Clinical trial NCT02939183
Conditions: Relapsed or Refractory Multiple Myeloma
Keywords: Multiple Myeloma
Sponsor: Amgen
Start date: 2017-01-17; Completion date: 2022-10-06
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in participants with relapsed refractory multiple myeloma.

Detailed description:
A multicenter, non-randomized, open-label, dose-exploration study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in participants with relapsed refractory multiple myeloma. The study will be conducted in two parts. Part 1 will evaluate the formulations of oprozomib in combination with dexamethasone only. Part 2 will evaluate the formulations of oprozomib administered at increasing dose levels (dose escalation) in combination with pomalidomide and dexamethasone.

Arms: arm 1: Oprozomib IR plus dexamethasone arm 2: Oprozomib GR plus dexamethasone arm 3: Oprozomib IR plus pomalidomide and dexamethasone arm 4: Oprozomib GR plus pomalidomide and dexamethasone arm 5: Oprozomib GR monotherapy, or oprozomib GR plus dexamethasone
Interventions: intervention 1: Immediate Release (IR) Formulation intervention 2: Gastro-Retentive (GR) Formulation intervention 3: Dexamethasone intervention 4: Pomalidomide
Intervention descriptions: intervention 1: Immediate Release (IR) Formulation intervention 2: Gastro-Retentive (GR) Formulation intervention 3: Dexamethasone intervention 4: Pomalidomide

Protocol documents:
Prot_000.pdf: 
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Product:  Oprozomib 
Protocol Number:  20160104 
Date:  27 January 2021 
Page 33 of 125 
CONFIDENTIAL 
 
 
Table 2.  Summary of Subject Incidence of Treatment-Emergent Adverse Events (Safety Analysis Set) 
 
Non-roll Over Subjects 
 
ODex 2/7 Schedule 
 
OPomd 2/7 Schedule 
 
 
IR 150 
mg/day 
(N  5) 
n () 
GR 150 
mg/day 
(N  8) 
n () 
ODex 2/7 
Total 
(N  13) 
n () 
 
IR 150 
mg/day 
(N  4) 
n () 
GR 150 
mg/day 
(N  4) 
n () 
IR 200 
mg/day 
(N  8) 
n () 
GR 200 
mg/day 
(N  5) 
n () 
IR 225 
mg/day 
(N  10) 
n () 
IR 250 
mg/day 
(N  8) 
n () 
OPomd 
2/7 Total 
(N  39) 
n () 
Total 
Subjects 
(N  52) 
n () 
All treatment-emergent adverse events 
4 (80.0) 
8 (100.0) 12 (92.3)  4 (100.0) 4 (100.0) 8 (100.0) 5 (100.0) 10 (100.0) 8 (100.0) 39 (100.0) 51 (98.1) 
Grade  2 
4 (80.0) 
8 (100.0) 12 (92.3)  4 (100.0) 4 (100.0) 8 (100.0) 5 (100.0) 10 (100.0) 8 (100.0) 39 (100.0) 51 (98.1) 
Grade  3 
3 (60.0) 
7 (87.5) 
10 (76.9)  4 (100.0) 4 (100.0) 8 (100.0) 5 (100.0) 
8 (80.0) 
6 (75.0) 
35 (89.7) 45 (86.5) 
Grade  4 
1 (20.0) 
1 (12.5) 
2 (15.4)  3 (75.0) 
2 (50.0) 
1 (12.5) 
4 (80.0) 
0 (0.0) 
1 (12.5) 
11 (28.2) 13 (25.0) 
Serious adverse events 
2 (40.0) 
2 (25.0) 
4 (30.8)  2 (50.0) 4 (100.0) 
6 (75.0) 
4 (80.0) 
3 (30.0) 
4 (50.0) 
23 (59.0) 27 (51.9) 
Leading to discontinuation of 
investigational product 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 1 (25.0) 
1 (25.0) 
2 (25.0) 
1 (20.0) 
0 (0.0) 
1 (12.5) 
6 (15.4) 
6 (11.5) 
Fatal adverse events 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (20.0) 
0 (0.0) 
0 (0.0) 
1 (2.6) 
1 (1.9) 
Treatment-related treatment-emergent 
adverse events 
4 (80.0) 
8 (100.0) 12 (92.3)  4 (100.0) 4 (100.0) 8 (100.0) 5 (100.0) 10 (100.0) 8 (100.0) 39 (100.0) 51 (98.1) 
Grade  2 
2 (40.0) 
6 (75.0) 
8 (61.5)  4 (100.0) 3 (75.0) 
7 (87.5) 
4 (80.0) 
9 (90.0) 
7 (87.5) 
34 (87.2) 42 (80.8) 
Grade  3 
1 (20.0) 
4 (50.0) 
5 (38.5)  4 (100.0) 3 (75.0) 
6 (75.0) 
1 (20.0) 
5 (50.0) 
5 (62.5) 
24 (61.5) 29 (55.8) 
Grade  4 
0 (0.0) 
1 (12.5) 
1 (7.7) 
 3 (75.0) 
2 (50.0) 
0 (0.0) 
1 (20.0) 
0 (0.0) 
1 (12.5) 
7 (17.9) 
8 (15.4) 
Serious adverse events 
0 (0.0) 
1 (12.5) 
1 (7.7) 
 1 (25.0) 
2 (50.0) 
2 (25.0) 
1 (20.0) 
1 (10.0) 
1 (12.5) 
8 (20.5) 
9 (17.3) 
Leading to discontinuation of 
investigational product 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 1 (25.0) 
1 (25.0) 
2 (25.0) 
1 (20.0) 
0 (0.0) 
1 (12.5) 
6 (15.4) 
6 (11.5) 
Fatal adverse events 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (20.0) 
0 (0.0) 
0 (0.0) 
1 (2.6) 
1 (1.9) 
Page 1 of 2 
Footnotes and abbreviations are on the last page of the table. 


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Product:  Oprozomib 
Protocol Number:  20160104 
Date:  27 January 2021 
Page 103 of 125 
CONFIDENTIAL 
 
 
17. 
APPENDICES 


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Product:  Oprozomib
Protocol Number:  20160104
Date:  13 December 2018
Page 1 of 8
CONFIDENTIAL
Amendment 4
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Oprozomib in Combination With Pomalidomide 
and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
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SAP_001.pdf: 
Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 1 of 38
CONFIDENTIAL 
Statistical Analysis Plan
Protocol Title:
A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Oprozomib in 
Combination With Pomalidomide and
Dexamethasone in Subjects With Relapsed or 
Refractory Multiple Myeloma
Short Protocol Title:
Phase 1b Study Evaluating OPomD in Relapsed or 
Refractory Multiple Myeloma (INTREPID-1)
Protocol Number:
20160104
NCT Number:
NCT02939183
Authors:
Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320
Phone: +1-805-447-1000
SAP Date:
Document Version
Date
Original (v1.0)
07 September 2017
Amendment 1 (v2.0)
19 August 2019


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 2 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Original (v1.0)
07 September 2017
Original Version
Amendment 1 (v2.0)
19 August 2019
Rationale:
The purpose of this SAP amendment is for: 
The protocol amendment of country-specific 
supplemental protocol for United States. This 
is an open label roll-over study of Oprozomib 
parent trials, which evaluates Oprozomib 
extended release (ER) tablet in multiple 
myeloma or Waldenstrom 
macrogolobulinemia patients. 
Changes: 
1.Introduction:
Deleted:
Protocol date -16 February 2017
Added: 
Protocol date - 13 December 2018
The global protocol and its country-specific 
US supplement for study 20160104, 
Oprozomib  dated 13 December 2018
2.1. Objective and Endpoints 
Primary Objective
Added:
Roll-over subjects only:
Evaluate the safety profile for all subjects on 
continued oprozomib treatment
Primary Endpoint
Added:
Roll-over subjects only:
Incidence of treatment-emergent adverse 
events and treatment-emergent serious 
adverse events for all subjects on continued 
oprozomib treatment
Page 1 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 3 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
2.2. Hypotheses and/or Estimations
Added:
For United States: for subjects previously 
treated on a separate Amgen protocol with 
oprozomib, the clinical hypothesis is that 
continued treatment with oprozomib will be 
well tolerated and sustain the response and/or 
clinical benefit achieved in previous 
oprozomib studies.
3.1. Study design
Added:
For United States: this multicenter, open-label 
study will permit subjects who have completed 
the planned duration of treatment on a 
separate Amgen oprozomib study to continue 
treatment. Subjects who participated in study 
20160104 are not eligible to roll-over into this 
part of the study after their study completion. 
Subjects who have completed the planned 
duration of oprozomib treatment on a 
separate Amgen protocol, are currently 
receiving oprozomib as a monotherapy or a 
combination of oprozomib with 
dexamethasone and have a stable disease or 
better at the time of screening are eligible to 
participate in this study.
3.2. Sample Size
Added:
In Part 1, at least 3 DLT-evaluable subjects 
will be enrolled for each of the oprozomib 
formulations.  
For United States: for the roll-over portion of 
the study, the sample size for this study 
cannot be determined prospectively, as it is 
contingent on the number of subjects 
completing previous studies or having clinical 
benefit but not otherwise being able to 
continue the previous oprozomib study.
Page 2 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 4 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
5.Definitions
Added: 
Study Treatment:
Any combination of oprozomib, pomalidomide 
and dexamethasone, or monotherapy of 
oprozomib.
Progression Free Survival:
Progression free survival data will be 
censored as described below:
1.Patients who are alive and do not have 
documented disease progression at the time 
of analysis will be censored at the date of the 
last disease assessment.
2.Patients who are alive and do not have 
disease assessment at the time of analysis 
will be censored at the first study dose date.
3.Patients who are alive without documented 
disease progression, and have withdrawn 
consent at the time of analysis will be 
censored at the date of the last disease 
assessment before withdrawal of consent.
4.Patients who have started an anti-cancer 
therapy other than the study treatment prior to 
documentation of disease progression will be 
censored at the date of the last disease 
assessment prior to start of new therapy.
Duration of Grade II GI Toxicity:
The intermittent adverse events will be 
excluded from the analysis of duration of 
Grade II GI toxicity, and not to be counted as 
one ongoing adverse event.
Page 3 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 5 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
Duration of Grade III or above GI Toxicity:
Duration of Grade III or above GI toxicity is 
defined as the number of days between the 
start date through to the subsequent end date 
of the Grade III or above GI toxicity, or where 
applicable date of censoring [end date of the 
Grade III or above GI toxicity or date of 
censoring – start date of the Grade III or 
above GI toxicity +1].  Subjects whose Grade 
III or above GI toxicity do not end while on 
study will be censored at the date when they 
are last on study.  Subjects who do not 
experience Grade III or above GI toxicity will 
be excluded from the analysis of duration of 
Grade III or above GI toxicity. The intermittent 
adverse events will be excluded from the 
analysis of duration of Grade III or above GI 
toxicity, and not to be counted as one ongoing 
adverse event.
Non-roll over subjects:
Subjects that were enrolled into this study and 
do not participate in the open-label roll-over 
part of the study will be referred to as “non-roll 
over subjects”. 
Roll-over subjects:
Subjects that were previously treated on a 
separate Amgen protocol and participate in 
the open-label roll-over part of the study will 
be referred to as “roll-over subjects”.
Treatment Emergent Adverse Events (TEAE):
Treatment-emergent adverse events are 
events categorized as Adverse Events (AEs) 
starting on or after first dose of investigational 
product as determined by the flag indicating if 
the adverse event started prior to the first 
dose on the Events CRF and up to and 
including 30 days after the last dose of 
investigational product or the End of Study 
date, whichever is earlier. 
Page 4 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 6 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
6.1. Safety Analysis Set
Added:
The safety population is defined as all 
subjects, excluding roll-over subjects, who 
receive any amount of oprozomib, 
pomalidomide and/or dexamethasone.
6.2. Safety Analysis Set for roll-over 
subjects (For United States site only)
Added:
The safety population for roll-over subjects is 
defined as all roll-over subjects who receive 
any amount of oprozomib and/or 
dexamethasone.
6.3. Efficacy Analysis Set
Added:
The efficacy population is defined as subjects, 
excluding roll-over subjects, who are included 
in the safety evaluable population, and have a 
baseline disease assessment and at least
1 post-baseline disease assessment
6.4. Pharmacokinetic Analyses Set
Added:
PK population is defined as subjects for whom 
at least 1 PK parameter can be adequately 
estimated, excluding roll-over subjects
7.1. Interim Analysis and Early Stopping 
Guidelines
Added sub-heading: 
Non-roll over subjects
The database will not be cleaned and an as-is 
snapshot of the database will be used in the 
analyses.
Page 5 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 7 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
7.2. Primary Analysis
Added: 
Sub-heading: Non-roll over subjects
Roll-over subjects: the main objective of the 
primary analysis of roll-over subjects is to 
evaluate the safety profile for all subjects on 
continued oprozomib treatment. Safety profile 
will be presented through descriptive statistics 
of safety data (treatment-emergent serious 
adverse events, treatment-emergent adverse 
events).
All available data up to and including the data 
cutoff date will be cleaned and a locked 
database will be used in the analysis.
7.3. Final Analysis
Added:
At that time the database will be cleaned, 
processed and a locked database will be used 
in the analysis.
9.2. Subject Accountability
Added:
Key study dates for the first subject enrolled, 
last subject enrolled, and last subject’s end of 
study will be presented for non-roll over 
subjects and roll-over subjects.
9.4.2. Medical History
Added:
The number (%) of subjects who experienced 
a prior disease or disorder will be summarized 
by system organ class and preferred term for 
non-roll over subjects and roll-over subjects.
Page 6 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 8 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
9.4.3. Baseline Characteristics
Added:
The following baseline characteristics will be 
summarized for non-roll over subjects:

ECOG performance Status

Disease stage

Myeloma light chain
o
Kappa light chain
o
Lambda light chain

Myeloma immunoglobulin
o
Immunoglobulin A
o
Immunoglobulin D
o
Immunoglobulin E
o
Immunoglobulin G
o
Immunoglobulin M

Pathology (FISH)
o
t(11;14)
o
del(13q;14)
o
t(4;14)
o
t(14;16)
o
Chromosome 1 abnormalities 
(ie, 1q21 amplification,
1p deletion)
o
Chromosome 13 
abnormalities (ie, 
chromosome 13 deletion)
o
Hyperdiploid
o
Non-hyperdiploid

Prior lines of therapy

Prior radiotherapy

Exposure and refractory status to 
o
Bortezomib
o
Carfilzomib
o
Lenadolimide
o
Pomalidomide
o
Anti-CD38 antibody (including 
Daratumumab)

Prior transplant
Page 7 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 9 of 38
CONFIDENTIAL 
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Amendment 1 (v2.0)
(Continued)
9.6.2. Adverse Events and Disease-related 
Events
Added:
Roll-over subjects: Subject incidence 
treatment-emergent adverse events and 
treatment-emergent serious adverse events 
will be tabulated by system organ class, 
preferred term, grade and preferred term in 
descending order of frequency.
9.6.3. Laboratory Test Results:
Added:
Sub-heading: Non-roll over subjects
Table heading: Table 9.6.3.1 List of analytes 
for non-roll over subjects 
Roll-over subjects:
Summary of clinical chemistry, hematology, 
urinalysis, and coagulation will be listed for 
each subject. Subjects laboratory parameters 
toxicities will be classified using CTCAE grade 
and their percentages will be tabulated. 
Summary CTCAE grade 3 and higher 
toxicities will be provided. 
Below is list of all lab tests performed for
roll-over subjects:
Table 9.6.3.2 List of Analytes for roll-over 
subjects
(attached above table from amended protocol)
9.7.1. Analysis of pharmacokinetic or 
pharmacokinetic/
 
endpoints
Added sub-heading:
Non-roll over subjects
Page 8 of 8


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 10 of 38
CONFIDENTIAL 
Table of Contents
Table of Contents .................................................................................................10
1.
Introduction...........................................................................................................14
2.
Objectives, Endpoints and Hypotheses.................................................................14
2.1
Objectives and Endpoints..........................................................................14
2.2
Hypotheses and/or Estimations.................................................................15
3.
Study Overview ....................................................................................................15
3.1
Study Design.............................................................................................15
3.2
Sample Size..............................................................................................17
4.
Covariates and Subgroups ...................................................................................17
4.1
Planned Covariates...................................................................................17
4.2
Subgroups.................................................................................................17
5.
Definitions.............................................................................................................17
6.
Analysis Sets........................................................................................................23
6.1
Safety Analysis Set ...................................................................................23
6.2
Efficacy Analysis Set.................................................................................23
6.3
Pharmacokinetic Analyses Set..................................................................23
7.
Planned Analyses.................................................................................................23
7.1
Interim Analysis and Early Stopping Guidelines ........................................23
7.2
Primary Analysis .......................................................................................23
7.3
Final Analysis............................................................................................24
8.
Data Screening and Acceptance...........................................................................24
8.1
General Principles.....................................................................................24
8.2
Data Handling and Electronic Transfer of Data..........................................25
8.3
Handling of Missing and Incomplete Data .................................................25
8.4
Detection of Bias.......................................................................................25
8.5
Outliers .....................................................................................................25
8.6
Distributional Characteristics.....................................................................25
8.7
Validation of Statistical Analyses...............................................................25
9.
Statistical Methods of Analysis..............................................................................26
9.1
General Considerations.............................................................................26
9.2
Subject Accountability ...............................................................................26
9.3
Important Protocol Deviations ...................................................................26
9.4
Demographic and Baseline Characteristics...............................................26
9.4.1
Demographics ...........................................................................26
9.4.2
Medical History..........................................................................27
9.4.3
Baseline Characteristics ............................................................27
9.5
Efficacy Analyses......................................................................................28


Product:  Oprozomib 
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9.5.1 
Analyses of Primary Efficacy Endpoint(s) ................................... 28 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) .............................. 28 
9.6 
Safety Analyses .......................................................................................... 28 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 28 
9.6.2 
Adverse Events and Disease-related Events ............................. 29 
9.6.3 
Laboratory Test Results ............................................................. 29 
9.6.3.1 
List of Analytes for Non-roll Over Subjects .............. 31 
9.6.3.2 
List of Analytes for Roll-over Subjects ..................... 32 
9.6.4 
Vital Signs ................................................................................... 32 
9.6.5 
Physical Measurements ............................................................. 32 
9.6.6 
Electrocardiogram ...................................................................... 32 
9.6.7 
Antibody Formation .................................................................... 33 
9.6.8 
Exposure to Investigational Product ........................................... 33 
9.6.9 
Exposure to Other Protocol-required Therapy ............................ 33 
9.6.10 
Exposure to Concomitant Medication ......................................... 33 
9.7 
Other Analyses ........................................................................................... 33 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/
 Endpoints ......................... 33 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 34 
9.7.3 
Analyses of Health Economic Endpoints .................................... 34 
10. 
Changes From Protocol-specified Analyses .......................................................... 34 
11. 
Literature Citations / References ............................................................................ 35 
12. 
Appendices ............................................................................................................ 36 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ......................................................... 37 


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 12 of 38
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List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition/Explanation
AE
adverse event
AUC
area under the concentration-time curve
AUCinf
AUC from time 0 to the time extrapolated to infinity
AUClast
area under the curve until the last measurable concentration
CR
complete response
CTCAE
Common Terminology Criteria for Adverse Events
DLRM
dose level review meeting
DLRT
dose level review team
DLT
dose limiting toxicity
ECG
electrocardiogram
End of study for individual 
subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
End of treatment
Last day of protocol specified treatment 
End of study (primary 
completion)
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the 
primary endpoint(s)
End of study (end of trial)
defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes 
multiple parts (eg, safety follow-up or survival assessment), the 
end of study would include these additional parts
GI
gastrointestinal
GR
gastro-retentive
IR
immediate release
IMWG
International Myeloma Working Group
Mg
milligram
mL
milliliter
MTD
maximum tolerated dose
RRMM
refractory multiple myeloma
Od
oprozomib in combination dexamethasone
OPomd
oprozomib in combination with pomalidomide and 
dexamethasone
ORR
overall response rate
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response


Product:  Oprozomib
Protocol Number:  20160104
Date:  19 August 2019
Page 13 of 38
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Abbreviation or Term
Definition/Explanation
SAE
serious adverse event
sCR
stringent complete response
Source Data
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research. The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents (original 
records or certified copies). (ICH Guideline (E6)). Examples of 
source data include Subject identification, Randomization
identification, and Stratification Value.
Study day 1
defined as the first day that protocol specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject
t1/2
terminal elimination half-life
Tmax
time when maximum plasma concentration is reached
VGPR
very good partial response


Product:  Oprozomib
Protocol Number:  20160104
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1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the global protocol and its country-specific US 
supplement for study 20160104, Oprozomib dated 13 December 2018. The scope of 
this plan includes the primary analysis and the final analysis that are planned and will be 
executed by the Amgen Global Biostatistical Science department unless otherwise 
specified.
2.
Objectives, Endpoints and Hypotheses
2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

Identify the maximum tolerated dose 
(MTD) of oprozomib formulations in 
combination with pomalidomide and 
dexamethasone (OPomd) in subjects with 
relapsed or refractory multiple myeloma 

Evaluate the safety and tolerability of the 
OPomd combination in subjects with 
relapsed or refractory multiple myeloma

Roll-over subjects only:
Evaluate the safety profile for all 
subjects on continued oprozomib 
treatment

Determine the MTD for each formulation 
of oprozomib in combination with 
pomalidomide and dexamethasone as the 
dose that has the highest posterior 
probability of having a dose limiting 
toxicity (DLT) rate within the target toxicity 
interval (15% to 25%), while the posterior 
probability of excessive/unacceptable 
toxicity (> 25% to 100%) is < 40%

Incidence of treatment-related, 
treatment-emergent adverse events and 
changes in laboratory test results

Roll-over subjects only:
Incidence of treatment-emergent 
adverse events and
treatment-emergent serious adverse 
events for all subjects on continued 
oprozomib treatment
Secondary

Characterize the pharmacokinetics (PK) 
of oprozomib

Evaluate the efficacy of the OPomd 
combination according to International 
Myeloma Working Group (IMWG) uniform 
response criteria

Identify the recommended formulation 
and Phase 3 dose (RP3D) of oprozomib 
in combination with pomalidomide and 
dexamethasone in subjects with relapsed 
or refractory multiple myeloma

PK parameters of oprozomib including, 
but not limited to, maximum observed 
concentration (Cmax), time to Cmax (tmax), 
and the area under the concentration-time 
curve from time 0 to the time of the last 
quantifiable concentration (AUClast)

Overall response and best overall 
response according to the IMWG uniform 
response criteria, progression free 
survival (PFS), and duration of response 
(DOR)
Page 1 of 2


Product:  Oprozomib
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CONFIDENTIAL 
Objectives
Endpoints
Page 2 of 2
2.2
Hypotheses and/or Estimations
At least one dose level of the formulations of oprozomib administered orally together
with pomalidomide and dexamethasone is expected to achieve acceptable safety and
tolerability in subjects with relapsed or refractory multiple myeloma.
For United States: for subjects previously treated on a separate Amgen protocol 
with oprozomib, the clinical hypothesis is that continued treatment with 
oprozomib will be well tolerated and sustain the response and/or clinical benefit 
achieved in previous oprozomib studies. 
3.
Study Overview
3.1
Study Design
This is a Phase 1b, multicenter, non-randomized, open-label, dose-exploration study of 
up to two formulations of oprozomib (an “immediate release” formulation [IR], and an 
“extended release gastro-retentive” formulation [GR]) administered according to a 
2/7 schedule (two consecutive days per week), in combination with pomalidomide and 
dexamethasone in subjects with relapsed or refractory multiple myeloma. The 
evaluation of the different formulations will start with the IR (for the initial 1 to 2 dose 
levels) however, for most of the study the two oprozomib formulations will be tested in 
parallel. The study will be conducted in two sequential parts: 

Part 1 – Evaluation of 2 formulations of oprozomib administered at 150 mg/day 
dose level in combination with dexamethasone (Od) only 

Part 2 – Evaluation of 2 formulations of oprozomib administered at increasing 
dose levels (dose escalation) in combination with pomalidomide and 
dexamethasone (OPomd)
Part 1 will test each formulation of oprozomib in combination with dexamethasone to 
evaluate the safety and tolerability of oprozomib in combination with dexamethasone at 
the starting dose level. Testing will begin with the IR formulation. If a dose modification 


Product:  Oprozomib
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Date:  19 August 2019
Page 16 of 38
CONFIDENTIAL 
of oprozomib is necessary, this will be decided based on analysis of emerging safety 
and PK data. Part 2 dose escalation will use the Bayesian 2-parameter logistic 
regression model with the new continual reassessment method (NCRM) applied to 
observed DLTs (Neuenschwander, 2008). Testing will begin with the IR formulation of 
oprozomib, and the starting dose level will be chosen based on the oprozomib dose 
determined during Part 1. All subjects will be treated during the first week only with a 
fixed, initial dose level of oprozomib. For all dosing days thereafter, the subjects will be 
treated with the appropriate dose level of oprozomib according to the dose escalation 
cohort being evaluated. It is anticipated that in Part 2, seven dose levels of oprozomib 
IR (between 150 mg and 300 mg/day, in increments of 25 mg) will be tested in 
combination with pomalidomide and dexamethasone. The number of dose levels, the 
increment of change as well as the minimum and maximum dose level of oprozomib to 
be tested may be adjusted during the study based on emerging safety and PK data. The 
application of the Bayesian algorithm will stop when the DLT rate of the recommended 
MTD has a probability within the target toxicity interval (15% to 25%) of ≥ 40%, an 
excessive/unacceptable interval (> 25% to 100%) of < 40%, and a minimum of
6 subjects have been treated at the MTD level or when the sample size reaches
36 subjects. In the event that evaluation of additional subjects is deemed necessary by 
the Dose Level Review Team (DLRT), extra subjects may be enrolled. The testing of 
the GR formulation will start after the first one or two cohorts of IR have been evaluated. 
The starting dose for the GR formulation will be determined based on the safety and PK 
data observed in the first cohorts of the IR dose escalation, and it will be at least one 
dose level lower than the highest dose tested of the IR formulation. The DLRT will 
review the available safety, efficacy, PK, and 
 data and recommend a formulation 
and a dose level for administration of oprozomib in the OPomd combination in future 
studies.
For United States: this multicenter, open-label study will permit subjects who have 
completed the planned duration of treatment on a separate Amgen oprozomib 
study to continue treatment. Subjects who participated in study 20160104 are not 
eligible to roll-over into this part of the study after their study completion.
Subjects who have completed the planned duration of oprozomib treatment on a 
separate Amgen protocol, are currently receiving oprozomib as a monotherapy or 
a combination of oprozomib with dexamethasone, and have a stable disease or 
better at the time of screening are eligible to participate in this study. 


Product:  Oprozomib
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For additional details please refer to Section 3.1 and the Study Schema.
3.2
Sample Size
Approximately 64 DLT evaluable subjects will be enrolled in this phase 1b study.
In Part 1, at least 3 DLT-evaluable subjects will be enrolled for each of the oprozomib 
formulations. In Part 2, a Bayesian design will be applied to evaluate the oprozomib 
formulations (IR and GR) administered at increasing dose levels in combination with 
pomalidomide and dexamethasone. The maximum sample size for testing the IR 
formulation is set to 
36 DLT evaluable subjects. The anticipated sample size under the assumption of 
11 cohorts evaluated for the GR formulation is 22 DLT evaluable subjects.
For United States: for the roll-over portion of the study, the sample size for this 
study cannot be determined prospectively, as it is contingent on the number of 
subjects completing previous studies, or having clinical benefit but not otherwise 
being able to continue the previous oprozomib study. 
4.
Covariates and Subgroups
4.1
Planned Covariates
No covariate or subgroup is pre-specified for the analysis of the primary, secondary, and
safety endpoints. The relationship of covariates to efficacy endpoints will be explored if
appropriate.
4.2
Subgroups
5.
Definitions
Age at Enrollment
Subject age at enrollment will be determined using the age in years reported in the
clinical database.
Baseline 
For any variable, unless otherwise specified the baseline is the last assessment taken
prior to the first administration of study treatment. For parameters/assessments not
scheduled to be performed (or scheduled but not performed) on the same day as the


Product:  Oprozomib
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Date:  19 August 2019
Page 18 of 38
CONFIDENTIAL 
first administration of study treatment, the baseline value is the value from the screening
period measured closest to the day of first administration of study treatment.
Baseline and Post-Baseline ECG Values in Triplicate 
The baseline ECG is defined as the mean of all pre-dose assessments; the mean of 
values in a triplicate should be calculated before taking the mean of the triplicate 
averages.
For all post-baseline ECG, the mean value for measurements taken at the same 
assessment will be calculated and used in the analysis.
For pre and post dose ECG measurements, unscheduled ECG measurements taken up 
to 5 minutes after the last assessments of a triplicate will be included in the average for a 
timepoint. Where an ECG is missing within a triplicate, all available data will be 
averaged for that timepoint.
Bazett-corrected QT Interval (QTcB)
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcB=QT/(RR/1000)1/2
Change From Baseline
Change from Baseline is the arithmetic difference between post-dose assessments and
Baseline value.
Change (absolute) from Baseline=(Post-baseline Value – Baseline Value)
Change (percent) from Baseline=[(Post-baseline Value – Baseline Value)/Baseline
Value]x100
Dose Limiting Toxicities (DLT) Window
The DLT window will be the initial 28 days of study treatment. The DLT window may be
extended to assess events starting within the window in case the DLT definition is time
dependent. Any adverse event occurring outside the DLT window that is determined by 
the investigator to be possibly related to the investigational product, which is seen more 
frequently or is more severe than expected or is persistent despite appropriate 
management, can be determined to be a DLT upon unanimous decision by the DLRT 
after review of the adverse event and all available safety data.  


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DLT Evaluable
In order to be DLT-evaluable, a subject would receive the doses of study treatment as
specified below during the 28 day DLT window:

All planned doses of oprozomib must be received

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
If the subject discontinues the treatment or misses a dose of oprozomib for reasons
other than DLT before completion of the DLT window, the DLRT will decide if the subject
is DLT-evaluable and will make the final decision on subject replacement.
Duration of Response (DOR)
Duration of response is defined as the number of days between the date of the 
first tumor assessment indicating an objective response through to the subsequent date 
of progression or death due to any cause, or where applicable date of censoring [date of
first progressive disease assessment or death or date of censoring – date of the first
objective response result +1].  Subjects who respond and have not progressed while on
study will be censored at the date of assessment of the last evaluable tumor
assessment. Subjects who do not achieve an objective response will be excluded from
the analysis of duration of response. Objective response is defined as any of the
following: stringent complete response (sCR), complete response (CR), very good partial
response (VGPR), or partial response (PR) (all according to Revised International
Myeloma Working Group Uniform Response Criteria [IMWG-URC]).
Enrollment Date
Enrollment Date is defined as the date when the dosing of investigational product
(oprozomib) is started.
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and
RR interval (msec), as follows:  QTcF=QT/(RR/1000)1/3
Use above definition for derivation only if QTcF is not collected in the CRF.
Investigational Product
The term ‘investigational product’ is used in reference to oprozomib.


Product:  Oprozomib
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Study Treatment
Any combination of oprozomib, pomalidomide and dexamethasone, or monotherapy of 
oprozomib.
Last Investigational Product Dose Date 
The last IP dose date for each subject is defined as the latest date IP is administered.
Maximum Tolerated Dose (MTD)
MTD for each formulation is defined as the dose that has the highest posterior
probability of having a DLT rate within the target toxicity interval (15% to 25%), while the
posterior probability of excessive/unacceptable toxicity (> 25% to 100%) is < 40%
Study Day 1
It is defined as the first day that protocol specified study treatment is administered to the 
subject.
Study Day
Post study day:   study day= (date - date of Study Day 1) + 1
Pre study day:    study day= (date – date of Study Day 1)
Time to Response (TTR)
Time to response defined as the interval from the first administration of study treatment
to the first documentation of confirmed response. Response is defined as any of the
following: stringent complete response (sCR), complete response (CR), very good partial
response (VGPR), or partial response (PR) (all according to Revised International
Myeloma Working Group Uniform Response Criteria [IMWG-URC].
Time to response is calculated as the number of days:
(date of first response – date of study day 1 +1). 
Time to response will be calculated only for subjects with response.
Treatment-Emergent Adverse Event (TEAE)
Treatment-emergent adverse events are events categorized as Adverse Events (AEs)
starting on or after first dose of investigational product as determined by the flag 
indicating if the adverse event started prior to the first dose on the Events CRF 
and up to and including 30 days after the last dose of investigational product or 
the End of Study date, whichever is earlier. 


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Page 21 of 38
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Treatment-Related AE
A treatment-related AE is any treatment-emergent AE that per investigator review has a
reasonable possibility of being caused by study treatment.
Disease-Related Events
Disease-Related Events are events (serious or non-serious) anticipated to occur in the
study population due to the underlying disease.
Cmax
Maximum observed serum concentration.
tmax
Time to Cmax
AUClast
Area under the concentration-time curve from time 0 (time of investigational product
administration) to the time of the last quantifiable concentration.
Progression free survival
The number of months from subject’s first study dose date to the earlier of disease
progression or death due to any cause.
         Progression free survival data will be censored as described below:

Patients who are alive and do not have documented disease 
progression at the time of analysis will be censored at the date of 
the last disease assessment.

Patients who are alive and do not have disease assessment at the 
time of analysis will be censored at the first study dose date.

Patients who are alive without documented disease progression, 
and have withdrawn consent at the time of analysis will be censored 
at the date of the last disease assessment before withdrawal of 
consent.

Patients who have started an anti-cancer therapy other than the 
study treatment prior to documentation of disease progression will 
be censored at the date of the last disease assessment prior to start 
of new therapy.


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Best Overall Response (BOR)
The best response that a subject achieved during study where the responses are ranked
from best to worst as follows: stringent complete response [sCR], complete response
[CR], very good partial response [VGPR], and partial response [PR], minimal response
[MR], stable disease [SD] and progressive disease [PD] (all according to Revised
International Myeloma Working Group Uniform Response Criteria [IMWG-URC])
Overall Response Rate (ORR)
Proportion of subjects with BOR of sCR, CR, VGPR or PR.
Duration of Grade II GI Toxicity
Duration of Grade II GI toxicity is defined as the number of days between the start date
through to the subsequent end date of the Grade II GI toxicity, or where applicable date
of censoring [end date of the Grade II GI toxicity or date of censoring – start date of the
Grade II GI toxicity +1].  Subjects whose Grade II GI toxicity do not end while on study
will be censored at the date when they are last on study. Subjects who do not
experience Grade II GI toxicity will be excluded from the analysis of duration of Grade II
GI toxicity. The intermittent adverse events will be excluded from the analysis of 
duration of Grade II GI toxicity, and not to be counted as one ongoing adverse 
event.
Duration of Grade III or above GI Toxicity
Duration of Grade III or above GI toxicity is defined as the number of days 
between the start date through to the subsequent end date of the Grade III or
above GI toxicity, or where applicable date of censoring [end date of the Grade III 
or above GI toxicity or date of censoring – start date of the Grade III or above GI 
toxicity +1].  Subjects whose Grade III or above GI toxicity do not end while on 
study will be censored at the date when they are last on study.  Subjects who do 
not experience Grade III or above GI toxicity will be excluded from the analysis of 
duration of Grade III or above GI toxicity. The intermittent adverse events will be 
excluded from the analysis of duration of Grade III or above GI toxicity, and not to 
be counted as one ongoing adverse event.
Non-roll over subjects
Subjects that were enrolled into this study and do not participate in the open-label 
roll-over part of the study will be referred to as “non-roll over subjects”. 


Product:  Oprozomib
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Roll-over subjects
Subjects that were previously treated on a separate Amgen protocol and 
participate in the open-label roll-over part of the study will be referred to as
“roll-over subjects”.
6.
Analysis Sets
6.1
Safety Analysis Set
The safety population for roll-over subjects is defined as all roll-over subjects who 
receive any amount of oprozomib and/or dexamethasone.
6.2
Efficacy Analysis Set
The efficacy population is defined as subjects, excluding roll-over subjects, who are 
included in the safety evaluable population, and have a baseline disease assessment 
and at least 1 post-baseline disease assessment.
6.3
Pharmacokinetic Analyses Set
PK population is defined as subjects for whom at least 1 PK parameter can be
adequately estimated, excluding roll-over subjects.
7.
Planned Analyses
7.1
Interim Analysis and Early Stopping Guidelines
Non-roll over subjects:
No formal interim analysis will be conducted. Safety data will be reviewed on an 
ongoing basis. Amgen, in consultation with the site investigator, will review in Dose 
Level Review Meetings (DLRMs) all available cumulative data by cohort prior to making 
dose escalation decisions. The database will not be cleaned and an as-is snapshot 
of the database will be used in the analyses.  Adverse events and DLTs observed in 
all subjects will be evaluated continually and fully integrated into all DLRMs and 
considered in all enrollment and dosing decisions.
7.2
Primary Analysis
Non-roll over subjects:
The main objectives of the primary analysis are to determine the MTD for each 
formulation of oprozomib in combination with pomalidomide and dexamethasone and 
further evaluate the safety, tolerability and efficacy of the OPomd combination in 
subjects with relapsed or refractory multiple myeloma. In addition, this analysis will be
used to possibly recommend the most appropriate oprozomib dose and formulation to be 
tested in future clinical trials in an OPomd combination. The selection of the oprozomib 


Product:  Oprozomib
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Page 24 of 38
CONFIDENTIAL 
recommended dose and formulation will be based on all data from the escalation 
cohorts.
Safety and tolerability will be assessed through summaries of study drug administration, 
DLTs, adverse events, changes in selected laboratory analytes, vital signs, and physical 
findings by dose level. Means and standard deviations will be used to summarize the 
total dose for each component of study drug received. All summaries will be presented 
by the assigned dose level and for all subjects.
All adverse event data will be listed by study site, dose level, subject identification 
number, and study day. All adverse events will be summarized by preferred term, 
appropriate thesaurus levels, and CTCAE (Version 4.03) toxicity grade. In addition, all 
serious adverse events, including deaths, will be listed separately and summarized.
Efficacy analyses of ORR and BOR will be performed using both the efficacy and safety
population as defined previously.
Roll-over subjects: the main objective of the primary analysis of roll-over subjects 
is to evaluate the safety profile for all subjects on continued oprozomib treatment. 
Safety profile will be presented through descriptive statistics of safety data 
(treatment-emergent serious adverse events, treatment-emergent adverse events).  
The primary analysis will be based on subject data collected up to two months from the 
date of last subject enrollment. All available data up to and including the data cutoff 
date will be cleaned and a locked database will be used in the analysis.
7.3
Final Analysis
The objective of the final analysis is to provide an update on safety and tolerability, and
efficacy results. The statistical methods used in the final analysis will be the same as
those employed in the primary analysis. The final analysis will be based on subject data
collected through study discontinuation or at the end of the study which includes the 
30 days safety follow-up, whichever occurs first. At that time the database will be 
cleaned, processed and a locked database will be used in the analysis. 
8.
Data Screening and Acceptance
8.1
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.


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8.2
Data Handling and Electronic Transfer of Data
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE
database.
8.3
Handling of Missing and Incomplete Data
The following imputation for missing or incomplete data will be performed if required:
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A.  If imputed dates are used, then they will be 
identified as such in the final study report.
Laboratory measurements that are below the quantification limits will be considered 
equal to the lower limit of quantification for all analyses unless explicitly noted otherwise. 
Non-pharmacokinetic measurements (eg,
 data) that are below the lower limit 
of quantification will be considered equal to half of the lower limit of quantification for all 
analyses unless specified otherwise.
PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters.
8.4
Detection of Bias
Lack of protocol compliance and the potential for biased statistical analyses will be
examined by assessing the incidence of important protocol deviations in each cohort.
The clinical study team will identify and document the criteria for important protocol
deviations.
8.5
Outliers
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice.
8.6
Distributional Characteristics
Where appropriate, the assumptions underlying the proposed statistical methodologies
will be assessed. If required, data transformations or alternative non-parametric 
methods of analyses will be utilized.
8.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  


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Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later.
9.
Statistical Methods of Analysis
9.1
General Considerations
All analyses for the study are 
 and hypothesis generating. Descriptive 
statistics will be used to summarize most analysis results.
Data analysis will occur at the following time points:

The primary analysis will occur when target enrollment is complete and each
subject either completes 2 months on study or withdraws from the study.

A final analysis is planned when the last subject is assessed or receives an
intervention for evaluation in the study.
9.2
Subject Accountability
A summary of subject disposition with discontinuation reasons, and oprozomib 
completion and discontinuation will be provided. Key study dates for the first subject 
enrolled, last subject enrolled, and last subject’s end of study will be presented for
non-roll over subjects and roll-over subjects.
A subject listing and summary noting inclusion in each analysis subset will be provided 
for all subjects enrolled. A subject listing noting duration of oprozomib administration, 
reason for discontinuation of treatment, and reason for discontinuing the study will be 
provided. A list of subjects screened but not enrolled (screen failures) will be provided.
9.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol.
9.4
Demographic and Baseline Characteristics
9.4.1
Demographics
Demographic (ie, age, age groups [18-64, 65-74, 75-84 and > = 85], sex, race, ethnicity)
and baseline characteristics will be summarized by dose cohort and overall using


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descriptive statistics. If multiple races have been reported for a subject, the subject will
be categorized as multiple race as well as by the combination of race.
9.4.2
Medical History
The number (%) of subjects who experienced a prior disease or disorder will be 
summarized by system organ class and preferred term for non-roll over subjects 
and roll-over subjects.
9.4.3
Baseline Characteristics
The following baseline characteristics will be summarized for non-roll over 
subjects:

ECOG performance Status

Disease stage

Myeloma light chain
o
Kappa light chain
o
Lambda light chain

Myeloma immunoglobulin
o
Immunoglobulin A
o
Immunoglobulin D
o
Immunoglobulin E
o
Immunoglobulin G
o
Immunoglobulin M

Pathology (FISH)
o
t(11;14)
o
del(13q;14)
o
t(4;14)
o
t(14;16)
o
Chromosome 1 abnormalities (ie, 1q21 amplification, 1p deletion)
o
Chromosome 13 abnormalities (ie, chromosome 13 deletion)
o
Hyperdiploid
o
Non-hyperdiploid

Prior lines of therapy

Prior radiotherapy

Exposure and refractory status to 
o
Bortezomib
o
Carfilzomib
o
Lenadolimide
o
Pomalidomide
o
Anti-CD38 antibody (including Daratumumab)

Prior transplant


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9.5 
Efficacy Analyses 
All efficacy assessments will follow IMWG uniform response criteria and be performed 
every 4 weeks (± 1 week).  See Section 9.5.2 for details. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
NA 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Overall response rate (defined as the proportion of best overall response of stringent 
complete response [sCR], complete response [CR], very good partial response [VGPR], 
and partial response [PR]), best overall response, PFS (defined as the number of 
months from subject’s first study dose date to the earlier of disease progression or death 
due to any cause), and DOR will be summarized for all subjects overall, by formulation, 
by dose cohort level, and by formulation and dose cohort level along with 
95% confidence intervals when applicable. 
All subjects who receive treatment with any amount of the OPomd and have a baseline 
disease assessment and at least 1 post-baseline disease assessment will be included in 
the efficacy analyses.  Additional efficacy analyses will be performed based on subjects 
who receive treatment with any amount of OPomd. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Subject incidence of all treatment emergent adverse events of interest will be tabulated 
by system organ class and preferred term.  Tables of fatal adverse events, serious 
adverse events, adverse events leading to withdrawal from investigational product, other 
protocol-required therapies or from study, and adverse events of interest will also be 
provided.  Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, 
and blood pressure) data will be displayed by visit and time (when available), with 
CTCAE (Version 4.03) Grade 3 and 4 values identified where appropriate.  Additionally, 
all laboratory data will be summarized by CTCAE Grade. 
ECG analyses include summary changes from baseline for ECG intervals, summaries of 
the proportion of subjects with on-study corrected QT interval (QTc) values that reach 
certain values (eg, > 450 msec), and summaries of the proportion of subjects with 
categorical changes from baseline (eg, < 30 msec). 


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9.6.2
Adverse Events and Disease-related Events
The number of DLTs and adverse events at each dose level will be summarized
separately for each oprozomib formulation in combination with dexamethasone and in
combination with pomalidomide and dexamethasone.
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term.
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
investigational product, and fatal adverse events and adverse events of interest when 
defined.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product, and fatal adverse events 
will be tabulated by system organ class and preferred term in alphabetical order. 
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term.
In addition, summaries of treatment-emergent and serious adverse events by preferred 
term in any treatment arm will be provided in descending order of frequency.  
Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade.
Subject incidence of disease-related events will be summarized for all 
treatment-emergent disease-related events and fatal disease-related events.
Roll-over subjects: Subject incidence treatment-emergent adverse events and 
treatment-emergent serious adverse events will be tabulated by system organ 
class, preferred term, grade and preferred term in descending order of frequency. 
9.6.3
Laboratory Test Results
Non-roll over subjects:
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each
subject. Values outside the normal laboratory reference ranges will be flagged as high 
or low on the listings.


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The number and percentage of subjects experiencing treatment emergent laboratory 
toxicities with worst post dose CTCAE grades of ≥1, ≥2, ≥3 and 4 will be presented. The 
direction of the laboratory worsening will be denoted. The summary will be presented for 
all laboratory parameters for which at least one subject experienced a treatment 
emergent toxicity with a worst grade ≥ 3.
Additionally, the number and percentage of subjects experiencing 1, 2, 3 and 
4 worsening CTCAE grade shifts from baseline will be presented. The direction of the 
laboratory worsening will again be denoted.
Shifts tables indicating the change between the baseline and the maximum post dose 
CTCAE grades for an increased value, and the maximum post dose grade for a 
decreased value will be provided for selected laboratory parameters of interest.
A listing of CTCAE grade 3 or higher laboratory toxicities will be provided. This listing 
will include all laboratory data for the subject and laboratory parameter of interest in 
order to provide proper context. A flag will indicate the grade 3 or higher toxicity. 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters of interest.
A summary of the change from baseline to the post dose maximum, time to post-dose 
maximum, change from baseline to the post dose minimum, and the time to the post 
dose minimum may also be provided for selected parameters of interest.
Below is list of all lab tests performed for non-roll over subjects:


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9.6.3.1 
List of Analytes for Non-roll Over Subjects  
 
Roll-over subjects: 
Summary of clinical chemistry, hematology, urinalysis, and coagulation will be 
listed for each subject. Subjects laboratory parameters toxicities will be classified 
using CTCAE grade and their percentages will be tabulated. Summary CTCAE 
grade 3 and higher toxicities will be provided.  
Below is list of all lab tests performed for roll-over subjects: 


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9.6.3.2 
List of Analytes for Roll-over Subjects 
 
9.6.4 
Vital Signs 
Vital signs data will be listed and reviewed for each subject.  Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline 
over time may be provided. 
9.6.5 
Physical Measurements 
The change in weight from baseline to each scheduled assessment time point will be 
summarized. 
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data, these data would not be expected to be useful for 
meta-analysis with data from other trials.  


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9.6.7
Antibody Formation
NA
9.6.8
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group.
9.6.9
Exposure to Other Protocol-required Therapy
Descriptive statistics will be produced to describe the exposure to each of the protocol 
specified treatment by treatment group.
9.6.10
Exposure to Concomitant Medication
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHO DRUG) dictionary.
9.7
Other Analyses
9.7.1
Analyses of Pharmacokinetic or Pharmacokinetic/
 
Endpoints
Non-roll over subjects:
The PK endpoints include, but are not limited to Cmax, tmax, and AUClast of oprozomib 
following dosing on cycle 1 day 8 and cycle 1 day 22.
Blood samples will be collected from all subjects for determination of plasma 
concentrations of oprozomib at time points specified in the schedule of assessments 
(Table 4 in the protocol). Individual oprozomib concentration-time data and summary 
statistics will be tabulated for each dose level. Individual, mean, and standard deviation 
concentration-time data may be plotted for each dose level. 
PK parameters will be calculated using non-compartmental methods. Actual dosing and 
sampling times will be used for calculation of PK parameters. PK parameter estimates 
will be summarized descriptively. Other pharmacokinetic parameters such as AUC from 
time 0 to the time extrapolated to infinity (AUCinf), apparent clearance (CL/F), and 
terminal half-life (t1/2) may be analyzed. Population PK modeling may be performed to 
better characterize the PK of oprozomib using intense sampling following dosing on 
cycle 1 day 8 and cycle 1 day 22 and sparse sampling in day 1 of cycles 1, 3 and 5.


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9.7.2
Analyses of Clinical Outcome Assessments
NA
9.7.3
Analyses of Health Economic Endpoints
NA
10.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.


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11.
Literature Citations / References
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of
the binomial. Biometricka 1934; 26, 404-13.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach
to phase I cancer trials. Statistics in Medicine 2008;27:2420-2439


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12.
Appendices


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant 
Medications
Imputation Rules for Partial or Missing Stop Dates
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year. If the stop date is entirely missing, assume 
the event or medication is ongoing. If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.
Imputation Rules for Partial or Missing Start Dates
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date


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