebo-controlled, double-blind, 
randomized Phase 3 component, where subjects will be 
randomized to receive the RP3D of oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
Part 2 will consist of a placebo-controlled, double-blind, 
randomized Phase 3 component, where subjects will be 
randomized to receive the RP3D of oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
Section 5 
(Study Design) 
This study will include subjects with primary refractory or 
relapsed and refractory multiple myeloma, i.e., those who 
have demonstrated disease progression on or within 60 days 
of their last therapy, and who have received at least 2 prior 
lines of therapy (including bortezomib and lenalidomide 
and/or thalidomide, and in the dose-expansion and Phase 3 
portions of the study only, been treated with adequate 
alkylator therapy). 
This study will include subjects with primary refractory or 
relapsed and refractory multiple myeloma, i.e., those who 
have demonstrated disease progression on or within 60 days 
of their last therapy, and who have received at least 2 prior 
lines of therapy (including bortezomib and lenalidomide 
and/or thalidomide, and in the dose-expansion and Phase 3 
portions of the study only, been treated with adequate 
alkylator therapy). 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Study design) 
All study subjects (i.e., Part 1 and Part 2) will receive 
oprozomib once daily (or placebo in the case of Phase 3 
subjects in the Pomd arm) either on Days 1–5 and 15–19, 
referred to hereafter as the 5/14 schedule, or an alternate 
schedule of once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23, 
referred to hereafter as the 2/7 schedule. 
All study subjects (i.e., Part 1 and Part 2) will receive 
oprozomib once daily (or placebo in the case of Phase 3 
subjects in the Pomd arm) either on Days 1–5 and 15–19, 
referred to hereafter as the 5/14 schedule, or an alternate 
schedule of once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23, 
referred to hereafter as the 2/7 schedule. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Study no 
longer 
divided into 
2 parts. 
Synopsis 
(Study design) 
In Part 1 of the study, the safety, MTD, PK/PDn, and RP3D 
of oprozomib when given in combination with 
pomalidomide and dexamethasone will be assessed using a 
standard 3+3 dose-escalation design. 
The safety, MTD, PK/PDn, and RP3D of oprozomib when 
given in combination with pomalidomide and 
dexamethasone will be assessed using a standard 
3+3 dose-escalation design. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
Part 1:  Phase 1b Dose Escalation and Dose Expansion 
Portions of the Study 
In Part 1 of the study, the safety, MTD, PK/PDn, and RP3D 
of oprozomib when given in combination with 
pomalidomide and dexamethasone will be assessed using a 
standard 3+3 dose-escalation design.  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 dose limiting toxicity (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.  If the starting dose of 
oprozomib cannot be safely administered with the labeled 
pomalidomide dose, or at sponsor discretion, then up to 
Part 1:  Phase 1b Dose Escalation and Dose Expansion 
Portions of the Study 
In Part 1 of the study, the safety, MTD, PK/PDn, and RP3D 
of oprozomib when given in combination with 
pomalidomide and dexamethasone will be assessed using a 
standard 3+3 dose-escalation design.  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 dose limiting toxicity (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.  If the starting dose of 
oprozomib cannot be safely administered with the labeled 
pomalidomide dose, or at sponsor discretion, then up to 2 
Removed 
duplicated 
text 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
2 possible alternative paths for oprozomib with lower 
pomalidomide doses will be explored.  (See tables below for 
primary and alternative dose escalation paths.)  Dose 
escalation will continue until sponsor discretion, the 
maximum planned dose of pomalidomide is reached, or 
≥ 2 DLTs occur in a cohort, whichever occurs first.  The 
prior cohort will be expanded to at least 6 subjects if not 
previously done to establish that dose as the MTD.  There 
may be more than 1 MTD for oprozomib if more than 1 dose 
level of pomalidomide is studied.  The MTD of oprozomib 
associated with each dose level of pomalidomide assessed 
will be the dose level where < 2 DLTs in 6 subjects are 
observed. 
There is no planned maximum dose of oprozomib to be 
studied as it is being added to the FDA approved regimen of 
pomalidomide/dexamethasone, however, this could be 
imposed at any time during the course of the study, based on 
Sponsor discretion.  The starting dose of oprozomib for the 
5/14 schedule is 150 mg, 3 dose levels below the established 
5/14 single agent MTD of 240 mg.  The starting dose of 
oprozomib for the 2/7 schedule is 210 mg, 3 dose levels 
below the established 2/7 single-agent MTD of 300 mg.  
Following dose escalation, the sponsor has the option of 
expanding 1 or both schedules in order to establish the 
RP3D and schedule. 
possible alternative paths for oprozomib with lower 
pomalidomide doses will be explored.  (See tables below for 
primary and alternative dose escalation paths.)  Dose 
escalation will continue until sponsor discretion, the 
maximum planned dose of pomalidomide is reached, or ≥ 2 
DLTs occur in a cohort, whichever occurs first.  The prior 
cohort will be expanded to at least 6 subjects if not 
previously done to establish that dose as the MTD.  There 
may be more than 1 MTD for oprozomib if more than 1 dose 
level of pomalidomide is studied.  The MTD of oprozomib 
associated with each dose level of pomalidomide assessed 
will be the dose level where < 2 DLTs in 6 subjects are 
observed.   
There is no planned maximum dose of oprozomib to be 
studied as it is being added to the FDA approved regimen of 
pomalidomide/dexamethasone, however, this could be 
imposed at any time during the course of the study, based on 
Sponsor discretion.  The starting dose of oprozomib for the 
5/14 schedule is 150 mg, 3 dose levels below the established 
5/14 single agent MTD of 240 mg.  The starting dose of 
oprozomib for the 2/7 schedule is 210 mg, 3 dose levels 
below the established 2/7 single-agent MTD of 300 mg.  
Following dose escalation, the sponsor has the option of 
expanding 1 or both schedules in order to establish the 
RP3D and schedule. 
Synopsis 
(Study design) 
During the Phase 1b portion of the study, assessment of 
DLTs will occur during the 28-day period of Cycle 1 
combination therapy. 
During this study, assessment of DLTs will occur during the 
28-day period of Cycle 1 combination therapy. 
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Study design) 
In the Phase 1b portion of the study, subjects must meet the 
following criteria to be considered evaluable for MTD 
determination during the 4-week DLT evaluation period 
unless a DLT occurs before the subject receives all planned 
doses of oprozomib for both the 5/14 and 2/7 dosing 
schedules: 
Subjects must meet the following criteria to be considered 
evaluable for MTD determination during the 4-week DLT 
evaluation period unless a DLT occurs before the subject 
receives all planned doses of oprozomib for both the 
5/14 and 2/7 dosing schedules: 
Study no 
longer 
divided into 
2 parts 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
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30 July 2019
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Clinical Study Protocol No. OPZ007 
Page 168 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Study design) 
Once the MTD(s) has been determined and the 
recommended dose for the expansion phase has been 
selected, a minimum of 20 additional subjects for 1 or both 
schedules of oprozomib at the sponsor’s discretion will be 
enrolled in the dose-expansion portion of Part 1in order to 
continue the evaluation of the safety and efficacy of the 
regimen as a prelude to initiation of the Phase 3 portion of 
the study.   
Once the MTD(s) has been determined and the 
recommended dose for the expansion phase has been 
selected, a minimum of 20 additional subjects for 1 or both 
schedules of oprozomib at the sponsor’s discretion will be 
enrolled in the dose-expansion portion of the study in order 
to continue the evaluation of the safety and efficacy of the 
regimen.   
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
Enrollment to the Phase 3 portion will not commence until 
the CSRC has evaluated all available safety information 
from a minimum of 10 subjects who have completed 
≥ 2 cycles of therapy and enrollment of the remaining 
10 subjects in Dose Expansion has occurred in 1 or both 
schedules if both were opened.   
Enrollment to the Phase 3 portion will not commence until 
the CSRC has evaluated all available safety information 
from a minimum of 10 subjects who have completed 
≥ 2 cycles of therapy and enrollment of the remaining 
10 subjects in Dose Expansion has occurred in 1 or both 
schedules if both were opened.  
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study design) 
Part 2:  Randomized Phase 3 Portion of the Study 
Randomization 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus placebo, 
respectively.  Central randomization will be implemented in 
this part of the study through the use of an Interactive Voice 
Response System / Interactive Web Response System 
(IVRS/IWRS).  Eligible subjects will be stratified by: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  Carfilzomib-naïve/sensitive
versus carfilzomib-refractory. Carfilzomib-sensitive
multiple myeloma patients are defined as having had
previously achieved a PR or greater with therapy that
includes carfilzomib (or carfilzomib monotherapy),
and did not experience PD until more than 60 days
after their last dose of carfilzomib.
Carfilzomib-refractory multiple myeloma is defined as
Part 2:  Randomized Phase 3 Portion of the Study 
Randomization 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus placebo, 
respectively.  Central randomization will be implemented in 
this part of the study through the use of an Interactive Voice 
Response System / Interactive Web Response System 
(IVRS/IWRS).  Eligible subjects will be stratified by: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  Carfilzomib-naïve/sensitive
versus carfilzomib-refractory. Carfilzomib-sensitive 
multiple myeloma patients are defined as having had 
previously achieved a PR or greater with therapy that 
includes carfilzomib (or carfilzomib monotherapy), 
and did not experience PD until more than 60 days 
after their last dose of carfilzomib. 
Carfilzomib-refractory multiple myeloma is defined as 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 230


Clinical Study Protocol No. OPZ007 
Page 169 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
disease that is nonresponsive while on primary or 
salvage therapy that includes carfilzomib, or that 
progresses on or within 60 days of last therapy. 
Within each stratum, treatment assignment will be made 
using a permuted block randomization scheme.   
Randomized treatment is to commence on the day of 
randomization (Day 1), if possible, but not more than 
5 calendar days after randomization.  Treatment initiation 
beyond 5 days after randomization must be approved by the 
Onyx study medical monitor or designee. 
disease that is nonresponsive while on primary or 
salvage therapy that includes carfilzomib, or that 
progresses on or within 60 days of last therapy.    
Within each stratum, treatment assignment will be made 
using a permuted block randomization scheme.  
Randomized treatment is to commence on the day of 
randomization (Day 1), if possible, but not more than 
5 calendar days after randomization.  Treatment initiation 
beyond 5 days after randomization must be approved by the 
Onyx study medical monitor or designee. 
Synopsis 
(Number of 
investigational 
sites) 
Section 5 
(Study Design) 
Approximately 35 study sites will participate in Part 1 of the 
study (15 sites for the Phase 1b dose-escalation and 
20 additional sites for the dose-expansion portions of the 
study). 
An additional 35 sites, for a total of approximately 70 sites, 
will participate in Part 2 of the study (Phase 3 portion of the 
study). 
Approximately 35 study sites will participate in this study 
(15 sites for the dose-escalation and 20 additional sites for 
the dose-expansion portions of the study). 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Planned 
number of 
subjects) 
Part 1:  Phase 1b (Dose-Escalation and Dose-Expansion 
Portions of the Study) 
Part 1:  Phase 1b (Dose-Escalation and Dose-Expansion 
Portions of the Study) 
Study is 
longer 
divided into 
2 parts 
Synopsis 
(Planned 
number of 
subjects) 
A total enrollment of approximately 82 subjects is planned 
for Part 1 of the study.  During the Phase 1b Dose-Escalation 
portion of Part 1, approximately 21 subjects will be enrolled 
for each schedule.   
A total enrollment of approximately 82 subjects is planned 
for this study.  During the Dose-Escalation portion, 
approximately 21 subjects will be enrolled for each 
schedule.   
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Planned 
number of 
subjects) 
A minimum of 20 additional subjects are planned for 
enrollment for each schedule at the sponsor’s discretion and 
treatment at the RP3D during the Phase 1b Dose-Expansion 
portion of Part 1 of the study.   
Part 2:  Randomized Phase 3 Portion of the Study 
During Part 2, the planned enrollment is approximately 
270 subjects.   
A minimum of 20 additional subjects are planned for 
enrollment for each schedule at the sponsor’s discretion and 
treatment at the RP3D during the Phase 1b Dose-Expansion 
portion of Part 1 of the study.   
Part 2:  Randomized Phase 3 Portion of the Study 
During Part 2, the planned enrollment is approximately 
270 subjects. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 231


Clinical Study Protocol No. OPZ007 
Page 170 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Therefore, the total planned enrollment will be 
approximately 352 subjects. 
Therefore, the total planned enrollment will be 
approximately 352 subjects. 
Synopsis 
(Sample size 
justification) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Sample size 
justification) 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, 157 PFS events are 
required to detect a 45.7% reduction in the risk of PFS 
(hazard ratio [HR] = 0.543) with 95% power and a 1-sided 
significance level of 0.025.  Enrollment of 270 subjects 
(2:1 OPomd versus Pomd, respectively) is consistent with 
reaching the required 157 events in approximately 
14 months, assuming an enrollment rate of approximately 
22 subjects per month, a drop-out rate of 5% at 18 months, 
and a median PFS of 3.8 and 7 months for Pomd and 
OPomd, respectively. 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, 157 PFS events are 
required to detect a 45.7% reduction in the risk of PFS 
(hazard ratio [HR] = 0.543) with 95% power and a 1-sided 
significance level of 0.025.  Enrollment of 270 subjects 
(2:1 OPomd versus Pomd, respectively) is consistent with 
reaching the required 157 events in approximately 
14 months, assuming an enrollment rate of approximately 
22 subjects per month, a drop-out rate of 5% at 18 months, 
and a median PFS of 3.8 and 7 months for Pomd and 
OPomd, respectively. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Study 
population) 
The study population will consist of subjects with primary 
refractory or relapsed and refractory, multiple myeloma, 
i.e., those who have demonstrated disease progression on or
within 60 days of their last therapy, and who have received 
at least 2 prior lines of therapy (including bortezomib and 
lenalidomide and/or thalidomide, and in the dose-expansion 
and Phase 3 portions of the study only, been treated with 
adequate alkylator), and who are considered to be 
appropriate for this clinical study by their treating 
physicians. 
The study population will consist of subjects with primary 
refractory or relapsed and refractory, multiple myeloma, i.e., 
those who have demonstrated disease progression on or 
within 60 days of their last therapy, and who have received 
at least 2 prior lines of therapy (including bortezomib and 
lenalidomide and/or thalidomide, and in the dose-expansion 
and Phase 3 portions of the study only, been treated with 
adequate alkylator), and who are considered to be 
appropriate for this clinical study by their treating 
physicians. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Reference 
therapy dose, 
and mode of 
administration) 
Placebo 
Oprozomib placebo tablet for Phase 3 
Placebo 
Oprozomib placebo tablet for Phase 3 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 232


Clinical Study Protocol No. OPZ007 
Page 171 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Treatment 
regimen[s]) 
Oral oprozomib or placebo taken Days 1–5 and 15-19 or 
Days 1, 2, 8, 9, 15, 16, 22, and 23, pomalidomide taken on 
21 of 28 days, and oral dexamethasone taken on Days 1, 2, 
8, 9, 15, 16, 22, and 23 
Oral oprozomib or placebo taken Days 1–5 and 15–19 or 
Days 1, 2, 8, 9, 15, 16, 22, and 23, pomalidomide taken on 
21 of 28 days, and oral dexamethasone taken on Days 1, 2, 
8, 9, 15, 16, 22, and 23 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Inclusion 
criteria) 
Section 6.1 
(Inclusion 
Criteria) 
b. 
In the dose-expansion and Phase 3 portions of the 
study only:  In addition to the above, treatment with 
adequate alkylator therapy, defined as: 
b. 
In the dose-expansion and Phase 3 portions of the 
study only:  In addition to the above, treatment with 
adequate alkylator therapy, defined as: 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Exclusion 
criteria:  
Disease 
Related) 
Section 6.2 
(Exclusion 
Criteria) 
b. 
For the Dose-Expansion portion and Part 2 of the 
study:  Prior pomalidomide treatment of any duration 
b. 
For the Dose-Expansion portion and Part 2 of the 
study:  Prior pomalidomide treatment of any duration 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Criteria for 
evaluation – 
Other 
In the Phase 1b Dose-Escalation and Dose-Expansion 
portions of the study, blood samples will be collected from 
all subjects for determination of plasma concentrations of 
oprozomib at 1 predose time point and up to 7 postdose time 
points on Day 1 of Cycle 1 and Cycle 2 (0.25, 0.5, 1, 2, 3, 4, 
and 6 hours postdose) and 1 predose time point on Day 2 of 
Cycle 1 for both schedules. 
In the Phase 3 portion of the study, PK samples will be 
collected from all randomized subjects at Cycle 1 Day 1 and 
Cycle 3 Day 1 and will be analyzed for oprozomib 
concentrations in OPomd subjects. 
In the Phase 1b Dose-Escalation and Dose-Expansion 
portions of the study, blood samples will be collected from 
all subjects for determination of plasma concentrations of 
oprozomib at 1 predose time point and up to 7 postdose time 
points on Day 1 of Cycle 1 and Cycle 2 (0.25, 0.5, 1, 2, 3, 4, 
and 6 hours postdose) and 1 predose time point on Day 2 of 
Cycle 1 for both schedules. 
In the Phase 3 portion of the study, PK samples will be 
collected from all randomized subjects at Cycle 1 Day 1 and 
Cycle 3 Day 1 and will be analyzed for oprozomib 
concentrations in OPomd subjects. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 233


Clinical Study Protocol No. OPZ007 
Page 172 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Criteria for 
evaluation – 
Other) 
Blood samples for quantitation of proteasome inhibition by 
oprozomib will be collected from all subjects in the Phase 1b 
portion of the study.   
Blood samples for quantitation of proteasome inhibition by 
oprozomib will be collected from all subjects in this study.  
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Criteria for 
evaluation – 
Other 
Analysis of genomic biomarkers that may predict response 
and resistance following treatment with proteasome 
inhibitors will be conducted for all subjects receiving 
oprozomib from all phases of the study who consent to 
optional genomic biomarker analysis. 
Analysis of genomic biomarkers that may predict response 
and resistance following treatment with proteasome 
inhibitors will be conducted for all subjects receiving 
oprozomib from all phases of the study who consent to 
optional genomic biomarker analysis. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Synopsis 
(Criteria for 
evaluation – 
Other) 
Bone marrow aspirate or biopsy collection does not need to 
be repeated if previously completed within 45 days prior to 
Cycle 1 Day 1 dosing, and for Phase 3 only, if it was 
processed at the central laboratory.  Additional bone marrow 
samples for biomarkers may be collected at disease 
progression (End of Study Treatment due to progressive 
disease [PD] or Long-term Follow-up) from all subjects who 
consent. 
Bone marrow aspirate or biopsy collection does not need to 
be repeated if previously completed within 45 days prior to 
Cycle 1 Day 1 dosing, and for Phase 3 only, if it was 
processed at the central laboratory.  Additional bone marrow 
samples for biomarkers may be collected at disease 
progression (End of Study Treatment due to progressive 
disease [PD] or Long-term Follow-up) from all subjects who 
consent. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Synopsis 
(Statistical 
methods and 
analyses – 
Safety 
Population and 
Efficacy 
Population) 
Safety Population (All Subjects) 
For Part 1 (Phase 1b Dose Escalation and Expansion) and 
Part 2 (Randomized Phase 3 Portion) of the study, the safety 
population includes all subjects receiving any amount of 
study treatment (oprozomib, placebo, pomalidomide, or 
dexamethasone).   
Efficacy Population 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
For the Phase 1b Dose-Escalation and Expansion portions of 
the study, the efficacy population is equivalent to the safety 
population. 
Safety Population (All Subjects) 
The safety population includes all subjects receiving any 
amount of study treatment (oprozomib, pomalidomide, or 
dexamethasone).   
Efficacy Population 
For this study, the efficacy population is equivalent to the 
safety population. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 234


Clinical Study Protocol No. OPZ007 
Page 173 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, the efficacy population 
will include all randomized subjects according to 
randomized treatment, consistent with the intent-to-treat 
(ITT) principle. 
Synopsis 
(Statistical 
methods and 
analyses – 
Endpoints) 
Endpoints 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by Schedule) 
Endpoints 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by Schedule) 
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Statistical 
methods and 
analyses – 
Primary, 
Secondary, and 
Exploratory 
headings) 
Primary Endpoints-Part 1 
Secondary Endpoints-Part 1 
Exploratory Endpoints-Part 1 
Primary Endpoints-Part 1 
Secondary Endpoints-Part 1 
Exploratory Endpoints-Part 1 
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Statistical 
methods and 
analyses) 
Part 2:  Randomized Phase 3 Portion of the Study 
Primary Endpoint-Part 2 

Progression-free survival, defined as time from
randomization to the earlier of disease progression
Part 2:  Randomized Phase 3 Portion of the Study 
Primary Endpoint-Part 2 

Progression-free survival, defined as time from
randomization to the earlier of disease progression 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 235


Clinical Study Protocol No. OPZ007 
Page 174 of 223 
CONFIDENTIAL 
determined by ORCA according to the IMWG-URC, 
or death due to any cause 
Secondary Endpoints-Part 2 

Overall survival, defined as time from randomization
to death due to any cause

Overall response, defined as the best response of sCR,
CR, VGPR, or PR as determined by ORCA according
to the IMWG-URC

Clinical benefit, defined as the best response of MR or
better, as determined by ORCA according to the the
IMWG-URC and modified EBMT criteria

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease
progression as determined by ORCA according to the
IMWG-URC, or death due to any cause

Improvement in renal function, as defined by an
increase in GFR of at least 10 mL/min

Improvement in hemoglobin, as defined by an
increase of at least 2 g/dL

Adverse events and laboratory abnormalities graded
according to NCI-CTCAE, Version 4.03

Vital signs and clinical laboratory results during and
following study drug administration

Change over time in bone pain and the impact of bone
pain measured with the BPI-SF

Change over time in the global health status/QoL
scale of the EORTC QLQ-C30

Change over time in the disease symptoms subscale of
the EORTC QLQ-MY20

Change over time in neurotoxicity symptoms
measured by the FACT/GOG-Ntx4 score (Version 4)

Change over time in health status assessed by
EQ-5D-5L
determined by ORCA according to the IMWG-URC, 
or death due to any cause 
Secondary Endpoints-Part 2 

Overall survival, defined as time from randomization
to death due to any cause 

Overall response, defined as the best response of sCR,
CR, VGPR, or PR as determined by ORCA according 
to the IMWG-URC 

Clinical benefit, defined as the best response of MR or
better, as determined by ORCA according to the the 
IMWG-URC and modified EBMT criteria 

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease 
progression as determined by ORCA according to the 
IMWG-URC, or death due to any cause 

Improvement in renal function, as defined by an
increase in GFR of at least 10 mL/min 

Improvement in hemoglobin, as defined by an
increase of at least 2 g/dL 

Adverse events and laboratory abnormalities graded
according to NCI-CTCAE, Version 4.03 

Vital signs and clinical laboratory results during and
following study drug administration 

Change over time in bone pain and the impact of bone
pain measured with the BPI-SF 

Change over time in the global health status/QoL
scale of the EORTC QLQ-C30  

Change over time in the disease symptoms subscale of
the EORTC QLQ-MY20 

Change over time in neurotoxicity symptoms
measured by the FACT/GOG-Ntx4 score (Version 4) 

Change over time in health status assessed by
EQ-5D-5L 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 236


Clinical Study Protocol No. OPZ007 
Page 175 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 

Population based PK parameters including, but not
limited to, area under the plasma concentration-time
curve (AUC) and Cmax, will be determined from
OPomd subjects
Exploratory Endpoints-Part 2 

Progression-free survival and overall response as
determined by the investigator according to the
IMWG-URC

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease
progression as determined by the investigator
according to the IMWG-URC or death due to any
cause

Clinical benefit as determined by the investigator
according to the IMWG-URC and modified EBMT
criteria

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease
progression or death due to any cause, as determined
by ORCA and the investigator according to the
IMWG-URC and modified EBMT criteria

Genomic biomarkers that may be correlated with
antitumor activity and resistance following treatment
with proteasome inhibitors

Neuropathy events (defined as Grade 2 or higher
peripheral neuropathy )

Change over time in all domains of the EORTC
QLQ-C30 and EORTC
QLQ-MY20 (excluding the global health scale and
disease symptoms subscale, respectively)

Population based PK parameters including, but not
limited to, area under the plasma concentration-time 
curve (AUC) and Cmax, will be determined from 
OPomd subjects 
Exploratory Endpoints-Part 2 

Progression-free survival and overall response as
determined by the investigator according to the 
IMWG-URC 

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease 
progression as determined by the investigator 
according to the IMWG-URC or death due to any 
cause 

Clinical benefit as determined by the investigator
according to the IMWG-URC and modified EBMT 
criteria 

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease 
progression or death due to any cause, as determined 
by ORCA and the investigator according to the 
IMWG-URC and modified EBMT criteria 

Genomic biomarkers that may be correlated with
antitumor activity and resistance following treatment 
with proteasome inhibitors 

Neuropathy events (defined as Grade 2 or higher
peripheral neuropathy ) 

Change over time in all domains of the EORTC
QLQ-C30 and EORTC 
QLQ-MY20 (excluding the global health scale and 
disease symptoms subscale, respectively) 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 237


Clinical Study Protocol No. OPZ007 
Page 176 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Statistical 
methods and 
analyses – 
Efficacy 
Analyses) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Progression-free survival and duration of response will be 
listed for all subjects by dose level and schedule.  Overall 
response rate and clinical benefit rate will be estimated for 
all subjects treated at the RP3D along with the associated 
95% exact binomial confidence intervals (CIs). 
Part 2:  Randomized Phase 3 Portion of the Study 
The primary analysis of PFS and other efficacy endpoints 
will be based on the ITT population, defined as all subjects 
randomized.  The primary inferential comparison for PFS 
between treatment groups will use the log-rank test stratified 
by the randomization stratification factors.  The HR will be 
estimated using a stratified Cox proportional hazards model.  
The distribution of PFS, including medians, will be 
summarized descriptively using the Kaplan-Meier method 
for each treatment group. Overall survival will be analyzed 
using the same method as for PFS.  Duration of response and 
DOCB will be summarized for each treatment group by 
Kaplan-Meier method; however, no formal inferential 
comparisons will be made for these endpoints, as responders 
constitute a nonrandom subset of the ITT population. 
Point estimates and 95% exact binomial CIs will be 
calculated for the ORR and CBR for each treatment group.  
Inferential comparison between treatment groups for these 
endpoints will be made using the Cochran-Mantel Haenszel 
chi-square test, stratified by the randomization stratification 
factors. 
Inferential testing of the primary efficacy endpoint and 
selected secondary endpoints (OS, ORR, CBR, improvement 
in renal function, improvement in hemoglobin, change over 
time in QLQ-MY20 total scale, and change over time in 
QLQ-C30 total scale) will be performed against an overall 
1-sided significance level of 0.025 in accordance with a 
closed testing procedure.   
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Progression-free survival and duration of response will be 
listed for all subjects by dose level and schedule.  Overall 
response rate and clinical benefit rate will be estimated for 
all subjects treated at the RP3D along with the associated 
95% exact binomial confidence intervals (CIs). 
Part 2:  Randomized Phase 3 Portion of the Study 
The primary analysis of PFS and other efficacy endpoints 
will be based on the ITT population, defined as all subjects 
randomized.  The primary inferential comparison for PFS 
between treatment groups will use the log-rank test stratified 
by the randomization stratification factors.  The HR will be 
estimated using a stratified Cox proportional hazards model.  
The distribution of PFS, including medians, will be 
summarized descriptively using the Kaplan-Meier method 
for each treatment group. Overall survival will be analyzed 
using the same method as for PFS.  Duration of response and 
DOCB will be summarized for each treatment group by 
Kaplan-Meier method; however, no formal inferential 
comparisons will be made for these endpoints, as responders 
constitute a nonrandom subset of the ITT population. 
Point estimates and 95% exact binomial CIs will be 
calculated for the ORR and CBR for each treatment group.  
Inferential comparison between treatment groups for these 
endpoints will be made using the Cochran-Mantel Haenszel 
chi-square test, stratified by the randomization stratification 
factors. 
Inferential testing of the primary efficacy endpoint and 
selected secondary endpoints (OS, ORR, CBR, improvement 
in renal function, improvement in hemoglobin, change over 
time in QLQ-MY20 total scale, and change over time in 
QLQ-C30 total scale) will be performed against an overall 
1-sided significance level of 0.025 in accordance with a 
closed testing procedure.  
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
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Clinical Study Protocol No. OPZ007 
Page 177 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Synopsis 
(Statistical 
methods and 
analyses – 
Safety 
Analyses) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
For the Phase 1b portion of the study, safety will be assessed 
through summaries of DLTs, AEs, changes in laboratory test 
results, ECGs, vital signs, and oprozomib, pomalidomide, 
and dexamethasone exposure.  All AE data collected will be 
listed by study site, cohort, subject number, and study day. 
For this study, safety will be assessed through summaries of 
DLTs, AEs, changes in laboratory test results, ECGs, vital 
signs, and oprozomib, pomalidomide, and dexamethasone 
exposure.  All AE data collected will be listed by study site, 
cohort, subject number, and study day. 
Study is no 
longer 
divided into 
2 parts 
Synopsis 
(Statistical 
methods and 
analyses – 
Safety 
Analyses) 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, safety data will be 
summarized according to treatment actually received. 
Safety analyses will be presented separately for Part 1 and 
Part 2 of the study and will include all AEs occurring on or 
after treatment on Cycle 1 Day 1 summarized by system 
organ class and preferred term using the Medical Dictionary 
for Regulatory Activities (current version of MedDRA), and 
NCI-CTCAE (Version 4.03) toxicity grade.  In addition, all 
serious adverse events, including deaths, will be listed 
separately and summarized.  Safety will be assessed through 
summaries of changes in laboratory results, ECGs, and vital 
signs.  Extent of exposure to the study treatment will be 
summarized using descriptive statistics. 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, safety data will be 
summarized according to treatment actually received. 
Safety analyses will be presented separately for Part 1 and 
Part 2 of the study and will include all AEs occurring on or 
after treatment on Cycle 1 Day 1 summarized by system 
organ class and preferred term using the Medical Dictionary 
for Regulatory Activities (current version of MedDRA), and 
NCI-CTCAE (Version 4.03) toxicity grade.  In addition, all 
serious adverse events, including deaths, will be listed 
separately and summarized.  Safety will be assessed through 
summaries of changes in laboratory results, ECGs, and vital 
signs.  Extent of exposure to the study treatment will be 
summarized using descriptive statistics. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 239


Clinical Study Protocol No. OPZ007 
Page 178 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 3.1 
(Introduction) 
This is a Phase 1b/Phase 3 clinical trial of the oral 
proteasome inhibitor, oprozomib, in subjects with primary 
refractory or relapsed and refractory multiple myeloma. 
This is a Phase 1b/Phase 3 clinical trial of the oral 
proteasome inhibitor, oprozomib, in subjects with primary 
refractory or relapsed and refractory multiple myeloma. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 3.1 
(Introduction) 
New text added 
Amendment 3: 
1. 
Data collection for subjects on active treatment 
is being pared down due to both the completion of this 
study’s analysis and its abbreviated clinical study report. 
Update text 
to reflect 
the rationale 
for 
Amendment
 3 
Section 3.5.1 
(Oprozomib) 
This study will assess both schedules in Part 1 of the study, 
as oprozomib has demonstrated preliminary activity in 
subjects with hematologic malignancies on both schedules 
(Kaufman 2013). 
This study will assess both schedules in this study, as 
oprozomib has demonstrated preliminary activity in subjects 
with hematologic malignancies on both schedules 
(Kaufman, 2013). 
Study is no 
longer 
divided into 
2 parts 
Section 4 
(Study 
Objectives) 
4.1 
PART 1:  PHASE 1B DOSE-ESCALATION AND 
DOSE-EXPANSION PORTIONS OF THE STUDY (BY 
SCHEDULE) 
4.1 
PART 1:  PHASE 1B DOSE-ESCALATION AND 
DOSE-EXPANSION PORTIONS OF THE STUDY (BY 
SCHEDULE) 
Study is no 
longer 
divided into 
2 parts 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 240


Clinical Study Protocol No. OPZ007 
Page 179 of 223 
CONFIDENTIAL 
Section 4.5 
(Part 2:  
Randomization 
Phase 3 Portion 
of the Study) 
4.5 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
Phase 3 objectives involve comparison of key outcome 
measures for subjects with primary refractory or relapsed 
and refractory multiple myeloma who are randomized to 
either oprozomib or placebo in combination with 
pomalidomide and dexamethasone, hereafter denoted by 
OPomd or Pomd, respectively. 
4.5.1 
PRIMARY OBJECTIVE 

To compare progression free survival (PFS), as
determined by Onyx Response Computational
Assessment (ORCA) according to the IMWG-URC,
between subjects treated with OPomd and those
treated with Pomd
4.5.2 
SECONDARY OBJECTIVES 

To compare the following between subjects treated
with OPomd and those treated with Pomd:
o
Overall survival (OS)
o
Overall response rate (ORR), the clinical benefit
rate (CBR), and duration of response (DOR) as
determined by ORCA according to the
IMWG-URC and modified EBMT criteria
o
Incidence of improvement in renal function, as
defined by an increase in glomerular filtration
rate (GFR) of at least 10 mL/min over baseline
at least once after the start of treatment
o
Incidence of improvement in hemoglobin as
defined by an increase of at least 2 g/dL over
baseline at least once after the start of treatment
o
Safety and tolerability
4.5 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
Phase 3 objectives involve comparison of key outcome 
measures for subjects with primary refractory or relapsed 
and refractory multiple myeloma who are randomized to 
either oprozomib or placebo in combination with 
pomalidomide and dexamethasone, hereafter denoted by 
OPomd or Pomd, respectively. 
4.5.1 
PRIMARY OBJECTIVE 

To compare progression free survival (PFS), as
determined by Onyx Response Computational 
Assessment (ORCA) according to the IMWG-URC, 
between subjects treated with OPomd and those 
treated with Pomd 
4.5.2 
SECONDARY OBJECTIVES 

To compare the following between subjects treated
with OPomd and those treated with Pomd: 
o
Overall survival (OS)
o
Overall response rate (ORR), the clinical benefit
rate (CBR), and duration of response (DOR) as 
determined by ORCA according to the 
IMWG-URC and modified EBMT criteria  
o
Incidence of improvement in renal function, as
defined by an increase in glomerular filtration 
rate (GFR) of at least 10 mL/min over baseline 
at least once after the start of treatment 
o
Incidence of improvement in hemoglobin as
defined by an increase of at least 2 g/dL over 
baseline at least once after the start of treatment 
o
Safety and tolerability
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 241


Clinical Study Protocol No. OPZ007 
Page 180 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
o
Bone pain and the impact of bone pain measured
with the BPI-SF
o
Health-related quality of life (HRQoL)
measured by the global health status/QoL scale
of the EORTC QLQ-C30
o
Disease symptoms as measured by the disease
symptoms subscale of EORTC QLQ-MY20
o
Neurotoxicity symptoms as measured by the
neurotoxicity subscale of the FACT/GOG-Ntx4
(Version 4)
o
Health status assessed with EQ-5D-5L

To evaluate population-based PK parameters of
oprozomib in the OPomd regimen
4.5.3 
EXPLORATORY OBJECTIVES 
To compare the following between subjects treated with 
OPomd and those treated with Pomd:  

Progression-free survival (PFS) and ORR as
determined by the investigator according to the
IMWG-URC

Duration of response (DOR), defined as the time from
the first evidence of confirmed PR or better to disease
progression or death due to any cause as determined
by the investigator according to the IMWG-URC

Clinical benefit rate (CBR) as determined by the
investigator according to the IMWG-URC and
modified EBMT criteria

Duration of clinical benefit (DOCB), defined as the
time from first evidence of  MR or better to disease
progression or death due to any cause, as determined
o
Bone pain and the impact of bone pain measured
with the BPI-SF 
o
Health-related quality of life (HRQoL)
measured by the global health status/QoL scale 
of the EORTC QLQ-C30 
o
Disease symptoms as measured by the disease
symptoms subscale of EORTC QLQ-MY20 
o
Neurotoxicity symptoms as measured by the
neurotoxicity subscale of the FACT/GOG-Ntx4 
(Version 4) 
o
Health status assessed with EQ-5D-5L

To evaluate population-based PK parameters of
oprozomib in the OPomd regimen 
4.5.3 
EXPLORATORY OBJECTIVES 
To compare the following between subjects treated with 
OPomd and those treated with Pomd: 

Progression-free survival (PFS) and ORR as
determined by the investigator according to the 
IMWG-URC 

Duration of response (DOR), defined as the time from
the first evidence of confirmed PR or better to disease 
progression or death due to any cause as determined 
by the investigator according to the IMWG-URC 

Clinical benefit rate (CBR) as determined by the
investigator according to the IMWG-URC and 
modified EBMT criteria 

Duration of clinical benefit (DOCB), defined as the
time from first evidence of  MR or better to disease 
progression or death due to any cause, as determined 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 242


Clinical Study Protocol No. OPZ007 
Page 181 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
by ORCA and the investigator according to the 
IMWG-URC and the modified EBMT criteria 

Genomic biomarkers that may correlate with
antitumor activity and resistance following treatment
with proteasome inhibitors

The incidence of neuropathy (events are defined as
Grade 2 or higher peripheral neuropathy)

HRQoL assessed with subscale scores of EORTC
QLQ-C30 (excluding global health status scale) and
EORTC QLQ-MY20 (excluding disease symptom
subscale)
by ORCA and the investigator according to the 
IMWG-URC and the modified EBMT criteria 

Genomic biomarkers that may correlate with
antitumor activity and resistance following treatment 
with proteasome inhibitors 

The incidence of neuropathy (events are defined as
Grade 2 or higher peripheral neuropathy) 

HRQoL assessed with subscale scores of EORTC
QLQ-C30 (excluding global health status scale) and 
EORTC QLQ-MY20 (excluding disease symptom 
subscale) 
Section 5 
(Study Design) 
There are 2 parts to this study.  Part 1 includes an 
open-label, Phase 1b, dose-escalation and dose-expansion 
portion (the equivalent of a small Phase 2) during which the 
RP3D will be identified. 
This study includes an open-label, Phase 1b, dose-escalation 
and dose-expansion portion (the equivalent of a small 
Phase 2) during which the RP3D will be identified. 
The study is 
no longer 
divided into 
2 parts 
Section 5 
(Study Design) 
During the Phase 1b portion of the study, subjects will 
receive Oprozomib ER Tablets according to their assigned 
dose cohort 
During this study, subjects will receive Oprozomib ER 
Tablets according to their assigned dose cohort 
The study is 
no longer 
divided into 
2 parts 
Section 5 
(Study Design) 
Part 2 will consist of a placebo-controlled, double-blind, 
randomized Phase 3 component where subjects will be 
randomized to receive the RP3D of oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
Part 2 will consist of a placebo-controlled, double-blind, 
randomized Phase 3 component where subjects will be 
randomized to receive the RP3D of oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 243


Clinical Study Protocol No. OPZ007 
Page 182 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5 
(Study Design) 
During Part 2 of the study, subjects will be randomized to 
oprozomib in combination with pomalidomide and 
dexamethasone (OPomd) at the RP3D and schedule 
determined during Part 1 of the study or placebo in 
combination with pomalidomide and dexamethasone 
(Pomd). 
During Part 2 of the study, subjects will be randomized to 
oprozomib in combination with pomalidomide and 
dexamethasone (OPomd) at the RP3D and schedule 
determined during Part 1 of the study or placebo in 
combination with pomalidomide and dexamethasone 
(Pomd). 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 5 
(Study Design) 
Treatment cycles for both parts of the study will last 
28 days. 
Treatment cycles for both parts of the study will last 
28 days. 
Redundant 
text 
Section 5 
(Study Design) 
Details of the study assessments required for both parts of 
this study are provided in Appendices A1, A2, B1, B2, C1, 
and C2. 
Details of the study assessments required for this study are 
provided in Appendices A1, A2, B1, and B2. 
Removed 
reference to 
Phase 3 part 
of study. 
Section 5.1 
(Dose-
escalation and 
Dose-
expansion 
Portions of the 
Study) 
5.1 
PART 1:  PHASE 1B DOSE-ESCALATION AND 
DOSE-EXPANSION PORTIONS OF THE STUDY 
5.1 
PART 1:  PHASE 1B DOSE-ESCALATION AND 
DOSE-EXPANSION PORTIONS OF THE STUDY 
The study is 
no longer 
divided into 
2 parts 
Section 5.1 
(Dose-
escalation and 
Dose-
expansion 
Portions of the 
Study) 
In Part 1 of the study, the safety, MTD, PK/PDn, and RP3D 
of oprozomib when given in combination with 
pomalidomide and dexamethasone will be assessed using a 
standard 3 + 3 dose-escalation design. 
In this study, the safety, MTD, PK/PDn, and RP3D of 
oprozomib when given in combination with pomalidomide 
and dexamethasone will be assessed using a standard 
3 + 3 dose-escalation design. 
The study is 
no longer 
divided into 
2 parts 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 244


Clinical Study Protocol No. OPZ007 
Page 183 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5.1.1 
Dose-
escalations 
Schema for the 
5/14 Oprozomi
b Dosing 
Schedule 
The primary and alternative pathways for dose escalation of 
oprozomib and pomalidomide in the Phase 1b portion of the 
study for the 5/14 schedule are summarized in Table 3 
through Table 5; these are examples, and are not inclusive of 
all possible dose-escalation paths. 
The primary and alternative pathways for dose escalation of 
oprozomib and pomalidomide in the Phase 1b portion of the 
study for the 5/14 schedule are summarized in Table 3 
through Table 5; these are examples, and are not inclusive of 
all possible dose-escalation paths. 
The study is 
no longer 
divided into 
2 parts 
Section 5.1.3 
(Dose-limiting 
Toxicities) 
The decision to escalate to the next higher dose of 
oprozomib in the Phase 1b portion of the study will be based 
on an assessment of study drug-related DLTs during Cycle 1 
by the CSRC. 
The decision to escalate to the next higher dose of 
oprozomib in this study will be based on an assessment of 
study drug-related DLTs during Cycle 1 by the CSRC. 
The study is 
no longer 
divided into 
2 parts 
Section 5.1.4 
(Subject 
Replacement) 
In the Phase 1b portion of the study, subjects must meet the 
following criteria to be considered evaluable for MTD 
determination during the 4-week DLT evaluation period 
unless a DLT occurs before the subject receives all planned 
doses of oprozomib for both the 5/14 and 2/7 dosing 
schedules: 
Subjects must meet the following criteria to be considered 
evaluable for MTD determination during the 4-week DLT 
evaluation period unless a DLT occurs before the subject 
receives all planned doses of oprozomib for both the 
5/14 and 2/7 dosing schedules: 
The study is 
no longer 
divided into 
2 parts 
Section 5.1.5 
(Dose 
Expansion) 
Once the MTD and the recommended dose for the expansion 
phase have been determined, a minimum of 20 additional 
subjects at 1 or both schedules of oprozomib at the sponsor’s 
discretion will be enrolled in the dose-expansion portion of 
Part 1 in order to continue the evaluation of the safety and 
efficacy of the regimen as a prelude to initiation of the 
Phase 3 portion of the study. 
Once the MTD and the recommended dose for the expansion 
phase have been determined, a minimum of 20 additional 
subjects at 1 or both schedules of oprozomib at the sponsor’s 
discretion will be enrolled in the dose-expansion portion of 
the study in order to continue the evaluation of the safety 
and efficacy of the regimen. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 245


Clinical Study Protocol No. OPZ007 
Page 184 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5.2 
(Part 2:  
Randomization 
Phase 3 Portion 
of the Study) 
5.2 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
Part 2 will consist of a placebo-controlled, double-blind 
randomized Phase 3 component.  Enrollment to the Phase 3 
portion will not commence until the CSRC has evaluated all 
available safety information from a minimum of 10 subjects 
who have completed ≥ 2 cycles of therapy and enrollment of 
the remaining 10 subjects in the dose expansion has occurred 
at 1 or both schedules per the sponsor’s discretion.  This 
information will inform the selection of a RP3D and 
schedule by the sponsor and CSRC.  During Part 2, subjects 
will be randomized in a 2:1 to receive oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
5.2 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
Part 2 will consist of a placebo-controlled, double-blind 
randomized Phase 3 component.  Enrollment to the Phase 3 
portion will not commence until the CSRC has evaluated all 
available safety information from a minimum of 10 subjects 
who have completed ≥ 2 cycles of therapy and enrollment of 
the remaining 10 subjects in the dose expansion has occurred 
at 1 or both schedules per the sponsor’s discretion.  This 
information will inform the selection of a RP3D and 
schedule by the sponsor and CSRC.  During Part 2, subjects 
will be randomized in a 2:1 to receive oprozomib or placebo 
administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or 
unacceptable toxicity. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 5.2 
(Estimated 
Study Duration 
and Study 
Closure) – 
previously 
Section 5.3 in 
Amendment 2 
The total study duration is expected to be approximately 
32-33 months. 
The total study duration is expected to be approximately 
12-13 months. 
Changed to 
reflect 
removal of 
Part 2 
(Phase 3) of 
the study 
Section 5.2 
(Estimated 
Study Duration 
and Study 
Closure) – 
previously 
Section 5.3 in 
Amendment 2 

Approximately 13 additional months will be required
to enroll subjects in the Phase 3 portion of the study

Assuming an enrollment rate of 22 subjects per
month, it is estimated that the final analysis of PFS
will occur approximately 17 months after the first
subject is enrolled in the Phase 3 portion of the study

Approximately 13 additional months will be required
to enroll subjects in the Phase 3 portion of the study 

Assuming an enrollment rate of 22 subjects per
month, it is estimated that the final analysis of PFS 
will occur approximately 17 months after the first 
subject is enrolled in the Phase 3 portion of the study 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 246


Clinical Study Protocol No. OPZ007 
Page 185 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5.3 
(Minimizing 
Bias) – 
previously 
Section 5.4 in 
Amendment 2 
5.4.1 
RANDOMIZATION 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus placebo, 
respectively.  Central randomization will be implemented in 
this part of the study through the use of an Interactive Voice 
Response System/Interactive Web Response System 
(IVRS/IWRS). 
Eligible subjects will be stratified by: 

Age:  < 75 years old versus ≥ 75 years old

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  Carfilzomib-naïve/sensitive
versus carfilzomib-refractory.  Carfilzomib-sensitive
multiple myeloma patients are defined as having had
previously achieved a PR or greater with therapy that
includes carfilzomib (or carfilzomib monotherapy),
and did not experience PD until more than 60 days
after their last dose of carfilzomib.
Carfilzomib-refractory multiple myeloma is defined as
disease that is nonresponsive while on primary or
salvage therapy that includes carfilzomib, or that
progresses on or within 60 days of last therapy.
Within each stratum, treatment assignment will be made 
using a permuted block randomization scheme.   
Treatment will begin on the day of randomization, if 
possible, but not more than 5 calendar days after 
randomization according to treatment group assignment.  
Treatment initiation beyond 5 days after randomization must 
be approved by the Onyx medical monitor or designee. 
5.4.1 
RANDOMIZATION 
After screening and eligibility determination, eligible 
subjects will be randomized in a 2:1 ratio to receive a 
regimen consisting of OPomd or Pomd plus placebo, 
respectively.  Central randomization will be implemented in 
this part of the study through the use of an Interactive Voice 
Response System/Interactive Web Response System 
(IVRS/IWRS). 
Eligible subjects will be stratified by: 

Age:  < 75 years old versus ≥ 75 years old

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  Carfilzomib-naïve/sensitive
versus carfilzomib-refractory.  Carfilzomib-sensitive 
multiple myeloma patients are defined as having had 
previously achieved a PR or greater with therapy that 
includes carfilzomib (or carfilzomib monotherapy), 
and did not experience PD until more than 60 days 
after their last dose of carfilzomib. 
Carfilzomib-refractory multiple myeloma is defined as 
disease that is nonresponsive while on primary or 
salvage therapy that includes carfilzomib, or that 
progresses on or within 60 days of last therapy.    
Within each stratum, treatment assignment will be made 
using a permuted block randomization scheme.  
Treatment will begin on the day of randomization, if 
possible, but not more than 5 calendar days after 
randomization according to treatment group assignment.  
Treatment initiation beyond 5 days after randomization must 
be approved by the Onyx medical monitor or designee. 
Section 5.3.1 
(Blinding) – 
previously 
Section 5.4.2 in 
Amendment 2 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
Both the Phase 1b dose-escalation and -expansion portions 
of Part 1 are open-label. 
Both the dose-escalation and dose-expansion portions of this 
study are open-label. 
The study 
no longer is 
divided into 
2 parts 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 247


Clinical Study Protocol No. OPZ007 
Page 186 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 5.3.1 
(Blinding) – 
previously 
Section 5.4.2 in 
Amendment 2 
Part 2:  Randomized Phase 3 Portion of the Study 
The second part of the study is a Phase 3, randomized, 
double-blind, placebo-controlled, multicenter clinical trial.  
In accordance with regulatory reporting requirements, Onyx 
will unblind the identity of the study medication for all 
unexpected SAEs that are considered by the investigator to 
be related to the study drug (oprozomib).  Unblinding for 
other reasons except as noted above before final analysis of 
the primary efficacy endpoint is not permitted. 
Under no circumstances are subjects who enroll in this study 
permitted to be rerandomized to this study and enroll for a 
second course of treatment.  The password-protected and/or 
encrypted electronic randomization list will be kept in a 
central repository by the sponsor’s unblinding 
statistician.  An open key to the code will not be available at 
the study site, to the sponsor’s monitors, project statisticians, 
or the project team at Onyx.  All other individuals directly 
involved in this study will remain blinded until the final 
analysis of the primary efficacy endpoint.  
For Phase 3 only, an independent, external Data Monitoring 
Committee (DMC) will monitor the conduct of the study and 
undertake periodic unblinded assessments of safety data to 
protect the safety of study subjects and ensure integrity of 
the study. 
Part 2:  Randomized Phase 3 Portion of the Study 
The second part of the study is a Phase 3, randomized, 
double-blind, placebo-controlled, multicenter clinical trial.  
In accordance with regulatory reporting requirements, Onyx 
will unblind the identity of the study medication for all 
unexpected SAEs that are considered by the investigator to 
be related to the study drug (oprozomib).  Unblinding for 
other reasons except as noted above before final analysis of 
the primary efficacy endpoint is not permitted. 
Under no circumstances are subjects who enroll in this study 
permitted to be rerandomized to this study and enroll for a 
second course of treatment.  The password-protected and/or 
encrypted electronic randomization list will be kept in a 
central repository by the sponsor’s unblinding 
statistician.  An open key to the code will not be available at 
the study site, to the sponsor’s monitors, project statisticians, 
or the project team at Onyx.  All other individuals directly 
involved in this study will remain blinded until the final 
analysis of the primary efficacy endpoint. 
For Phase 3 only, an independent, external Data Monitoring 
Committee (DMC) will monitor the conduct of the study and 
undertake periodic unblinded assessments of safety data to 
protect the safety of study subjects and ensure integrity of 
the study. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 9 
(Study Drug) 
New text added 
No changes in drug product, dosage, or treatment-
regimen occurred in this protocol amendment from the 
previous version. 
Added text 
to explain 
no changes 
to dose in 
Amendment 
3 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 248


Clinical Study Protocol No. OPZ007 
Page 187 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 10.1 
(Oprozomib 
Treatment 
Administration) 
10.1 
OPROZOMIB AND PLACEBO TREATMENT 
ADMINISTRATION 
Oprozomib ER Tablets or placebo (for Phase 3 only) will be 
administered in single daily doses. 
10.1 
OPROZOMIB AND PLACEBO TREATMENT 
ADMINISTRATION 
Oprozomib ER Tablets or placebo (for Phase 3 only) will be 
administered in single daily doses. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.1 
(Oprozomib 
Treatment 
Administration) 
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, subjects who permanently discontinue 
pomalidomide or oprozomib may continue on study.  If both 
pomalidomide and oprozomib are permanently discontinued, 
study treatment will be discontinued but the subject will be 
followed until disease progression.  In the Phase 3 portion of 
the study, subjects who permanently discontinue any or all 
components of study treatment for reasons other than 
progressive disease will continue the remaining study 
treatment, if any, and be followed for disease progression. 
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, subjects who permanently discontinue 
pomalidomide or oprozomib may continue on study.  If both 
pomalidomide and oprozomib are permanently discontinued, 
study treatment will be discontinued but the subject will be 
followed until disease progression.  In the Phase 3 portion of 
the study, subjects who permanently discontinue any or all 
components of study treatment for reasons other than 
progressive disease will continue the remaining study 
treatment, if any, and be followed for disease progression. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.2 
(Pomalidomide 
Treatment 
Administration) 
The starting dose of pomalidomide for the Phase 1b portion 
of the study is 4 mg once daily, orally, on Days 1–21 of 
repeated 28-day cycles until disease progression. 
The starting dose of pomalidomide for this study is 4 mg 
once daily, orally, on Days 1–21 of repeated 28-day cycles 
until disease progression. 
The study is 
no longer 
divided into 
2 parts 
Section 10.4 
(Dose 
Modification 
Guidelines) 
Monotherapy with dexamethasone is not allowed in the 
Phase 1b dose-escalation and dose-expansion portions of the 
study.  In the event that oprozomib or pomalidomide is 
permanently discontinued in Phase 3 only, dexamethasone 
may be continued.   
Monotherapy with dexamethasone is not allowed in the 
Phase 1b dose-escalation and dose-expansion portions of the 
study.  In the event that oprozomib or pomalidomide is 
permanently discontinued in Phase 3 only, dexamethasone 
may be continued.  
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.4.1 
(Dose 
Reductions) 
For the Phase 1b study, the initial cohort will start at an 
oprozomib dose level of 150 mg for the 5/14 schedule and 
210 mg for the 2/7 schedule. 
For this study, the initial cohort will start at an oprozomib 
dose level of 150 mg for the 5/14 schedule and 210 mg for 
the 2/7 schedule. 
The study is 
no longer 
divided into 
2 parts 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 249


Clinical Study Protocol No. OPZ007 
Page 188 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 10.4.1 
(Dose 
Reductions) 
Modifications of the dose of oprozomib/placebo will occur 
in up to three 30-mg decrements down to a minimum dose of 
150 mg. 
Modifications of the dose of oprozomib/placebo will occur 
in up to three 30-mg decrements down to a minimum dose of 
150 mg. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.4.1 
(Dose 
Reductions) 
For Parts 1 and 2 of the study, dose reduction levels for 
pomalidomide are provided in Table 11.   
The dose reduction levels for pomalidomide are provided in 
Table 11.   
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.4.1 
(Dose 
Reductions) 
In the event oprozomib or pomalidomide is permanently 
discontinued in Phase 3 only, dexamethasone may be 
continued.   
In the event oprozomib or pomalidomide is permanently 
discontinued in Phase 3 only, dexamethasone may be 
continued. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 10.5 
(Definition of 
Dose-limiting 
Toxicity) 
During the Phase 1b portion of the study, assessment of 
DLTs will occur during the 28-day period of Cycle 1 
combination therapy. 
During this study, assessment of DLTs will occur during the 
28-day period of Cycle 1 combination therapy. 
The study is 
no longer 
divided into 
2 parts. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 250


Clinical Study Protocol No. OPZ007 
Page 189 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 11.3 
(Disease 
Response 
Assessments) 
The schedule of disease assessments for treated subjects is 
provided in Appendices A1, A2, B1, B2, C1, and C2.  
Disease response will be assessed by the investigator.  
Beginning with Cycle 1, assessments are to be completed at 
the end of every 4-week cycle for the first 18 months of 
study treatment, and then at the end of every other cycle 
(every 8 weeks), beginning with Month 20, for the 
remainder of study treatment and throughout long-term 
follow-up. 
The schedule of disease assessments for treated subjects is 
provided in Appendices A1, A2, B1, and B2, C1, and C2.  
Disease response will be assessed by the investigator.  
Beginning with Cycle 1, assessments are to be completed at 
the end of every 4-week cycle for the first 18 months of 
study treatment, and then at the end of every other cycle 
(every 8 weeks), beginning with Month 20, for the 
remainder of study treatment and throughout long-term 
follow-up. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Section 11.4.1 
(Pharmacokinet
ic 
Measurements) 
11.4.1.1 PHASE 1B DOSE ESCALATION AND 
EXPANSION 
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, blood samples will be collected from all 
subjects from both schedules to measure plasma 
concentrations of oprozomib at 1 predose time point and up 
to 7 postdose time points on Day 1 of Cycle 1 and Cycle 2 
(0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose) and 1 predose 
time point on Day 2 of Cycle 1.  Estimates of oprozomib PK 
parameters will be determined when possible. 
11.4.1.2 Phase 3 
In the Phase 3 portion of the study, samples will be collected 
from all subjects enrolled in the OPomd and the Pomd + 
placebo treatment arms.  The plasma samples will be 
randomly obtained from each sampling window below on 
Day 1 of Cycle 1 and Cycle 3.  The first postdose sampling 
window in Cycle 1 and Cycle 3 will be between 1 to 
2.5 hours and the second postdose sampling window will be 
between 2.75 to 5 hours.  Plasma samples from the OPomd 
arm will be analyzed for oprozomib concentrations (note the 
difference between sample collection and sample analysis).  
Population PK parameter estimates and variability in these 
estimates will be determined using a population-based 
analysis method. 
11.4.1.1 PHASE 1B DOSE ESCALATION AND 
EXPANSION 
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, blood samples will be collected from all 
subjects from both schedules to measure plasma 
concentrations of oprozomib at 1 predose time point and up 
to 7 postdose time points on Day 1 of Cycle 1 and Cycle 2 
(0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose) and 1 predose 
time point on Day 2 of Cycle 1.  Estimates of oprozomib PK 
parameters will be determined when possible. 
11.4.1.2 Phase 3 
In the Phase 3 portion of the study, samples will be collected 
from all subjects enrolled in the OPomd and the Pomd + 
placebo treatment arms.  The plasma samples will be 
randomly obtained from each sampling window below on 
Day 1 of Cycle 1 and Cycle 3.  The first postdose sampling 
window in Cycle 1 and Cycle 3 will be between 1 to 2.5 
hours and the second postdose sampling window will be 
between 2.75 to 5 hours.  Plasma samples from the OPomd 
arm will be analyzed for oprozomib concentrations (note the 
difference between sample collection and sample analysis). 
Population PK parameter estimates and variability in these 
estimates will be determined using a population-based 
analysis method. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 251


Clinical Study Protocol No. OPZ007 
Page 190 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 11.4.2 
(Pharmacodyna
mic 
Measurements) 
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, blood samples for the quantitation of 
proteasome inhibition by oprozomib will be collected from 
all subjects for both schedules at 1 predose time point, up to 
2 postdose time points (4 and 6 hours postdose) on Day 1 of 
Cycle 1 and Cycle 2, and 1 predose timepoint on Day 2 of 
Cycle 1.  These timepoints are also specified in the 
Laboratory Manual.  Blood samples for PDn analyses will 
not be collected in Phase 3.   
In the Phase 1b dose-escalation and dose-expansion portions 
of the study, blood samples for the quantitation of 
proteasome inhibition by oprozomib will be collected from 
all subjects for both schedules at 1 predose time point, up to 
2 postdose time points (4 and 6 hours postdose) on Day 1 of 
Cycle 1 and Cycle 2, and 1 predose timepoint on Day 2 of 
Cycle 1.  These timepoints are also specified in the 
Laboratory Manual.  Blood samples for PDn analyses will 
not be collected in Phase 3.   
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 11.4.3 
(Genomic 
Measurements) 
Analysis of genomic biomarkers that may predict for 
response and resistance following treatment with proteasome 
inhibitors will be conducted for all subjects from all phases 
of the study who consent to optional genomic biomarker 
analysis. 
Analysis of genomic biomarkers that may predict for 
response and resistance following treatment with proteasome 
inhibitors will be conducted for all subjects in the study who 
consent to optional genomic biomarker analysis. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 11.4.3 
(Genomic 
Measurements) 
Bone marrow aspirate or biopsy collection does not need to 
be repeated if previously completed within 45 days prior to 
Cycle 1 Day 1 dosing, and for Phase 3 only, if it was 
processed at the central laboratory.  Additional bone marrow 
samples for biomarkers may be collected at disease 
progression (End of Study Treatment due to PD or 
Long-Term Follow-Up) from all subjects who consent.   
Bone marrow aspirate or biopsy collection does not need to 
be repeated if previously completed within 45 days prior to 
Cycle 1 Day 1 dosing, and for Phase 3 only, if it was 
processed at the central laboratory.  Additional bone marrow 
samples for biomarkers may be collected at disease 
progression (End of Study Treatment due to PD or 
Long-Term Follow-Up) from all subjects who consent.   
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Section 11.5 
(Patient-
reported 
Outcomes 
Assessments 
Beginning with Cycle 1, HRQoL/PRO assessments are to be 
completed at the beginning of every cycle prior to drug 
administration through End of Study Treatment/Early 
Discontinuation visit during the dose-expansion portion of 
the trial, and at the beginning of every cycle prior to drug 
administration through End of Study Treatment/Early 
Discontinuation visit and then every 12 weeks during the 
long-term follow-up in the Phase 3 portion of the study. 
Beginning with Cycle 1, HRQoL/PRO assessments are to be 
completed at the beginning of every cycle prior to drug 
administration through End of Study Treatment/Early 
Discontinuation visit during the dose-expansion portion of 
the trial, and at the beginning of every cycle prior to drug 
administration through End of Study Treatment/Early 
Discontinuation visit and then every 12 weeks during the 
long-term follow-up in the Phase 3 portion of the study. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 252


Onyx Therapeutics 
Clinical Study Protocol No. OPZ007 
Oprozomib ER Tablets 
Page 191 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 12 
(Study and 
Study 
Treatment 
Discontinuation
) 
New text added 
Any subject who withdraws without PD will no longer be 
followed with long-term assessments every 4 weeks through 
18 months on study, and then every 8 weeks thereafter, 
beginning with Month 20, until progression or initiation of 
next therapy under Amendment 3. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Section 12.1 
(Study 
Treatment 
Discontinuation
) 
For both parts of the study, subjects may withdraw from 
study treatment at any time. 
For this study, subjects may withdraw from study treatment 
at any time. 
Study is no 
longer 
divided into 
2 parts 
Section 12.1 
(Study 
Treatment 
Discontinuation
) 
Part 1 Phase 1b Dose Escalation and Expansion Only 
Part 1 Phase 1b Dose Escalation and Expansion Only 
Study is no 
longer 
divided into 
2 parts 
Section 12.3 
(Long-term 
Follow-up 
After completion of the End of Study Treatment visit, 
subjects will be followed for disease progression, OS, and 
quality of life (QOL).   
After completion of the End of Study Treatment visit, 
subjects will be followed for disease progression, OS, and 
quality of life (QOL).   
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 253


Clinical Study Protocol No. OPZ007 
Page 192 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 12.3 
(Long-term 
Follow-up 

For subjects who have not progressed at end of study
treatment, disease response assessments will be
performed every 4 weeks through 18 months on study,
and then every 8 weeks thereafter, beginning with
Month 20, until progression or initiation of next
therapy

For subjects who have not progressed at end of study
treatment, disease response assessments will no
longer be performed every 4 weeks through
18 months on study, and then every 8 weeks
thereafter, beginning with Month 20, until progression
or initiation of next therapy under Amendment 3
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Section 12.3 
(Long-term 
Follow-up) 
Quality of Life 

For Phase 3 only, in long-term follow-up, QOL
questionnaires will be collected from subjects
(regardless of disease status) every 12 weeks.
Quality of Life 

For Phase 3 only, in long-term follow-up, QOL
questionnaires will be collected from subjects 
(regardless of disease status) every 12 weeks.  
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 12.4 
(Study 
Treatment) 

The DMC recommends termination of the Phase 3
portion of the study

The DMC recommends termination of the Phase 3
portion of the study 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 254


Clinical Study Protocol No. OPZ007 
Page 193 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 13.5 
(Serious 
Adverse Event 
Reporting and 
Documentation 
Requirements) 
Onyx Drug Safety must be notified of the occurrence of any 
SAE within 24 hours of the investigator, designee, or site 
personnel’s knowledge of the event.  The SAE will be 
reported by completing and submitting the SAE report form 
through the EDC system.  In the event that the EDC system 
is not available, paper SAE report forms may be used to 
report the 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 of the 
occurrence of any SAE within 24 hours of the investigator, 
designee, or site personnel’s knowledge of the event.  
The SAE will be reported by completing and submitting the 
SAE report form through the EDC system.  In the event that 
the EDC system is not available, paper SAE report forms 
may be used to report the 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 Contingency Report Form (see 
Appendix N) 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 off line 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 off line, then the site can report this 
information on a paper Serious Adverse Event Report 
Form (see Appendix N). 
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 
event data to Amgen Global Patient Safety within 
24 hours of receipt of the information. 
Update 
safety 
reporting 
language 
with latest 
template. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 255


Clinical Study Protocol No. OPZ007 
Page 194 of 223 
CONFIDENTIAL 
Section 13.6 
(Pregnancy 
Reporting) 
Pregnancy occurring in a female subject, or in a male 
subject’s partner, while enrolled in this clinical trial through 
30 days after the subject’s last dose of study drug, although 
not considered an SAE, must be reported to Onyx Drug 
Safety on a Pregnancy Reporting Form within 24 hours of 
the investigator, designee, or site personnel learning of the 
event.  If the subject is pregnant, all study treatment must be 
discontinued immediately and the pregnancy must be 
reported to the investigator and sponsor within 24 hours. 
In the event of a pregnancy in the partner of a male subject, 
the pregnant partner will be asked to complete an 
authorization form prior to the collection of any pregnancy 
data.  If such authorization is provided by the partner, the 
investigator will follow the pregnancy of the male subject’s 
partner until completion or termination of the pregnancy.  
Any abnormal maternal, fetal, or neonatal outcomes must be 
reported to Onyx Drug Safety as a follow-up on the 
Pregnancy Reporting Form within the same time parameters 
as stated above for report of a pregnancy.  If the outcome of 
the pregnancy meets an SAE criterion (e.g., spontaneous 
abortion, stillbirth, neonatal death, or fetal or neonatal 
congenital anomaly), the investigator will report the SAE 
through the EDC system. 
A fetus exposed to study drug by a parent (female subject or 
male subject’s partner) will be followed until a minimum of 
12 weeks after birth.  Follow-up may be extended at the 
discretion of the Onyx study medical monitor.  All findings 
inclusive of SAEs will be reported to Onyx Drug Safety 
within 24 hours of the investigator, designee, or site 
personnel learning of the event.  Subject to the parents’ 
continuing authorization, SAEs that may occur in these 
infants will be reported to Onyx Drug Safety. 
Pregnancy occurring in a female subject, or in a male 
subject’s partner, while enrolled in this clinical trial through 
30 days after the subject’s last dose of study drug, although 
not considered an SAE, must be reported to Amgen Global 
Patient Safety on an Amgen Pregnancy Notification 
Worksheet (Appendix O) within 24 hours of the 
investigator, designee, or site personnel learning of the 
event.  If the subject is pregnant, all study treatment must be 
discontinued immediately and the pregnancy must be 
reported to the investigator and sponsor within 24 hours.  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 O).  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).
Update 
pregnancy 
reporting 
language 
with latest 
template. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
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Clinical Study Protocol No. OPZ007 
Page 195 of 223 
CONFIDENTIAL 

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 13.5.  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
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
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Clinical Study Protocol No. OPZ007 
Page 196 of 223 
CONFIDENTIAL 
discontinuing protocol-required therapies, the 
information will be recorded on the Pregnancy 
Notification Worksheet (Appendix O).  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 P) and submitted
to Amgen Global Patient Safety within 24 hours of
the investigator’s knowledge of event.
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 

Study treatment will be discontinued if female
subject breastfeeds during the study as described in
exclusion criterion 22.
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 14.1 
(Study 
Endpoints) 
14.1.1 
PART 1:  PHASE 1B DOSE ESCALATION AND 
DOSE EXPANSION PORTIONS OF THE STUDY (BY 
SCHEDULE) 
14.1.1 
PART 1:  PHASE 1B DOSE ESCALATION AND 
DOSE EXPANSION PORTIONS OF THE STUDY (BY 
SCHEDULE) 
The study is 
no longer 
divided into 
2 parts 
Section 14.1.1 
(Primary 
Endpoints) – 
previously 
Section 14.1.1.
1 in 
Amendment 2 
14.1.1 
PRIMARY ENDPOINTS-PART 1 
14.1.1 
PRIMARY ENDPOINTS-PART 1 
The study is 
longer 
divided into 
2 parts 
Section 14.1.2 
(Secondary 
Endpoints) – 
previously 
Section 14.1.1.
2 in 
Amendment 2 
14.1.2 
SECONDARY ENDPOINTS-PART 1 
14.1.2 
SECONDARY ENDPOINTS-PART 1 
The study is 
no longer 
divided into 
2 parts 
Section 14.1.3 
(Exploratory 
Endpoints) – 
previously 
Section 14.1.1.
3 in 
Amendment 2 
14.1.3 
EXPLORATORY ENDPOINTS-PART 1 
14.1.3 
EXPLORATORY ENDPOINTS-PART 1 
The study is 
no longer 
divided into 
2 parts 
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CONFIDENTIAL 
Section 14.1.2 
(Part 2:  
Randomized 
Phase 3 Portion 
of the Study) 
14.1.2 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
14.1.2.1 Primary Endpoint-Part 2 

Progression-free survival, defined as time from
randomization to the earlier of disease progression
determined by ORCA according to the IMWG-URC,
or death due to any cause.
14.1.2.2 Secondary Endpoints-Part 2 

Overall survival defined as time from randomization
to death due to any cause

Overall response, defined as the best response of sCR,
CR, VGPR, or PR as determined by ORCA according
to the IMWG-URC

Clinical benefit, defined as the best response of MR or
better, as determined by ORCA according to the
IMWG-URC and modified EBMT criteria

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease
progression, as determined by ORCA according to the
IMWG-URC, or death due to any cause

Improvement in renal function, as defined by an
increase in GFR of at least 10 mL/min

Improvement in hemoglobin, as defined by an
increase of at least 2 g/dL

Adverse events and laboratory abnormalities graded
according to NCI-CTCAE, Version 4.03

Vital signs and clinical laboratory results during and
following study drug administration

Bone pain and the impact of bone pain measured with
the BPI-SF

Change over time in the global health status/QoL
scale of the EORTC QLQ-C30

Change over time in the disease symptoms subscale of
the EORTC QLQ-MY20
14.1.2 
PART 2:  RANDOMIZED PHASE 3 PORTION 
OF THE STUDY 
14.1.2.1 Primary Endpoint-Part 2 

Progression-free survival, defined as time from
randomization to the earlier of disease progression 
determined by ORCA according to the IMWG-URC, 
or death due to any cause. 
14.1.2.2 Secondary Endpoints-Part 2 

Overall survival defined as time from randomization
to death due to any cause 

Overall response, defined as the best response of sCR,
CR, VGPR, or PR as determined by ORCA according 
to the IMWG-URC 

Clinical benefit, defined as the best response of MR or
better, as determined by ORCA according to the 
IMWG-URC and modified EBMT criteria 

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease 
progression, as determined by ORCA according to the 
IMWG-URC, or death due to any cause 

Improvement in renal function, as defined by an
increase in GFR of at least 10 mL/min 

Improvement in hemoglobin, as defined by an
increase of at least 2 g/dL 

Adverse events and laboratory abnormalities graded
according to NCI-CTCAE, Version 4.03 

Vital signs and clinical laboratory results during and
following study drug administration 

Bone pain and the impact of bone pain measured with
the BPI-SF 

Change over time in the global health status/QoL
scale of the EORTC QLQ-C30  

Change over time in the disease symptoms subscale of
the EORTC QLQ-MY20 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 

Change over time in neurotoxicity symptoms
measured by the FACT/GOG-Ntx4 score (Version 4)

Change over time in health status assessed by
EQ-5D-5L

Population based PK parameters including, but not
limited to, area under the plasma concentration time
curve (AUC) and Cmax, determined for OPomd
subjects
14.1.2.3 Exploratory Endpoints-Part 2 

Progression-free survival and overall response, as
determined by the investigator according to the
IMWG-URC

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease
progression as determined by the investigator
according to the IMWG-URC or death due to any
cause

Clinical benefit as determined by the investigator
according to the IMWG-URC and modified EBMT
criteria

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease
progression or death due to any cause, as determined
by ORCA and the investigator according to the
IMWG-URC and modified EBMT criteria

Genomic biomarkers that may be correlated with
antitumor activity and resistance following treatment
with proteasome inhibitors

Neuropathy events (defined as Grade 2 or higher
peripheral neuropathy)

Change over time in all domains of the EORTC
QLQ-C30 and EORTC QLQ-MY20 (excluding the
global health scale and disease symptoms subscale,
respectively)

Change over time in neurotoxicity symptoms
measured by the FACT/GOG-Ntx4 score (Version 4) 

Change over time in health status assessed by
EQ-5D-5L 

Population based PK parameters including, but not
limited to, area under the plasma concentration time 
curve (AUC) and Cmax, determined for OPomd 
subjects 
14.1.2.3 Exploratory Endpoints-Part 2 

Progression-free survival and overall response, as
determined by the investigator according to the 
IMWG-URC 

Duration of response, defined as the time from the
first evidence of confirmed PR or better to disease 
progression as determined by the investigator 
according to the IMWG-URC or death due to any 
cause 

Clinical benefit as determined by the investigator
according to the IMWG-URC and modified EBMT 
criteria 

Duration of clinical benefit (DOCB), defined as the
time from first evidence of MR or better to disease 
progression or death due to any cause, as determined 
by ORCA and the investigator according to the 
IMWG-URC and modified EBMT criteria 

Genomic biomarkers that may be correlated with
antitumor activity and resistance following treatment 
with proteasome inhibitors 

Neuropathy events (defined as Grade 2 or higher
peripheral neuropathy) 

Change over time in all domains of the EORTC
QLQ-C30 and EORTC QLQ-MY20 (excluding the 
global health scale and disease symptoms subscale, 
respectively) 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 14.3 
(Data 
Monitoring 
Committee) 
In Part 1 of the study, safety will be monitored by a CSRC 
for both the Phase 1b dose-escalation and dose-expansion 
portions of the study.  
In the Phase 3 portion of the study, no formal efficacy 
interim analyses are planned for the PFS primary endpoint.  
An interim analysis of OS, the key secondary endpoint, is 
planned at the time of primary analysis of PFS.  Details of 
the efficacy monitoring plan for OS are described in 
Section 14.5.2.2.  
Overall survival may be evaluated by the DMC in their 
ongoing safety review during the course of the study.  As the 
objective of this evaluation is not to declare OS efficacy 
before the planned efficacy interim and final analyses of OS, 
alpha level will not be adjusted for these reviews.  
An independent DMC will be convened for the Phase 3 
portion of the study and will act in an advisory capacity to 
the sponsor with respect to safeguarding the interests of 
study subjects, assessing interim safety and efficacy (OS 
secondary only) data, and for monitoring the overall conduct 
of the study.  To enhance the integrity of the study, the DMC 
may also formulate recommendations relating to the 
selection, recruitment, and retention of subjects, 
management of subjects, improving adherence to protocol 
treatment, and the procedures for data management and 
quality control.  
The DMC will meet to review safety data on a periodic 
basis, but no less frequently than approximately every 
6 months.  The initial meeting should occur within 3 months 
after approximately 30 subjects are enrolled in the Phase 3 
portion of the study.  Unplanned safety review meetings of 
the DMC may be called at any time by the sponsor or the 
DMC Chair if additional review of safety data is warranted. 
The membership criteria and other details of the DMC will 
be described in the DMC Charter. 
In this study, safety will be monitored by a CSRC for both 
the dose-escalation and dose-expansion portions of the 
study.  
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 
14.5.1.1 (Safety 
Population) 
All subjects receiving any amount of study treatment 
(oprozomib, placebo, pomalidomide, or dexamethasone) will 
be included in safety analyses.  In the Phase 3 portion of the 
study, subjects will be included in the treatment group 
corresponding to the actual treatment received.   
All subjects receiving any amount of study treatment 
(oprozomib, placebo, pomalidomide, or dexamethasone) will 
be included in safety analyses.  In the Phase 3 portion of the 
study, subjects will be included in the treatment group 
corresponding to the actual treatment received. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 
14.5.1.2 
(Efficacy 
Population) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
For Part 1 of the study, the efficacy population is equivalent 
to the safety population. 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, the efficacy population 
will include all randomized subjects as randomized, 
i.e., according to the intent to treat (ITT) principle.
For this study, the efficacy population is equivalent to the 
safety population. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 14.5.2 
(Efficacy 
Analyses) 
All efficacy analyses will be presented separately for Part 1 
and Part 2 of the study. 
14.5.2.1 Part 1:  Phase 1b Dose-Escalation and 
Dose-Expansion Portions of the Study 
All efficacy analyses will be presented separately for Part 1 
and Part 2 of the study. 
14.5.2.1 Part 1:  Phase 1b Dose-Escalation and 
Dose-Expansion Portions of the Study 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Section 14.5.2 
(Efficacy 
Analyses) 
14.5.2.2 Part 2:  Randomized Phase 3 Portion of the Study 
Unless otherwise noted, all primary and secondary efficacy 
analyses will include all randomized subjects analyzed 
according to the ITT principle (Section 14.5.1), i.e., subjects 
will be analyzed by the treatment assigned at randomization. 
Primary Efficacy Analysis 
The primary efficacy endpoint for the Phase 3 portion of the 
study is PFS, defined as the time from randomization to the 
earlier of disease progression or death due to any cause.  
Disease progression will be determined using the 
IMWG-URC (Appendix D).  Response and disease 
progression will be determined using a validated computer 
algorithm (ORCA) as well as by local investigators.  The 
primary analysis of PFS will be based on ORCA-assessed 
outcomes.  The PFS outcomes assessed by the investigators 
will serve as a supportive analysis of the primary analysis of 
PFS. 
For purposes of calculating PFS, the start date for PD is the 
date at which progression is first observed.  The duration of 
PFS will be right censored according to the conventions 
described in Table 18. 
Table 18 Date of Progression or Censoring for Progression 
free Survival 
Situation 
Date of Progression 
or Censoring 
Outcome 
No baseline disease 
assessments 
Date of 
randomization 
Censored 
No postbaseline 
disease assessments 
and alive 
Date of 
randomization + 1 
day 
Censored 
New anticancer 
treatment started 
before 
documentation of 
PD or death 
Date of last disease 
assessment prior to 
start of a new 
anticancer treatment 
Censored 
14.5.2.2 Part 2:  Randomized Phase 3 Portion of the Study 
Unless otherwise noted, all primary and secondary efficacy 
analyses will include all randomized subjects analyzed 
according to the ITT principle (Section 14.5.1), i.e., subjects 
will be analyzed by the treatment assigned at randomization. 
Primary Efficacy Analysis 
The primary efficacy endpoint for the Phase 3 portion of the 
study is PFS, defined as the time from randomization to the 
earlier of disease progression or death due to any cause.  
Disease progression will be determined using the 
IMWG-URC (Appendix D).  Response and disease 
progression will be determined using a validated computer 
algorithm (ORCA) as well as by local investigators.  The 
primary analysis of PFS will be based on ORCA-assessed 
outcomes.  The PFS outcomes assessed by the investigators 
will serve as a supportive analysis of the primary analysis of 
PFS. 
For purposes of calculating PFS, the start date for PD is the 
date at which progression is first observed.  The duration of 
PFS will be right censored according to the conventions 
described in Table 18. 
Table 18 Date of Progression or Censoring for Progression 
free Survival 
Situation 
Date of Progression 
or Censoring 
Outcome 
No baseline disease 
assessments 
Date of 
randomization 
Censored 
No postbaseline 
disease assessments 
and alive 
Date of 
randomization + 1 
day 
Censored 
New anticancer 
treatment started 
before 
documentation of 
PD or death 
Date of last disease 
assessment prior to 
start of a new 
anticancer treatment 
Censored 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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CONFIDENTIAL 
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 primary analysis of PFS will be conducted when 
157 PFS events have occurred.    
The primary inferential comparison between treatment 
groups for PFS will be based on the stratified log-rank test at 
an overall 0.025 (1-sided) significance level using 
randomization stratification factors as strata: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  carfilzomib naïve/sensitive versus
carfilzomib-refractory. Carfilzomib-sensitive multiple
myeloma patients are defined as having had
previously achieved a PR or greater with therapy that
includes carfilzomib (or carfilzomib monotherapy),
and did not experience PD until more than 60 days
after their last dose of carfilzomib.
Carfilzomib-refractory multiple myeloma is defined as
disease that is nonresponsive while on primary or
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 primary analysis of PFS will be conducted when 
157 PFS events have occurred. 
The primary inferential comparison between treatment 
groups for PFS will be based on the stratified log-rank test at 
an overall 0.025 (1-sided) significance level using 
randomization stratification factors as strata: 

Age:  < 75 years versus ≥ 75 years

Number of prior therapies:  2 versus 3 or more

Carfilzomib status:  carfilzomib naïve/sensitive versus
carfilzomib-refractory. Carfilzomib-sensitive multiple 
myeloma patients are defined as having had 
previously achieved a PR or greater with therapy that 
includes carfilzomib (or carfilzomib monotherapy), 
and did not experience PD until more than 60 days 
after their last dose of carfilzomib. 
Carfilzomib-refractory multiple myeloma is defined as 
disease that is nonresponsive while on primary or 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
salvage therapy that includes carfilzomib, or that 
progresses on or within 60 days of last therapy. 
The hazard ratio between the 2 treatment arms will be 
estimated using a stratified Cox proportional hazards model.  
The distribution of PFS, including medians, will be 
summarized descriptively using the Kaplan- Meier method 
for each treatment group.  The 95% CIs for median and 
other quartiles of PFS will be constructed using the method 
of Brookmeyer and Crowley (1982).  Duration of follow-up 
for PFS will be estimated by the reverse Kaplan-Meier 
method of Schemper (1996). 
Secondary Efficacy Analyses 
Overall survival is defined as the time from randomization to 
death due to any cause.  Subjects who are alive or lost to 
follow-up as of the data analysis cutoff date will be right 
censored.  The censoring date will be determined from the 
subject’s last known date alive.   
Final analysis of OS will be performed when 211 deaths 
have occurred.  Two hundred and eleven (211) deaths will 
provide 75% power to detect a 32% decrease in the risk of 
OS for OPomd versus Pomd (HR = 0.68) at the 1-sided 
0.025 level of significance.  Under exponential distribution, 
23.5 months versus 16 months is assumed for median OS for 
the OPomd and Pomd arms, respectively.  The assumed 
median OS of 16 months for the Pomd group is based on a 
Phase 2 study of pomalidomide/dexamethasone 
(Jagannath 2012).  Under these assumptions, and assuming 
10% lost to follow-up for OS at 60 months, 211 deaths are 
expected to occur approximately 56 months after the study 
starts. 
The interim analysis for OS will occur at the time of the 
primary analysis of PFS.  The primary analysis of PFS is 
anticipated to occur approximately 14 months after the first 
subject is randomized.  Approximately 30% of the total 
number of death events is expected at the time of the 
primary PFS analysis.  The interim and final analysis of OS 
will be performed using an O’Brien-Fleming group 
salvage therapy that includes carfilzomib, or that 
progresses on or within 60 days of last therapy. 
The hazard ratio between the 2 treatment arms will be 
estimated using a stratified Cox proportional hazards model.  
The distribution of PFS, including medians, will be 
summarized descriptively using the Kaplan- Meier method 
for each treatment group.  The 95% CIs for median and 
other quartiles of PFS will be constructed using the method 
of Brookmeyer and Crowley (1982).  Duration of follow-up 
for PFS will be estimated by the reverse Kaplan-Meier 
method of Schemper (1996). 
Secondary Efficacy Analyses 
Overall survival is defined as the time from randomization to 
death due to any cause.  Subjects who are alive or lost to 
follow-up as of the data analysis cutoff date will be right 
censored.  The censoring date will be determined from the 
subject’s last known date alive.  
Final analysis of OS will be performed when 211 deaths 
have occurred.  Two hundred and eleven (211) deaths will 
provide 75% power to detect a 32% decrease in the risk of 
OS for OPomd versus Pomd (HR = 0.68) at the 1-sided 
0.025 level of significance.  Under exponential distribution, 
23.5 months versus 16 months is assumed for median OS for 
the OPomd and Pomd arms, respectively.  The assumed 
median OS of 16 months for the Pomd group is based on a 
Phase 2 study of pomalidomide/dexamethasone 
(Jagannath 2012).  Under these assumptions, and assuming 
10% lost to follow-up for OS at 60 months, 211 deaths are 
expected to occur approximately 56 months after the study 
starts. 
The interim analysis for OS will occur at the time of the 
primary analysis of PFS.  The primary analysis of PFS is 
anticipated to occur approximately 14 months after the first 
subject is randomized.  Approximately 30% of the total 
number of death events is expected at the time of the 
primary PFS analysis.  The interim and final analysis of OS 
will be performed using an O’Brien-Fleming group 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
sequential monitoring plan.  The monitoring plan will 
include an upper boundary for benefit constructed using a 
false-positive error rate of 0.025 (Table 19).  The 
Lan-Demets alpha spending function approach will be used 
to adjust the O’Brien-Fleming boundary if the actual interim 
analysis does not correspond to the projected information 
time. 
Table 19 O’Brien-Fleming Monitoring Boundary for Benefit 
Informati
on 
Fraction 
Deat
h 
Even
ts 
Stud
y 
Mont
h 
Bounda
ry 
(Reject 
Ho) 
1-Sided 
Significan
ce Level 
Alph
a 
Spen
t 
30% 
63 
14 
3.929 
0.000042 
0.00
0 
100% 
211 
56 
1.96 
0.025 
0.02
5 
Statistical analyses conducted for OS will be identical to 
those described for PFS.  In addition to the key secondary 
endpoint of OS, inferential testing will be conducted for 
ORR, CBR, improvement in renal function, improvement in 
hemoglobin, change over time in QLQ-MY20 total scale, 
and change over time in QLQ-C30 total scale. 
Inferential testing of primary and selected secondary 
endpoints will be performed against an overall 1-sided 
significance level of 0.025 in accordance with a closed 
testing procedure (CTP).  The CTP will be used to account 
for inflation of the overall type 1 error rate due to hypothesis 
testing of multiple endpoints. 
The CTP will be structured as follows:  If the null hypothesis 
for the primary efficacy endpoint of PFS is rejected at the 
1-sided 0.025 level of significance, then testing of the 
aforementioned secondary endpoints will proceed in a 
sequential step down manner.   
sequential monitoring plan.  The monitoring plan will 
include an upper boundary for benefit constructed using a 
false-positive error rate of 0.025 (Table 19).  The 
Lan-Demets alpha spending function approach will be used 
to adjust the O’Brien-Fleming boundary if the actual interim 
analysis does not correspond to the projected information 
time. 
Table 19 O’Brien-Fleming Monitoring Boundary for Benefit 
Informati
on 
Fraction 
Deat
h 
Even
ts 
Stud
y 
Mont
h 
Bounda
ry 
(Reject 
Ho) 
1-Sided 
Significan
ce Level 
Alph
a 
Spen
t 
30% 
63 
14 
3.929 
0.000042 
0.00
0 
100% 
211 
56 
1.96 
0.025 
0.02
5 
Statistical analyses conducted for OS will be identical to 
those described for PFS.  In addition to the key secondary 
endpoint of OS, inferential testing will be conducted for 
ORR, CBR, improvement in renal function, improvement in 
hemoglobin, change over time in QLQ-MY20 total scale, 
and change over time in QLQ-C30 total scale. 
Inferential testing of primary and selected secondary 
endpoints will be performed against an overall 1-sided 
significance level of 0.025 in accordance with a closed 
testing procedure (CTP).  The CTP will be used to account 
for inflation of the overall type 1 error rate due to hypothesis 
testing of multiple endpoints. 
The CTP will be structured as follows:  If the null hypothesis 
for the primary efficacy endpoint of PFS is rejected at the 
1-sided 0.025 level of significance, then testing of the 
aforementioned secondary endpoints will proceed in a 
sequential step down manner.  
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Testing of selected secondary efficacy endpoints will 
continue, provided the null hypothesis for each previously 
tested endpoint is rejected.  Otherwise, no further testing will 
be done. The sequential order in which efficacy endpoints 
will be tested is as follows:  

PFS

OS

ORR

CBR

Improvement in renal function

Improvement in hemoglobin

Change over time in QLQ-C30 global health scale

Change over time in QLQ-MY20 disease symptoms
subscale
Overall response rate will be estimated based on the 
proportion of subjects in each treatment group who achieve 
sCR, CR, VGPR, or PR as their best response across the 
entire treatment duration.  The inferential comparison 
between treatment groups for this endpoint will be made 
using the Cochran-Mantel Haenszel chi-square test, stratified 
by the randomization stratification factors.  Approximate 
95% CIs will be calculated by treatment group for the true 
ORR.  An estimate of the common odds ratio for overall 
response will be provided as a measure of the relative 
treatment effect.  The odds ratio (and 95% CI) will be 
estimated using the Mantel-Haenszel method.  The Pomd 
group will serve as the reference treatment group in the 
calculation of the odds ratio.    
Clinical benefit rate will be estimated based on the 
proportion of subjects in each group who achieve sCR, CR, 
VGPR, PR, or MR, and will be analyzed in the same manner 
as described previously for ORR. 
Improvement in renal function is defined as an increase in 
GFR of ≥ 10 mL/min.  
Testing of selected secondary efficacy endpoints will 
continue, provided the null hypothesis for each previously 
tested endpoint is rejected.  Otherwise, no further testing will 
be done. The sequential order in which efficacy endpoints 
will be tested is as follows: 

PFS

OS

ORR

CBR

Improvement in renal function

Improvement in hemoglobin

Change over time in QLQ-C30 global health scale

Change over time in QLQ-MY20 disease symptoms
subscale 
Overall response rate will be estimated based on the 
proportion of subjects in each treatment group who achieve 
sCR, CR, VGPR, or PR as their best response across the 
entire treatment duration.  The inferential comparison 
between treatment groups for this endpoint will be made 
using the Cochran-Mantel Haenszel chi-square test, stratified 
by the randomization stratification factors.  Approximate 
95% CIs will be calculated by treatment group for the true 
ORR.  An estimate of the common odds ratio for overall 
response will be provided as a measure of the relative 
treatment effect.  The odds ratio (and 95% CI) will be 
estimated using the Mantel-Haenszel method.  The Pomd 
group will serve as the reference treatment group in the 
calculation of the odds ratio.  
Clinical benefit rate will be estimated based on the 
proportion of subjects in each group who achieve sCR, CR, 
VGPR, PR, or MR, and will be analyzed in the same manner 
as described previously for ORR. 
Improvement in renal function is defined as an increase in 
GFR of ≥ 10 mL/min. 
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CONFIDENTIAL 
Improvement in hemoglobin is defined as an increase of 
≥ 2 g/dL.  
Incidence of improvement in renal function and 
improvement in hemoglobin will be analyzed in the same 
manner as described previously for ORR. 
Duration of response and DOCB will be summarized for 
each treatment group by Kaplan-Meier method; however, no 
formal inferential comparisons will be made for these 
endpoints, as responders constitute a nonrandom subset of 
the ITT population. 
Quality of life will be assessed by the European 
Organization for Research and Treatment (EORTC) 30-item 
QLQ-C30 test and by the 20-item QLQ-MY20 module 
specifically designed to address the quality of life for those 
with multiple myeloma (Appendix E).  The primary 
constructed scales from the QLC-C30 are: 

Global Health Status/QoL

Physical Functioning, Role Functioning

Emotional Functioning

Cognitive Functioning

Social Functioning
Nine additional scales can be derived:  Fatigue, Nausea and 
Vomiting, Pain, Dyspnoea, Insomnia, Appetite Loss, 
Constipation, Diarrhea, and Financial Difficulties. 
The QLQ-MY20 EORTC questionnaire was developed to 
assess the quality of life in cancer subjects with multiple 
myeloma.  The QLQ-MY20 includes 20 items assessing 
disease symptoms, side effects of treatment, body image, 
and future perspective.  There are 3 multi-item scales 
(Disease Symptoms Scale, Side Effects of Treatment Scale, 
and Future Perspective Scale) and 1 single-item scale (Body 
Image).  
Scoring procedures are similar for both questionnaires and 
can be found in the EORTC QLQ-C30 Scoring Manual, 
Version 3.  The analysis and reporting of all QOL data will 
be performed using the ITT population. 
Improvement in hemoglobin is defined as an increase of 
≥ 2 g/dL. 
Incidence of improvement in renal function and 
improvement in hemoglobin will be analyzed in the same 
manner as described previously for ORR. 
Duration of response and DOCB will be summarized for 
each treatment group by Kaplan-Meier method; however, no 
formal inferential comparisons will be made for these 
endpoints, as responders constitute a nonrandom subset of 
the ITT population. 
Quality of life will be assessed by the European 
Organization for Research and Treatment (EORTC) 30-item 
QLQ-C30 test and by the 20-item QLQ-MY20 module 
specifically designed to address the quality of life for those 
with multiple myeloma (Appendix E).  The primary 
constructed scales from the QLC-C30 are: 

Global Health Status/QoL

Physical Functioning, Role Functioning

Emotional Functioning

Cognitive Functioning

Social Functioning
Nine additional scales can be derived:  Fatigue, Nausea and 
Vomiting, Pain, Dyspnoea, Insomnia, Appetite Loss, 
Constipation, Diarrhea, and Financial Difficulties. 
The QLQ-MY20 EORTC questionnaire was developed to 
assess the quality of life in cancer subjects with multiple 
myeloma.  The QLQ-MY20 includes 20 items assessing 
disease symptoms, side effects of treatment, body image, 
and future perspective.  There are 3 multi-item scales 
(Disease Symptoms Scale, Side Effects of Treatment Scale, 
and Future Perspective Scale) and 1 single-item scale (Body 
Image). 
Scoring procedures are similar for both questionnaires and 
can be found in the EORTC QLQ-C30 Scoring Manual, 
Version 3.  The analysis and reporting of all QOL data will 
be performed using the ITT population. 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Section(s) 
Changed from 
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Rationale 
Changes over time in QLQ-C30 global health status scores 
will be compared between treatment groups using a 
restricted maximum likelihood-based linear mixed model for 
repeated measures data under the missing at random 
assumption.  Formal inferential testing will not be performed 
for the QOL subscales of EORTC QLQ-C30 and 
QLQ-MY20 (except for disease symptoms subscale).  
Instead, the analysis of these endpoints will be descriptive 
only and considered exploratory.  Details of the analyses and 
the impact and handling of missing data in analyses will be 
addressed in the SAP. 
Changes over time in QLQ-C30 global health status scores 
will be compared between treatment groups using a 
restricted maximum likelihood-based linear mixed model for 
repeated measures data under the missing at random 
assumption.  Formal inferential testing will not be performed 
for the QOL subscales of EORTC QLQ-C30 and 
QLQ-MY20 (except for disease symptoms subscale).  
Instead, the analysis of these endpoints will be descriptive 
only and considered exploratory.  Details of the analyses and 
the impact and handling of missing data in analyses will be 
addressed in the SAP. 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Section 14.5.3 
(Safety 
Analysis) 
The safety population will be used in all safety analyses (see 
Section 14.5.1.1).  Results of safety analyses will be 
presented separately for Part 1 and Part 2 of the study. 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
For the Phase 1b portion of the study, safety data will be 
summarized for each cohort and for the pooled cohorts.  
Safety will be assessed through summaries of DLTs, AEs, 
changes in laboratory test results, ECGs, vital signs, and 
oprozomib, pomalidomide, and dexamethasone exposure.  
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, safety data will be 
summarized grouped according to treatment actually 
received. 
Treatment-emergent AEs are defined as AEs that start on or 
after the first day study treatment is administered and within 
30 days of the last administration of study treatment or 
before start of subsequent anticancer treatment (whichever 
occurs first).  Treatment-emergent AEs will be summarized 
by the number and percentage of subjects who experienced 
the event, according to system organ class and preferred 
term.  A subject experiencing multiple instances of the same 
AE will be counted once within each system organ class and 
similarly counted once within each preferred term.  Adverse 
event incidence rates may also be calculated based on other 
measures of subject exposure (e.g., total number of treatment 
cycles administered).  Adverse events will also be 
summarized by NCI-CTCAE Version 4.03 severity grade 
and by relationship to each study drug.  For AEs not 
adequately addressed by NCI-CTCAE Version 4.03, the 
severity grading described in Table 17 may be used.  
Additional summaries may also be provided for SAEs and 
events resulting in the permanent discontinuation of therapy.  
All AEs will be included in individual subject listings.  
Incidence, severity, and duration of specific signs and 
symptoms indicative of neuropathy and other neurotoxicities 
will be assessed.  The appropriate terms in these categories 
The safety population will be used in all safety analyses (see 
Section 14.5.1.1). 
For this study, safety data will be summarized for each 
cohort and for the pooled cohorts.  Safety will be assessed 
through summaries of DLTs, AEs, changes in laboratory test 
results, ECGs, vital signs, and oprozomib, pomalidomide, 
and dexamethasone exposure. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
will be codified and analyses performed to provide a subject 
incidence of those with the relevant events.   
Laboratory parameters will be summarized using descriptive 
statistics, by postdose shifts in toxicity grades of laboratory 
parameters relative to baseline, changes from baseline, and 
data listings of clinically significant abnormalities.  The 
changes in hematology, chemistry, and other laboratory 
values will be summarized descriptively for each scheduled 
and unscheduled protocol assessment time point.  Changes 
will be calculated relative to the values collected at baseline 
and on the first day of each cycle of treatment.  The 
incidence of Grade 3 and 4 hematological toxicities 
(including neutropenia, thrombocytopenia, and anemia) will 
be provided by treatment cycle and across all treatment 
cycles.  The use of blood transfusions (platelets, RBC) 
and/or growth factor support will be summarized.  Subject 
listings of all laboratory data collected during the study will 
be presented.  Laboratory values outside normal limits will 
be identified in the subject listings. 
Vital sign results (systolic and diastolic blood pressure, 
pulse, respiration, and temperature) and ECGs will be 
summarized descriptively. 
Section 14.5.5 
(Pharmacokinet
ic Analyses) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
In the Phase 1b Dose-Escalation and Dose-Expansion 
portions of the study, blood samples will be collected from 
all subjects for determination of plasma concentrations of 
oprozomib at 1  predose time point and up to 7 postdose 
time points on Day 1 of Cycle 1 and Cycle 2 (0.25, 0.5, 1, 2, 
3, 4, and 6 hours postdose) and 1 predose time point on 
Day 2 of Cycle 1 for both schedules. 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
In the Phase 1b Dose-Escalation and Dose-Expansion 
portions of the study, blood samples will be collected from 
all subjects for determination of plasma concentrations of 
oprozomib at 1 predose time point and up to 7 postdose time 
points on Day 1 of Cycle 1 and Cycle 2 (0.25, 0.5, 1, 2, 3, 4, 
and 6 hours postdose) and 1 predose time point on Day 2 of 
Cycle 1 for both schedules. 
The study is 
no longer 
divided into 
2 parts 
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CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Section 14.5.5 
(Pharmacokinet
ic Analyses) 
Part 2:  Randomized Phase 3 Portion of the Study 
In Phase 3, population PK of oprozomib will be 
characterized in the OPomd regimen.  The population 
modeling program will be used to fit a nonlinear mixed 
effects model to estimate PK parameters including Cmax, 
AUC, clearance, the inter- and intrasubject variability, and 
the population variability in the parameter estimates.  
The sparse sampling concentrations obtained from subjects 
in this study and results from other oprozomib studies with 
intensive sampling will be used in the development of a 
structural model.  The best model will be evaluated by 
goodness-of-fit statistics and reduction in the objective 
function and posterior predictive checks.  Subject 
characteristics such as age, gender, body weight, body 
surface area (BSA), and race will be included in the model 
to identify potential covariates affecting PK of oprozomib.  
Potential correlations of relevant PK parameters with dose, 
safety or efficacy outcomes, and other covariates may be 
explored. 
Part 2:  Randomized Phase 3 Portion of the Study 
In Phase 3, population PK of oprozomib will be 
characterized in the OPomd regimen.  The population 
modeling program will be used to fit a nonlinear mixed 
effects model to estimate PK parameters including Cmax, 
AUC, clearance, the inter- and intrasubject variability, and 
the population variability in the parameter estimates.  
The sparse sampling concentrations obtained from subjects 
in this study and results from other oprozomib studies with 
intensive sampling will be used in the development of a 
structural model.  The best model will be evaluated by 
goodness-of-fit statistics and reduction in the objective 
function and posterior predictive checks.  Subject 
characteristics such as age, gender, body weight, body 
surface area (BSA), and race will be included in the model 
to identify potential covariates affecting PK of oprozomib. 
Potential correlations of relevant PK parameters with dose, 
safety or efficacy outcomes, and other covariates may be 
explored. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Section 14.7 
(Determination 
of Sample Size) 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study 
A total enrollment of approximately 82 subjects is planned 
for Part 1 of the study.  During the Part 1 Phase 1b 
dose-escalation portion of the study, approximately 
21 subjects are expected to be enrolled for each schedule.   
A total enrollment of approximately 82 subjects is planned 
for this study.  During the dose-escalation portion of the 
study, approximately 21 subjects are expected to be enrolled 
for each schedule.   
The study is 
no longer 
divided into 
2 parts 
Section 14.7 
(Determination 
of Sample Size) 
A minimum of 20 additional subjects are planned for 
enrollment and treatment for 1 or both schedules at the 
sponsor’s discretion at the RP3D during the Phase 1b 
dose-expansion portion of Part 1 of the study.   
A minimum of 20 additional subjects are planned for 
enrollment and treatment for 1 or both schedules at the 
sponsor’s discretion at the RP3D during the Phase 1b 
dose-expansion portion of Part 1 of the study.   
The study is 
no longer 
divided into 
2 parts 
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Section(s) 
Changed from 
Changed to 
Rationale 
Section 14.7 
(Determination 
of Sample Size) 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, 157 PFS events are 
required to detect a 45.7% reduction in the risk of PFS 
(HR = 0.543) with 95% power and a 1-sided significance 
level of 0.025.  Enrollment of 270 subjects (2:1 OPomd 
versus Pomd, respectively) is consistent with reaching the 
required 157 events in approximately 14 months, assuming 
an enrollment rate of approximately 22 subjects per month, a 
5% drop-out rate at 18 months, and a median PFS of 3.8 and 
7 months for Pomd and OPomd, respectively. 
Therefore, the total planned enrollment will be 
approximately 352 subjects for the entire study. 
Part 2:  Randomized Phase 3 Portion of the Study 
For the Phase 3 portion of the study, 157 PFS events are 
required to detect a 45.7% reduction in the risk of PFS 
(HR = 0.543) with 95% power and a 1-sided significance 
level of 0.025.  Enrollment of 270 subjects (2:1 OPomd 
versus Pomd, respectively) is consistent with reaching the 
required 157 events in approximately 14 months, assuming 
an enrollment rate of approximately 22 subjects per month, a 
5% drop-out rate at 18 months, and a median PFS of 3.8 and 
7 months for Pomd and OPomd, respectively. 
Therefore, the total planned enrollment will be 
approximately 352 subjects for the entire study. 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Appendix A1 
(Schedule of 
Study 
Assessments – 
Long-term 
Follow-up 
column) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
Long-term 
Follow-up 
column) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
Long-term 
Follow-up 
column) 
Appendix B2 
(Schedule of 
Visit 
Long-term Follow-up 
SPEP/UPEP/Serum 
FLC Immunofixationn 
X 
Skeletal Surveyo 
X 
Plasmacytoma 
Evaluationp 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
Visit 
Long-term Follow-up 
SPEP/UPEP/Serum 
FLC Immunofixationn 
X 
Skeletal Surveyo 
X 
Plasmacytoma 
Evaluationp 
X 
Bone Marrow Aspirate 
and FISH Analysesq, 
X 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
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Clinical Study Protocol No. OPZ007 
Page 213 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Study 
Assessments – 
Long-term 
Follow-up 
column) 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote b) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote b) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote b) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote b) 
New text added 
All other physical examinations will be limited physical 
examinations only if clinically indicated. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote c) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote c) 
New text added 
Neurological assessments (BPNS and if applicable record 
AEs with CTCAE grading) will be performed at Screening 
and on Day 1 of every cycle starting from Cycle 2 if 
clinically indicated and at the End of Study 
Treatment/Early Discontinuation (See Appendix M). 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
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Clinical Study Protocol No. OPZ007 
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CONFIDENTIAL 
Section(s) 
Changed from 
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Rationale 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote c) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote c) 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote f) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote f) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote f) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote f) 
For Cycle 2, vital signs are required.  For Cycles 3 and 
higher, vital signs are required... 
For Cycle 2, if clinically indicated, vital signs are required.  
For Cycles 3 and higher, if clinically indicated, vital signs 
are required... 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote g) 
New text added 
Perform ECG approximately within 1 hour before (predose) 
and approximately 1 hour after (postdose) administration of 
oprozomib for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24 and then 
every 6 months solely if clinically indicated, until 
progression or unacceptable toxicity.  Perform standard ECG 
Provide 
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for those on 
study 
treatment as 
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Clinical Study Protocol No. OPZ007 
Page 215 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote g) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote g) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote g) 
assessment at Screening and End of Study Treatment/Early 
Discontinuation visit. 
study has 
completed 
its 
abbreviated 
report 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote i) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote i) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote i) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote i) 
New text added 
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), done 
locally if clinically indicated. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
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Clinical Study Protocol No. OPZ007 
Page 216 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote j) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote j) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote j) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote j) 
New text added 
Day 1 samples for laboratory analyses can be drawn within 
72 hours prior to dosing on Day 1 for all subsequent cycles after 
Cycle 1 only if clinically indicated. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote l) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote l) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote l) 
New text added 
Coagulation tests, done locally if clinically indicated, and 
includes the following:  Prothrombin time, activated partial 
thromboplastin time, and international normalized ratio. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
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Section(s) 
Changed from 
Changed to 
Rationale 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote l) 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote o) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote o) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote o) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote o) 
For subjects who did not progress during treatment with 
bone lesions present at Baseline, skeletal survey will 
continue to be measured every 4 weeks as clinically 
indicated (every 28 days ± 4 days) until PD.  During 
long-term follow-up, skeletal survey evaluation should be 
performed as clinically indicated. 
p For subjects who did not progress during treatment with bone 
lesions present at Baseline, skeletal survey will no longer be 
required.  During long-term follow-up, skeletal survey 
evaluation will also no longer be required. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote p) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote p) 
For subjects with plasmacytoma at Baseline and did not 
progress during treatment, plasmacytoma will continue to be 
measured every 4 weeks as clinically indicated (every 
28 days ± 4 days) until PD.  During long-term follow-up, 
plasmacytoma evaluation should be performed as clinically 
indicated. 
For subjects with plasmacytoma at Baseline and did not 
progress during treatment, plasmacytoma will no longer be 
required.  During long-term follow-up, plasmacytoma 
evaluation will also no longer be required. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
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Clinical Study Protocol No. OPZ007 
Page 218 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote p) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote p) 
Appendix A1 
(Schedule of 
Study 
Assessments – 
footnote q) 
Appendix A2 
(Schedule of 
Study 
Assessments – 
footnote q) 
Appendix B1 
(Schedule of 
Study 
Assessments – 
footnote q) 
Appendix B2 
(Schedule of 
Study 
Assessments – 
footnote q) 
Bone marrow aspirate will also be collected at disease 
progression (may be collected at End of Study 
Treatment/Early Discontinuation due to PD or during 
Long-Term Follow-Up) for subjects who consent to optional 
genomic biomarker analysis. 
Bone marrow aspirate will also be collected at disease 
progression if clinically indicated (may be collected at End 
of Study Treatment/Early Discontinuation due to PD; it will 
no longer be required during Long-term Follow-up) for 
subjects who consent to optional genomic biomarker 
analysis. 
Provide 
convenience 
for those on 
study 
treatment as 
study has 
completed 
its 
abbreviated 
report 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 280


Clinical Study Protocol No. OPZ007 
Page 219 of 223 
CONFIDENTIAL 
Appendix C1 
(Schedule of 
Study 
Assessments) – 
entire appendix 
deleted 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 281


Clinical Study Protocol No. OPZ007 
Page 220 of 223 
CONFIDENTIAL 
Appendix C2 
(Schedule of 
Study 
Assessments) – 
entire appendix 
deleted 
Removed 
Phase 3 text 
to reflect 
what data 
was 
collected 
for the 
study 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 282


Clinical Study Protocol No. OPZ007 
Page 221 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix N 
(Example 
Electronic 
Serious 
Adverse Event 
Contingency 
Report Form) 
APPENDIX N  Example Electronic Serious Adverse 
Event Contingency Report Form 
Provide 
updated 
adverse 
event 
reporting 
form. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 283


Clinical Study Protocol No. OPZ007 
Page 222 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix O 
(Example 
Amgen 
Pregnancy 
Notification 
Worksheet) 
APPENDIX O  EXAMPLE AMGEN PREGNANCY 
NOTIFICATION WORKSHEET 
Provide 
updated 
pregnancy 
reporting 
worksheet. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 284


Clinical Study Protocol No. OPZ007 
Page 223 of 223 
CONFIDENTIAL 
Section(s) 
Changed from 
Changed to 
Rationale 
Appendix P 
(Example 
Amgen 
Lactation 
Notification 
Worksheet) 
APPENDIX P  EXAMPLE AMGEN LACTATION 
NOTIFICATION WORKSHEET 
Provide 
updated 
lactation 
reporting 
worksheet. 
Onyx Therapeutics 
Oprozomib ER Tablets 
 
Approved 
 
 
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130411
30 July 2019
Page 285

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN   
PROTOCOL OPZ007 
Phase 1b/3 Multicenter Study of Oprozomib, Pomalidomide, and Dexamethasone in Primary 
Refractory or Relapsed and Refractory Multiple Myeloma Subjects 
Sponsor: Onyx Pharmaceuticals, an Amgen subsidiary 
One Amgen Center Dr.  
Thousand Oaks, CA 91320 
(805) 447-4897
Date:        JUNE 21, 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: 6/21/2016 
NCT Number: NCT01999335
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Onyx Pharmaceuticals Inc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol OPZ007 
Signature Page 
 Date: _
 
, PhD 
Senior Manager, Biostatistics 
_______________ Date: _______ _ 
, PhD 
Director, Global Biostatistics 
_______________ Date: _______ _ 
, MD 
Medical Monitor: Oprozomib 
_______________ Date: _______ __ 
, PharmD 
Medical Sciences Director 
page 2 


Onyx Phannaceuticals Inc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol OPZ007 
Signature Page 
_____________________________ Date: ________________ _ 
, PhD 
Senior Manager, Biostatistics 
Date: -
__ 
, PhD 
Director, Global Biostatistics 
_____________________________ Date: ________________ _ 
, MD 
Medical Monitor: Oprozomib 
_____________________________ Date: ________________ _ 
, PharmD 
Medical Sciences Director 
page 2 


Onyx Pharmaceuticals Tnc. 
Prepared by: 
Reviewed by: 
Statistical Analysis Plan For Protocol OPZ007 
Signature Page 
______________ D9te, 
, PhD 
Senior Manager, Biostatistics 
______________ Dare: _______ ___ 
, PhD 
Director, Global Biostatistics 
, MD 
Medical Monitor: Oprozomib 
_____________ Date: _______ _ 
, PhannD 
Medical Sciences Director 
page 2 


Dnvx Pharmaceuticals Inc. 
Statistical Analvsis Plan For Protocol OPZ007 
Signature Page 
Prepared by; 
_____________ Dale, _______ _ 
, PhD 
Senior Manager, Biostatistics 
Reviewed by: 
______________ Dale: 
, PhD 
Dircctor, Global Biostatistics 
Date: 
, MD 
Medical Monitor: Oprozomib 
 
 Pharr
Medical Sciences Director 
page 2 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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 
ORR  
overall response rate 
PD 
progressive disease 
PDn 
pharmacodynamic 
PFS 
progression-free survival 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 4
Abbreviation or Term 
Definition 
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 OPZ007 
 
page 5
TABLE OF CONTENTS 
 
 
1 
INTRODUCTION ............................................................................................ 8 
2 
STUDY OVERVIEW ....................................................................................... 8 
2.1 
Overall Study Design ............................................................................... 8 
2.2 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion Portions of the 
Study 
10 
2.3 
Study Objectives - Part 1:  Phase 1b Dose-Escalation and 
Dose-Expansion Portions of the Study (by Schedule) .................................................. 11 
2.3.1 
Primary Objectives................................................................................. 11 
2.3.2 
Secondary Objectives............................................................................. 11 
2.4 
Sample Size Justification ....................................................................... 12 
3 
STUDY ENDPOINTS ................................................................................... 14 
3.1 
Primary Endpoints ................................................................................. 14 
PART 1: 
14 
3.2 
Secondary Endpoints ............................................................................. 14 
PART 1: 
14 
4 
ANALYSIS POPULATIONS ........................................................................ 14 
5 
ANALYTIC DEFINITIONS ........................................................................... 15 
5.1 
Study Day 1............................................................................................ 15 
5.2 
Study Day............................................................................................... 15 
5.3 
Baseline .................................................................................................. 15 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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6 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ................... 15 
7 
STATISTICAL METHODS ........................................................................... 16 
7.1 
General Considerations .......................................................................... 16 
7.2 
Disposition of Subjects .......................................................................... 16 
7.3 
Demographic and Baseline Characteristics ........................................... 17 
7.3.1 
Demographic and Baseline Characteristics ........................................... 17 
7.3.2 
Disease Characteristics .......................................................................... 17 
7.3.3 
Prior Cancer Therapies .......................................................................... 18 
7.4 
Treatments and Medications .................................................................. 19 
7.4.1 
Study Drug Administration .................................................................... 19 
7.5 
Efficacy Analyses .................................................................................. 19 
7.5.1 
Overall Response Rate ........................................................................... 19 
7.5.2 
Duration of Response ............................................................................. 20 
7.6 
Safety Analysis ...................................................................................... 20 
7.6.1 
Adverse Events ...................................................................................... 20 
7.6.2 
Laboratory Data ..................................................................................... 22 
7.6.3 
Vital Signs and Weight .......................................................................... 23 
7.6.4 
12-Lead Electrocardiogram ................................................................... 23 
7.6.5 
Prior and Concomitant Medications ...................................................... 23 
7.6.6 
Protocol Deviations ................................................................................ 23 
7.7 
Handling of Dropouts or Missing Data .................................................. 23 
7.8 
Interim Analysis and Data Monitoring .................................................. 24 
 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 8
1 
INTRODUCTION 
This statistical analysis plan (SAP) was prepared for an abbreviated clinical study report 
(aCSR) for the Part 1 of the study in accordance with Protocol OPZ007, dated 08 July 
2014 (amendment 2), and describes the analyses of data collected within the scope of the 
Part 1 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 aCSR 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 is a Phase 1b/3 study of oprozomib (OPZ) in combination with pomalidomide 
(POM) and dexamethasone (DEX) in subjects with primary refractory or relapsed and 
refractory multiple myeloma.  There are 2 parts to this study.  Part 1 includes an 
open-label, Phase 1b, dose-escalation and dose-expansion portion (the equivalent of a 
small Phase 2) during which the RP3D will be identified.  Further evaluation of safety 
and efficacy will be assessed during the dose-expansion portion.  During the Phase 1b 
portion of the study, subjects will receive Oprozomib ER Tablets according to their 
assigned dose cohort.  Part 2 will consist of a placebo-controlled, double-blind, 
randomized Phase 3 component where subjects will be randomized to receive the RP3D 
of oprozomib or placebo administered orally in combination with pomalidomide and 
dexamethasone in 28-day cycles until disease progression or unacceptable toxicity. 
This study will include subjects with primary refractory or relapsed and refractory 
multiple myeloma, i.e., those who have demonstrated disease progression on or within 
60 days of their last therapy, and who have received at least 2 prior lines of therapy 
(including bortezomib and lenalidomide and/or thalidomide, and in the dose-expansion 
and Phase 3 portions of the study only, been treated with adequate alkylator therapy).  


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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Subjects whose last therapy was bortezomib and who were not refractory but developed 
bortezomib intolerance, as defined by the development of Grade 2 peripheral neuropathy 
with pain or ≥ Grade 3 peripheral neuropathy after ≥ 2 consecutive cycles, are eligible. 
Treatment cycles are 28 days in duration.  Two (2) oprozomib dosing schedules will be 
assessed during dose escalation.  Subjects will receive oprozomib once daily either on 
Days 1–5 and 15–19, referred to hereafter as the 5/14 schedule, or an alternate schedule 
of once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23, referred to hereafter as the 2/7 
schedule.  Pomalidomide will be given on Days 1–21 and dexamethasone will be given 
on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every 28-day cycle. 
During Part 2 of the study, subjects will be randomized to oprozomib in combination 
with pomalidomide and dexamethasone (OPomd) at the RP3D and schedule determined 
during Part 1 of the study or placebo in combination with pomalidomide and 
dexamethasone (Pomd). 
Approximately 35 study sites will participate in Part 1 of the study (15 sites for the 
Phase 1b dose-escalation and 20 additional sites for the dose-expansion portions of the 
study).  An additional 35 sites, for a total of approximately 70 sites, will participate in 
Part 2 of the study (Phase 3 portion of the study). 
Treatment cycles for both parts of the study will last 28 days.  Disease assessments will 
be performed every 4 weeks for subjects in both arms for 18 months.  Further disease 
assessments will be conducted every 8 weeks after this period, beginning with Month 20.  
Details of the study assessments required for both parts of this study are provided in 
Appendices A1, A2, B1, B2, C1, and C2 of the protocol. 
The readiness of Phase 3 portion (Part 2) of the study was assessed after Part 1 was 
completed and three areas of concern were identified below: 
• GI tolerability profile, though acceptable in relapsed/refractory disease, needed 
improvement 
• Formulation determined not to be robust 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 10
• High intrapatient PK variability discovered in Clinical Pharmacology Study 
A decision was made to reformulate, and determine if a new, robust formulation could 
improve PK variability and GI tolerability.  Therefore the Part 2 of the study was 
cancelled and an aCSR would be produced for the Part 1 of the study. 
 
2.2 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion Portions of the Study 
In Part 1 of the study, the safety, MTD, PK/PDn, and RP3D of oprozomib when given in 
combination with pomalidomide and dexamethasone will be assessed using a standard 
3 + 3 dose-escalation design.  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.  If the starting dose of 
oprozomib cannot be safely administered with the labeled pomalidomide dose or at 
sponsor discretion, then up to 2 possible alternative dose-escalation paths for oprozomib 
with lower pomalidomide doses will be explored (See tables below for primary and 
alternative dose-escalation paths).  Dose escalation will continue until sponsor discretion, 
the maximum planned dose of pomalidomide is reached, or ≥ 2 DLTs occur in a cohort, 
whichever occurs first.  The prior cohort will be expanded to at least 6 subjects if not 
previously done to establish it as the MTD.  There may be more than 1 MTD of 
oprozomib if more than 1 dose level of pomalidomide is studied.  The MTD for 
oprozomib associated with each dose level of pomalidomide assessed will be the dose 
level where < 2 DLTs in 6 subjects are observed.   
There is no planned maximum dose of oprozomib to be evaluated as it is being added to 
the FDA-approved regimen of pomalidomide/dexamethasone, however, this could be 
imposed at any time during the course of the study, based on sponsor discretion.  The 
starting dose of oprozomib for the 5/14 schedule is 150 mg, 3 dose levels below the 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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established single-agent MTD of 240 mg.  The starting dose of oprozomib for the 2/7 
schedule is 210 mg, 3 dose levels below the established 2/7 single-agent MTD of 300 mg.  
The MTD will be determined as outlined in the protocol for each schedule.  Following 
dose escalation, the sponsor has the option of expanding 1 or both schedules in order to 
establish the RP3D and schedule.  
The sponsor, with input from the Cohort Safety Review Committee ([CSRC] consisting 
of investigators, sponsor’s medical monitor, and sponsor’s drug safety representative), 
will determine which dose and schedule of oprozomib in combination with 
pomalidomide and dexamethasone to use for the dose-expansion (i.e., the RP3D) portion 
of the study.  The sponsor has the option of expanding 1 or both schedules in order to 
establish the RP3D and schedule.  The RP3D may differ from the MTD, but will not be 
higher than the MTD, and will be selected based upon the assessment of the safety, 
tolerability, PK, PDn, preliminary activity, and other variables to be observed across 
multiple cycles of combination therapy. 
2.3 
Study Objectives - Part 1:  Phase 1b Dose-Escalation and Dose-Expansion 
Portions of the Study (by Schedule) 
2.3.1 Primary Objectives 
• To determine the maximum tolerated dose (MTD) and identify the recommended 
Phase 3 dose (RP3D) and schedule of oprozomib in combination with 
pomalidomide and dexamethasone (OPomd) in subjects with primary refractory 
or relapsed and refractory multiple myeloma 
• To evaluate the safety and tolerability of the OPomd combination in subjects with 
primary refractory or relapsed and refractory multiple myeloma 
2.3.2 Secondary Objectives 
• To estimate the overall response rate (ORR) of OPomd, defined as the proportion 
of subjects with an overall response of stringent complete response (sCR), 
complete response (CR), very good partial response (VGPR), or partial response 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 12
(PR) as determined by investigator according to the International Myeloma 
Working Group- Uniform Response Criteria (IMWG-URC) 
• To estimate the clinical benefit rate (CBR) of OPomd, defined as the proportion 
of subjects with an overall response of minimal response (MR) or better as 
determined by investigator according to the IMWG-URC and modified European 
Group for Blood and Marrow Transplantation (EBMT) criteria 
• To characterize the pharmacokinetics (PK) of oprozomib in the OPomd regimen 
 
2.4 
Sample Size Justification 
Part 1:  Phase 1b Dose-Escalation and Dose-Expansion Portions of the Study 
A total enrollment of approximately 82 subjects is planned for Part 1 of the study.  
During the Part 1 Phase 1b dose-escalation portion of the study, approximately 21 
subjects are expected to be enrolled for each schedule.  The estimated sample size for the 
dose-escalation part of the study is based on standard 3 + 3 dose-escalation rules, with 
expectations that 2–3 dosing cohorts of 3–6 subjects per cohort will be required to 
establish the MTD.  A minimum of 6 subjects must be treated at the MTD.  For each 
schedule, more than 1 MTD for oprozomib may be established if additional dose levels of 
pomalidomide are assessed.  The MTD for oprozomib in combination with each dose 
level of pomalidomide will be the dose(s) where < 2 DLTs in 6 subjects are observed.   
The actual number of required subjects will depend on both the total number of cohorts, 
and the need to expand a given cohort from 3 to 6 subjects in order to identify the MTD.  
Properties of the dose-escalation rules for different underlying DLT rates are provided in 
Table 1.   
Table 1 
Properties of the Dose-Escalation Rules for Different Underlying DLT 
Rates 
Underlying Rate 
of DLT 
Probability of Enrolling  
3 Additional Subjects 
Probability that Dose is 
Determined to be 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 13
Tolerated 
0.10 
0.24 
0.91 
0.20 
0.38 
0.71 
0.33 
0.44 
0.43 
0.40 
0.43 
0.31 
0.50 
0.38 
0.17 
0.60 
0.29 
0.08 
DLT = dose-limiting toxicity. 
The criteria for selecting the RP3D for each schedule at the sponsor’s discretion will 
include assessment of the safety, tolerability, and preliminary activity of oprozomib 
observed across multiple cycles.  In addition, both PK and PDn assessments to 
demonstrate adequate exposure and proteasome inhibition will be a key factor.  The 
CSRC will review the data and provide guidance in selection of the RP3D.  Therefore the 
RP3D may differ from the MTD, but will not be higher than the MTD.  A minimum of 20 
additional subjects are planned for enrollment and treatment for 1 or both schedules at the 
sponsor’s discretion at the RP3D during the Phase 1b dose-expansion portion of Part 1 of 
the study.  In the dose-expansion portion of the study, if the true ORR ≥ 40%, then the 
probability of seeing at least 7 responses among the 26 subjects (6 treated at the MTD 
during escalation + 20 in the expansion) is approximately 94%. 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 14
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoints   
Part 1: 
• DLTs 
• Adverse events and laboratory abnormalities graded according to NCI-CTCAE, 
Version 4.03 
• Vital signs and clinical laboratory results during and following study drug 
administration  
3.2 
Secondary Endpoints   
Part 1: 
• Overall response, defined as the best response of sCR, CR, VGPR, or PR, as 
determined by investigator according to the IMWG-URC 
• Clinical benefit, defined as defined as the best response of MR or better, as 
determined by investigator according to the IMWG-URC and modified EBMT 
criteria  
• Pharmacokinetic parameters, including maximum plasma concentration (Cmax), 
time to maximum concentration (Tmax), area under the plasma concentration time 
curve from time 0 to last time point (AUC0-τ), and area under the plasma 
concentration time curve from time 0 to time infinity (AUC0-∞) using 
noncompartmental methods 
 
4 
ANALYSIS POPULATIONS    
All subjects who receive at least 1 dose of study treatment in Part 1 of the study 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.  


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 15
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 
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, POM or 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.   


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 16
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 
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).   


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 17
• 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 
• Ethnicity 
• Race 
• Baseline ECOG performance status 
• Baseline fertility status 
• Baseline weight (kg) 
• Baseline height (cm) 
7.3.2 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 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
page 18
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) 
7.3.3 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 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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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 OPZ, POM and DEX. 
• Duration of treatment (weeks), defined as (date of last dose – date of first 
dose + 1) divided by 7  for OPZ, POM and DEX 
• Total number of treatment cycles during which one full daily dose of OPZ, POM 
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, POM and DEX. 
• Total doses received  across all cycles of OPZ, POM and DEX 
• Dose modifications of study drug based on AE action taken data 
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 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), very good partial response (vGPR), or partial response (PR) as defined by 
International Myeloma Working Group Uniform Response Criteria (IMWG-URC). 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 along with the 


Onyx Pharmaceuticals Inc. 
                                  Statistical Analysis Plan For Protocol OPZ007 
 
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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 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. 
7.6 
Safety Analysis 
All safety analyses will be based on the Safety population. 
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 


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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  
• 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  
• TEAEs grade 3 or higher (PT) 
• treatment-related adverse events (OPZ, POM, DEX, and study drug) 


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• serious TEAEs 
• TEAEs that led to permanent discontinuation of study drug (OPZ, POM, DEX 
and study treatment) 
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. 
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) 
 


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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.   
 
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. Statistical/Analytical Issues 
 
7.7 
Handling of Dropouts or Missing Data 
The handling of dropouts and missing disease status assessments for the efficacy 
variables is described in their definitions. 


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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. 
7.8 
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 
next-lower dose cohort may be expanded.  The committee must agree that dose escalation 
to the next cohort is appropriate before it proceeds.