Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone, in Combination With Lenalidomide or Oral Cyclophosphamide in Patients With Newly Diagnosed Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Amgen

16.1.1 
Protocol and Amendments 
Protocol Amendment 3, dated 27 February 2018 was generated and approved. Shortly 
thereafter, a decision was made to terminate the study program, and the amendment 
was not implemented. The last version of the protocol, under which the study was active, 
was Amendment 2, dated 15 October 2014.  
Product: 
Date: 
Oprozomib
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Clinical Study Protocol No. OPZ003
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CONFIDENTIAL
CLINICAL STUDY PROTOCOL
Protocol Title:
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and 
Dexamethasone in Combination with Lenalidomide or Oral 
Cyclophosphamide in Patients with Newly Diagnosed Multiple 
Myeloma
Protocol Number:
OPZ003
Name of Investigational 
Product:
Oprozomib
IND Number:
117,851
Sponsor:
Onyx Therapeutics
249 E. Grand Avenue
South San Francisco, CA  94080  US
Study Medical Monitor:
, MD
Senior Medical Director, Clinical Science
249 E. Grand Avenue
South San Francisco, CA 94080  US
Email: 
Date of Original 
Protocol:
17 May 2013
Amendment 1/Date:
19 September 2013
Amendment 2/Date:
15 October 2014
Confidentiality 
Statement:
This material is the property of Onyx Therapeutics, a wholly owned 
subsidiary of Onyx Pharmaceuticals, an Amgen subsidiary.  The material is 
highly confidential and is to be used only in connection with matters 
authorized by a senior representative of Onyx Therapeutics, and no part of 
it is to be disclosed to a third party without the express prior written 
permission of Onyx Therapeutics.
Compliance Statement:
This study will be conducted in accordance with Protocol OPZ003, the
International Conference on Harmonisation (ICH), Good Clinical Practice 
(GCP) guidelines, and the applicable country and regional regulatory 
requirements.
Product: 
Date: 
Oprozomib
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NCT Number: NCT01881789
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov

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CONFIDENTIAL
PROTOCOL APPROVAL SIGNATURE PAGE
Protocol Title:
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and 
Dexamethasone in Combination with Lenalidomide or Oral 
Cyclophosphamide in Patients with Newly Diagnosed Multiple 
Myeloma
Protocol Number:
OPZ003
Sponsor:
Onyx Therapeutics
249 E. Grand Avenue
South San Francisco, CA  94080  US
Date of Original
Protocol:
17 May 2013
Amendment 1:
19 September 2013
Amendment 2:
15 October 2014
Approved by:
<See Electronic Signature>
MD
Vice President, Clinical Development
Date
APPROVALS STATEMENT
This document is signed with electronic signatures at Onyx Therapeutics, a wholly owned subsidiary of Onyx 
Pharmaceuticals, an Amgen subsidiary. Electronic signatures made by our employees, agents, or 
representatives, located anywhere in the world, are the legally binding equivalent of traditional handwritten 
signatures.
Product: 
Date: 
Oprozomib
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CONFIDENTIAL
PROTOCOL ACCEPTANCE PAGE
Issue/Date:  OPZ003/Amendment 2/15 October 2014
I have read this protocol for Study OPZ003 entitled:
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in 
Combination with Lenalidomide or Oral Cyclophosphamide in Patients with Newly 
Diagnosed Multiple Myeloma
As investigator, I understand and agree to conduct this study as outlined herein.
Investigator Name (print)
Investigator Signature
Date
Signature on this page assures the sponsor that, to the best of the investigator’s knowledge, the affiliated 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all governing regulatory 
obligations and the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) while conducting this clinical investigation.  Once signed, the original of this form should be detached 
from the protocol and returned to Onyx Therapeutics or its designee (please retain a copy for your files).
Product: 
Date: 
Oprozomib
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CONFIDENTIAL
SYNOPSIS
Name of 
sponsor/company:
Onyx Therapeutics
Name of product:
Oprozomib
Title of study and 
protocol number:
Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone, in 
Combination with Lenalidomide or Oral Cyclophosphamide in Patients with Newly 
Diagnosed Multiple Myeloma
Protocol Number OPZ003
Study objective(s):
Primary Objectives
Phase 1b

To establish the maximum tolerated dose (MTD) of oprozomib given in 
combination with lenalidomide and dexamethasone (ORd) or with 
cyclophosphamide and dexamethasone (OCyd).

To evaluate the safety and tolerability of the ORd and OCyd combination regimens,
as assessed by the type, incidence, severity and seriousness of adverse events (AEs),
and abnormalities in selected laboratory analytes.
Phase 2 

To estimate the antitumor activity of the ORd and OCyd combination regimens, as 
measured by overall response rate (ORR) and complete response rate (CRR).

To evaluate the safety and tolerability of the ORd and OCyd combination regimens,
as assessed by the type, incidence, severity and seriousness of AEs and 
abnormalities in selected laboratory analytes.
Secondary Objectives

To evaluate population pharmacokinetic (PK) parameter estimates of oprozomib,
and may include its metabolite(s), and the variability in these estimates.

To estimate the duration of response (DOR).

To estimate progression-free survival (PFS).
Exploratory Objectives

To evaluate pharmacodynamics (PDn) biomarkers that may correlate with antitumor 
activity.

To evaluate genomic biomarkers that may predict response and resistance following 
treatment with proteasome inhibitors.
Study design:
This is an open-label, Phase 1b/2, two-combination regimen, non-randomized, 
multicenter study (see study schema below).  
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Oprozomib
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CONFIDENTIAL
Study design
(cont'd):
Study Schema for OPZ003
The ORd combination regimen treatment cycles are 28 days in duration.  Subjects 
enrolled under the original protocol and Amendment 1 will receive oprozomib once daily 
on Days 1 through 5 and Days 15 through 19 (referred to as the 5/14 schedule).  Subjects 
enrolled under Amendment 2 will receive oprozomib once daily on 2 consecutive days 
every 7 days; specifically on Days 1, 2, 8, 9, 15, 16, 22, and 23 (referred to as the 
2/7 schedule).  All subjects on the ORd arm will receive lenalidomide at a dose of 25 mg 
will be given on Days 1 through 21 and dexamethasone at a dose of 20 mg will be given 
on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every 28-day cycle (see dose administration 
schemas below).
Dose Administration Schema for Oprozomib, Lenalidomide, and 
Dexamethasone (ORd) 5/14 Schedule (Original Protocol and Amendment 1)
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CONFIDENTIAL
Study design
(cont'd):
Dose Administration Schema for Oprozomib, Lenalidomide, and 
Dexamethasone (ORd) 2/7 Schedule (Amendment 2)
The ORd combination will be administered until progression of disease, unacceptable 
toxicity, or for 24 cycles (approximately 24 months), whichever occurs first.  Subjects 
who complete 24 cycles of treatment, and have stable disease or better, will continue on 
oprozomib, with or without dexamethasone premedication (4 mg/day) until progression 
of disease or unacceptable toxicity.  Lenalidomide will be administered for a maximum 
of 24 cycles.  Dexamethasone will be administered at a dose of 20 mg/day, as described 
above, through the first cycle, after which the dose may be decreased to 10 mg/day in 
subjects > 75 years of age, at the discretion of the investigator.
The OCyd regimen treatment cycles are 28 days in duration.  One (1) oprozomib dosing 
schedule (2/7) will be assessed during dose escalation.  All study subjects will receive 
oprozomib administered orally, once daily on 2 consecutive days every 7 days; 
specifically on Days 1, 2, 8, 9, 15, 16, 22, and 23 (referred to as the 2/7 schedule) in 
combination with oral cyclophosphamide at a dose of 300 mg/m2 on Days 1, 8, and 15, 
and dexamethasone at a dose of 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 of 28-day 
cycles (see dose administration schema below).  Dexamethasone will be administered at 
a dose of 20 mg/day, as described above, through the first cycle, after which the dose 
may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the 
investigator.
Product: 
Date: 
Oprozomib
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CONFIDENTIAL
Study design
(cont'd):
Dose Administration Schema for Oprozomib, Cyclophosphamide, and 
Dexamethasone (OCyd) 2/7 Schedule (Amendment 2)
The OCyd combination will be administered until progression of disease, unacceptable 
toxicity, or for 8 cycles (approximately 8 months), whichever occurs first.  Subjects who 
complete 8 cycles of treatment and who have stable disease or better will continue on 
oprozomib, with dexamethasone premedication.  Dexamethasone dosing, premedication 
and low-dose (e.g., 20 mg or 10 mg), should continue for a total of 24 cycles or until 
progression of disease or unacceptable toxicity.  Subjects who complete 24 cycles of 
oprozomib therapy (total) without evidence of progression may continue therapy with or 
without dexamethasone, premedication or low-dose.  A taper of dexamethasone after 
24 cycles may be utilized per institutional guidelines.  Cyclophosphamide will be 
administered for a maximum of 8 cycles.  
Note:  Subjects receiving either treatment regimen, who complete at least 4 cycles of 
study treatment and achieve a confirmed response (i.e., partial response [PR], very good 
partial response [VGPR], complete response [CR], or stringent complete response [sCR]) 
may, after discussion with the Onyx study medical monitor, suspend study treatment for 
up to 6 weeks to undergo a hematopoietic stem cell harvest.  Stem cell mobilization will 
be conducted using a noncytotoxic regimen such as granulocyte colony-stimulating 
factor (G-CSF).  These subjects may then resume study treatment until progression of 
disease, unacceptable toxicity, or for a total of 24 cycles of treatment with lenalidomide 
or a total of 8 cycles of treatment with cyclophosphamide, followed by oprozomib 
treatment with low-dose dexamethasone (20 mg or 10 mg) for subjects free from 
progression, as described above.
Phase 1b:  The Phase 1b portion of the study will identify any dose-limiting toxicities 
(DLTs) and determine the MTD, evaluate the safety and tolerability, and assess PK/PDn 
of oprozomib when administered as described above in subjects with newly diagnosed 
symptomatic multiple myeloma (see the Study Population section below for details).  
A standard 3 + 3 dose-escalation scheme will be used.  For each combination regimen, 
oprozomib doses will be escalated in sequential cohorts of 3 subjects with expansion to up 
to 6 subjects if a DLT is observed in 1 of the first 3 subjects.  The doses of lenalidomide, 
cyclophosphamide, and dexamethasone will remain fixed in all dose cohorts.  
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CONFIDENTIAL
Study design
(cont'd):
The initial cohort dose levels for each combination regimen is as follows:

Original Protocol and Amendment 1 - ORd (5/14 schedule):  210 mg/day of 
oprozomib (current 5/14 cohort dose level is 150 mg/day of oprozomib)
There have been 2 dose de-escalations in the ORd 5/14 arm in response to dose 
limiting toxicities (DLTs) occurring at the 210 mg and the 180 mg cohort level.

Amendment 2 - ORd (2/7 schedule):  210 mg/day of oprozomib

Amendment 2 - OCyd (2/7 schedule):  210 mg/day of oprozomib
The dose of oprozomib for cohorts will be escalated or de-escalated in 30 mg increments 
until the MTD is established.  Subjects on the 5/14 schedule will not have their 
oprozomib dose escalated above 150 mg/day.
There will not be a predefined maximum dose to be studied.  Subjects will be evaluated 
for DLTs according to the National Cancer Institute - Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 4.03.  
In the event that the ORd cohort at the 210 mg dose (2/7 schedule) is found to exceed the 
MTD, dosing will proceed at 180 mg or a lower dose as agreed to by the Cohort Safety 
Review Committee (CSRC), comprised of the Onyx study medical monitor, Onyx safety 
representative, and the active investigators. 
In the event that the initial OCyd cohorts at the 210 mg dose (2/7 schedule) are found to 
exceed the MTD, dosing will proceed at 180 mg or a lower dose as agreed to by the 
CSRC. Intrasubject dose escalation to the MTD or recommended Phase 2 dose (RP2D)
may be permitted once that dose has been determined and after a discussion has occurred 
between the treating physician and Onyx study medical monitor.
Maximum Tolerated Dose
For each dosing schedule, the MTD will be defined as the highest dose at which a DLT is 
observed in fewer than 2 of 6 patients.  At least 6 patients must be treated at the MTD for 
a minimum of 1 cycle to establish this dose as tolerated.
Dose-Limiting Toxicities:  During the Phase 1b portion, assessment of DLTs will occur 
during the first cycle of combination therapy (first 4 weeks).  
For the purposes of this study, a DLT is defined as any of the following treatment-related 
events occurring in the first 28 days of treatment:
Nonhematologic DLT:

Any ≥ Grade 3 nonhematologic toxicity with the following exceptions or 
qualifications:
o
≥ Grade 3 nausea, vomiting, diarrhea, or constipation will be considered a 
DLT only if lasting for > 7 days, despite optimal supportive care, including 
(at a minimum) a 5-hydroxytryptamine type-3 (5-HT3) antagonist and 
aprepitant for nausea/vomiting and (e.g. Imodium) and diphenoxylate/atropine 
(e.g., Lomotil) for diarrhea
o
Asymptomatic Grade 3 hypophosphatemia is not considered a DLT
o
Grade 3 hyperglycemia or toxicity solely due to dexamethasone is not 
considered a DLT (see dose reduction guidelines for dexamethasone in Section 
9.3.2)
o
Grade 3 fatigue lasting < 14 days is not considered a DLT
o
Grade 3 rash attributed specifically to lenalidomide is not a DLT 
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Study design
(cont'd):
Hematologic DLT:

Grade 4 neutropenia:  Absolute neutrophil count (ANC) < 0.5 × 109/L lasting 
≥7 days, despite myeloid growth factor support

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)

Grade 4 thrombocytopenia lasting ≥ 7 days or

Grade 4 thrombocytopenia lasting < 7 days with > Grade 2 clinically significant 
bleeding or < 10,000 platelets requiring platelet transfusion, or 

Grade ≥3 thrombocytopenia with clinically significant bleeding or requiring platelet 
transfusion.
Note:  Grade 4 anemia will not be considered a DLT, but should be treated with 
supportive measures in accordance with institutional guidelines.
Subject Replacement
Phase 1b: 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:

A minimum of 8 of 10 planned doses of oprozomib must be received for the 
5/14 dosing schedule

A minimum of 7 of 8 planned doses of oprozomib must be received for the 
2/7 dosing schedule

A minimum of 6 of 8 planned doses of dexamethasone must be received 

All 3 planned doses of cyclophosphamide must be received (OCyd combination 
regimen only)

A minimum of 17 of 21 planned doses of lenalidomide must be received (ORd 
combination regimen only)

Subjects not meeting all of the above criteria or assessed as unevaluable will be 
replaced.  Subjects who do not meet the criteria above because of a DLT will be 
considered DLT-evaluable.  
Subjects who discontinue study treatment for any reason after Cycle 1 will not be 
replaced.  
Phase 2:  The Phase 2 portion of the study will include up to 35 additional subjects in 
each of the 2 combination regimens, with the same eligibility criteria as those in Phase 1b.  
Phase 2 subjects will be treated at the RP2D of oprozomib identified during the Phase 1b 
portion of the study in order to better characterize the safety and tolerability, antimyeloma 
activity, and PK.  The RP2D determined by the CSRC may or may not be the same as the 
MTD, and will be assessed on the basis of the totality of safety and PK/PDn data.  
Subjects enrolled under Amendment 2 will receive Oprozomib Extended Release (ER) 
Tablets.
Pharmacokinetics:  A sparse sampling strategy will be employed for PK sample 
collection from all subjects for both phases of the study.  Blood samples for determination 
of plasma concentrations of oprozomib and metabolite(s) will be collected for subjects in 
both phases of the study at time points and blood volumes detailed in the Laboratory 
Manual.  Population-based PK analyses will be performed for oprozomib and, may 
include its metabolite(s).  
Pharmacodynamics:  Blood samples for the determination of proteasome inhibition by 
oprozomib will be drawn from all subjects in Phase 1b at the time points specified in the 
Laboratory Manual.
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CONFIDENTIAL
Study design
(cont'd):
Genomics:  Analysis of genetic, gene expression, and cell surface biomarkers that may 
predict response and resistance following treatment with proteasome inhibitors will be 
conducted on all subjects from both phases of the study who consent to optional genomic 
biomarker analysis.  These analyses will be performed on a bone marrow aspirate 
collected at Baseline, prior to dosing on Cycle 1 Day 1 (C1D1), and a sample of blood 
and/or saliva will be collected at Baseline, prior to dosing on C1D1.  The bone marrow 
aspirate used for Genomics is the remaining portion of bone marrow sample left after the 
amount required for fluorescent in situ hybridization (FISH) is performed.  No additional 
bone marrow sample is required at Baseline. Additional bone marrow samples for 
biomarkers may be collected at the End of Study Treatment visit from all subjects who 
consent.  End of Study Treatment is defined as at disease progression or at the end of 
protocol-defined therapy if end of treatment is due to progressive disease (PD).
Activity:  The International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) will be used to evaluate response.  Disease response assessments will be 
performed at the end of every 4-week cycle for 24 cycles of ORd or OCyd treatment, and 
will continue every 8 weeks thereafter, until confirmed PD (see study schema and dose 
administration schemas for details on the duration of cyclophosphamide dosing). Overall 
response rate and CRR will be determined based on subjects’ best overall response.   
Safety:  Safety assessments will include monitoring and assessment of all AEs, selected
laboratory analytes, 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 last administration of all study drugs.  All subjects will be closely 
monitored for both expected and unexpected AEs.  The safety and tolerability of 
oprozomib will be assessed through documentation of AEs graded according to 
NCI-CTCAE (Version 4.03).
Study population:
The study population will consist of patients with newly diagnosed, symptomatic multiple 
myeloma for whom a hematopoietic stem cell transplant is not planned or scheduled 
during the study or are considered ineligible for hematopoietic stem cell transplant at the 
discretion of the investigator, and who are considered to be appropriate for this clinical 
study by their treating physicians.
Number of 
investigational 
sites:
Approximately 20 sites in the United States (US) will participate in this study.
Planned number of 
subjects:
Total enrollment of up to approximately 134 evaluable subjects is planned for this study, 
including up to approximately 64 evaluable subjects for the Phase 1b portion of the study 
(40 and 24 for ORd and OCyd, respectively) and approximately 70 subjects for the Phase 
2 portion of the study (35 subjects for each combination regimen).
Sample size 
justification:
The estimated sample size for the dose-escalation portion of the study of up to 40 subjects 
for the ORd combination regimen and up to 24 subjects for the OCyd combination 
regimen is based upon standard 3 + 3 dose-escalation rules and the expectation that 2–6 
dosing cohorts of 3–6 subjects per cohort will be required to establish the MTD for each 
treatment regimen.  Enrollment of 35 additional subjects in each combination regimen
during the Phase 2 portion of the study is based upon the goal of ruling out an ORR < 
85% and a CRR < 50% based upon the approximate lower 1-sided 90% confidence 
interval for each parameter.  This sample size is based upon a simulation of a multinomial 
outcome of CR, PR, or PD for various cohort sizes.  With 35 subjects per combination 
regimen, and an assumed true ORR and true CRR of 95% and 75%, respectively, the 
probability of ruling out an ORR < 85% and a CRR < 50% with 90% confidence is 
approximately 88%, from the simulation described above.  The same assumptions for 
ORR and CRR are used in determining the sample size for each combination regimen.   
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Duration of study/
treatment periods:
The total study duration is expected to be approximately 59 months based upon the 
assumption that approximately 35 months may be required to enroll all subjects
(approximately 23 months to enroll Phase 1b subjects and up to approximately 12 months 
to enroll Phase 2 subjects) and that the average time on study will be approximately 
24 months.  
Following completion of 24 cycles of ORd or OCyd treatment, disease response 
assessments will continue every 8 weeks until confirmed PD.
For subjects who discontinue treatment before PD occurs (such as for an AE, 
noncompliance, etc.), disease response assessments will be performed every 4 weeks 
during the first 24 months of the study and every 8 weeks thereafter, until confirmed PD, 
or the start of alternative, nonprotocol antimyeloma therapy.  
Subjects must complete an End of Study Treatment visit approximately 4 weeks after the 
last study treatment for safety follow-up.  
Test product, dose, 
and mode of 
administration:
Oprozomib Tablets containing 60, 90, or 120 mg of oprozomib or Oprozomib ER Tablets
with strengths of 120, 150, 180, 210, 240, and 270 mg to be given orally (PO) 
Lenalidomide 25 mg to be given PO 
Cyclophosphamide 300 mg/m2 (up to 600 mg) to be given PO
Dexamethasone 20 mg to be given PO
New Oprozomib Formulation:  A new oprozomib tablet, the Oprozomib ER Tablet, will 
be introduced in the trial with Amendment 2.  There are minimal changes in the tablet 
coating and ratio of current excipients, and no change in the ratio of active pharmaceutical 
ingredient to excipients.  Given these minimal changes, the new Oprozomib ER Tablet is 
not expected to result in altered exposure or additional adverse events related to 
formulation.  
Subjects enrolled in the original protocol or Amendment 1 will receive Oprozomib 
Tablets and may receive Oprozomib ER Tablets when available.  Subjects enrolled under 
Amendment 2 will receive Oprozomib ER Tablets only.
Reference therapy
Not applicable.
Treatment 
regimen(s):
Oprozomib will be administered in a 28-day cycle at the assigned dose in combination 
with dexamethasone and either lenalidomide (ORd) or cyclophosphamide (OCyd):

Oprozomib administered on Days 1 through 5 and Days 15 through 19
(5/14 schedule) or on Days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule)

Lenalidomide administered on Days 1 through 21, for those subjects receiving the 
ORd combination regimen (5/14 and 2/7 schedules)

Cyclophosphamide administered on Days 1, 8, and 15, for those subjects receiving 
the OCyd combination regimen (2/7 schedule only)

Dexamethasone administered on Days 1, 2, 8, 9, 15, 16, 22, and 23, for all subjects 
in the study (5/14 and 2/7 schedules)
Oprozomib doses may be reduced in 30-mg decrements for up to 2 dose reductions for 
toxicities per the discretion of the investigator.  Interruption of oprozomib dosing for 
> 4 weeks for any reason will result in permanent discontinuation of oprozomib.  No dose 
reductions of oprozomib are allowed in Cycle 1.
Subjects who permanently discontinue lenalidomide or cyclophosphamide for reasons 
other than disease progression may continue treatment with oprozomib and
dexamethasone, until disease progression as described above.  After 24 months, the dose 
of dexamethasone may be decreased to premedication doses (4 mg) with allowances for a 
taper as clinically indicated.  
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Treatment 
regimen(s) 
(cont’d):
Subjects receiving the ORd treatment regimen who permanently discontinue oprozomib 
for reasons other than disease progression following the completion of Cycle 1, may 
continue treatment with lenalidomide and dexamethasone until disease progression or for 
a maximum of 24 cycles, whichever occurs first.  Subjects who discontinue both 
lenalidomide and oprozomib may not continue treatment with dexamethasone alone.  
Subjects receiving the OCyd treatment regimen who permanently discontinue oprozomib 
for reasons other than disease progression following the completion of Cycle 1, may 
continue treatment with cyclophosphamide and dexamethasone until disease progression
or for a maximum of 8 cycles, whichever occurs first.  Subjects who discontinue both 
cyclophosphamide and oprozomib may not continue treatment with dexamethasone alone.
Inclusion criteria:
Main inclusion criteria
1.
Newly diagnosed multiple myeloma patients for whom treatment is indicated per the 
National Comprehensive Cancer Network (NCCN) guidelines, and for whom a 
hematopoietic stem cell transplant is not planned or scheduled during the study or are 
considered ineligible for hematopoietic stem cell transplant, with 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 hour
c. Serum free light chain (SFLC):  Involved SFLC level ≥10 mg/dL provided 
SFLC ratio is abnormal 
2.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2
3.
Males and females ≥18 years of age
4.
Adequate hepatic function, with bilirubin ≤1.5 times the upper limit of normal 
(ULN), aspartate aminotransferase (AST) ≤3 times ULN, and alanine 
aminotransferase (ALT) ≤3 times ULN (Note:  Patients with documented Gilbert 
Syndrome may be enrolled with an elevated unconjugated bilirubin after discussion 
with the Onyx study medical monitor)
5.
Absolute neutrophil count ≥ 1.0 × 109/L, hemoglobin ≥7.0 g/dL, and platelet count 
≥75 × 109/L
a. Patients must not have received platelet transfusions for at least 1 week prior to 
Screening
b. Screening ANC must be independent of G-CSF or granulocyte/
macrophage-colony stimulating factor (GM-CSF) support for at least 1 week 
and pegylated G-CSF support for ≥2 weeks
c. Patients may receive red blood cell transfusions or supportive care with 
erythropoietin or darbepoetin in accordance with institutional guidelines
6.
Creatinine clearance rate of ≥ 50 mL/min, either measured or calculated using the 
formula of Cockcroft and Gault [(140 – age) × mass (kg) / (72 × serum creatinine 
mg/dL)].  Multiply result by 0.85 if female.  
7.
Patients must sign a written informed consent form in accordance with federal, local, 
and institutional guidelines
8.
For both treatment regimens (ORd and OCyd):  Females of childbearing potential 
(FCBP) must agree to ongoing pregnancy testing and to practice contraception as 
outlined in the Revlimid Risk Evaluation and Mitigation Strategy (REMS) Guide.
Two effective contraceptive methods must be used by FCBP for at least 4 weeks 
prior to start of lenalidomide or cyclophosphamide therapy, during therapy, and 
during dose interruptions, and for 3 months following the discontinuation of 
oprozomib.  Postmenopausal females (> 45 years old and without menses for 
> 24 consecutive months) and surgically sterilized females are exempt from these 
requirements.  
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Inclusion criteria 
(cont’d):
9.
For both treatment regimens (ORd and OCyd):  Male subjects must agree to practice 
contraception as outlined in the Revlimid REMS Guide. Male subjects receiving 
lenalidomide or cyclophosphamide must use an effective method of contraception 
during any sexual contact with FCBP during the study, even if the subject has 
undergone a successful vasectomy, and for 3 months following the discontinuation 
of oprozomib.
Exclusion criteria:
Main exclusion criteria
1.
Radiation therapy within 2 weeks prior to first dose
2.
Any prior systemic antimyeloma therapy except oral steroids (dexamethasone up to a 
total dose of 160 mg or equivalent within 14 days prior to the first dose of study 
treatment).  Use of topical or inhaled steroids is acceptable.  
3.
Participation in an investigational therapeutic study within 3 weeks prior to first dose
4.
Plasmapheresis is not permitted at any time during the Screening period or while the 
subject is receiving study treatment.  If a subject that 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.
5.
Major surgery within 3 weeks prior to first dose
6.
Clinically significant gastrointestinal (GI) bleed in the 6 months prior to C1D1 first 
dose
7.
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 prior to first dose
8.
A history of deep vein thrombosis or pulmonary embolism, with contraindication to 
anticoagulation and antiplatelet options
9.
Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 
weeks prior to first dose
10. Known or suspected human immunodeficiency virus (HIV) infection or subjects who 
are HIV seropositive
11. Active hepatitis A, B, or C infection
12. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of first 
dose
13. Other malignancy within the past 3 years except those considered cured by surgical 
resection including some cases of:
Adequately treated basal or squamous cell carcinoma of the skin 
Thyroid cancer
Carcinoma in situ of the cervix or breast
Prostate cancer with Gleason Score of 6 or less with stable prostate-specific 
antigen levels
14. Plasma cell leukemia
15. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes)
16. Known amyloidosis
17. Uncontrolled diabetes or hypertension
18. Female subjects who are pregnant or nursing
19. Any clinically significant psychiatric or medical condition that, in the opinion of the 
investigator, could increase patient risk, interfere with protocol adherence, or a 
subject’s ability to give informed consent 
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Overview of 
treatment and 
assessments:
Treatments will be given in 28-day cycles.  Details are provided in the Schedule of 
Assessments.
Criteria for evaluation:
Efficacy 
variables:
Disease response assessments will be performed at the end of every 4-week cycle for
24 cycles of ORd or OCyd treatment, and will continue every 8 weeks thereafter, until 
confirmed PD (see study schema and dose administration schemas for details on the 
duration of cyclophosphamide dosing).
Safety variables: The safety and tolerability of oprozomib will be assessed using the following measures:  
AEs graded according to the NCI-CTCAE (Version 4.03), blood counts, serum 
chemistries, vital signs, and ECGs.  
Other:
Pharmacokinetics: Blood samples will be drawn for plasma concentration of oprozomib 
and its metabolite(s) at various time points during the study.  Population PK parameter 
estimates and variability in these estimates for oprozomib (and possibly its metabolite [s])
will be determined using a sparse sampling strategy and population-based analysis 
methodology.  
Pharmacodynamics:  Blood samples will be drawn for assessments of proteasome 
inhibition in whole blood and peripheral blood mononuclear cells (PBMCs) via a 
fluorogenic substrate assay or enzyme–linked immunosorbent assay.  
Genomics:  Whole genome sequencing (WGS), whole exome sequencing (WES), whole 
transcriptome sequencing (RNA-Seq), and/or other forms of nucleic acid and protein 
quantification will be conducted on isolated tumor (CD138+) cells from bone marrow 
samples taken at Baseline, prior to dosing on C1D1, and at disease progression.  In 
addition, WGS or WES will be performed on a normal tissue sample (e.g., saliva or CD3+
T-cells isolated from PBMCs) to distinguish germline mutations from somatic mutations 
in tumor cell samples.  Data will be analyzed to characterize whether drug response is 
related to alterations in genes regulated by or involved in immunoglobulin production and 
protein homeostasis, i.e., IGH, as well as in genes regulated by or involved in the 
activation of nuclear factor kappa light chain enhancer of activated B cell (NF-Kappa B)
transcription factors. Immunoglobulin levels in tumor cells will be quantified by qPCR, 
or immunocytochemistry and/or other protein or gene expression quantification methods. 
These data will also be used to derive hypotheses about mechanisms of drug response, 
resistance, and safety.
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Statistical methods 
and analyses:
Phase 1b:  The Safety population includes all subjects receiving treatment with any 
amount of the treatment regimen (oprozomib and dexamethasone with either lenalidomide 
or cyclophosphamide) under study.  
Phase 2:  Safety and efficacy analyses will be performed using the Safety population. 
Additional efficacy analyses will be performed using the Response Evaluable population, 
defined as subjects who are included in the Safety population, and have a baseline disease 
assessment and at least 1 postbaseline disease assessment, or dropped out due to AE or 
other reasons prior to first post-baseline disease assessment.
The safety endpoints for both combination regimens (ORd and OCyd) in the Phase 1b and 
Phase 2 portions of the study are the incidence, nature, and severity of AEs, serious 
adverse events (SAEs), and DLTs (Phase 1b only) of oprozomib, given in combination 
with dexamethasone, and either lenalidomide or cyclophosphamide, as well as changes 
from baseline in selected laboratory analytes, vital signs, and ECG findings.
For both combination regimens (ORd and OCyd), the primary efficacy endpoints for the 
Phase 2 portion of the study are overall response and CR for subjects treated at the 
recommended Phase 2 dose.
Response evaluation will be carried out according to the International Myeloma Working 
Group - Uniform Response Criteria (IMWG-URC).

Overall response:  defined as a best overall response of sCR, CR, VGPR, or PR

Complete response:  defined as a best overall response of sCR or CR
Point estimates for the ORR and CRR along with the approximate lower 1-sided 90% 
confidence intervals will be calculated. 
The distributions of time-to-event endpoints (DOR and PFS) will be summarized 
descriptively using the Kaplan-Meier method.
Safety and tolerability will be assessed through summaries of study drug administration, 
DLTs (Phase 1b only), AEs, changes in laboratory analytes, ECGs, and vital signs by 
dose cohort, the combined MTD dose levels, and for all subjects.  All AE data will be 
listed by study site, treatment regimen, dose cohort, subject number, and study day.  All 
AEs occurring on or after treatment on C1D1 will be summarized by system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA), 
and NCI-CTCAE (Version 4.03) toxicity grade.  In addition, all SAEs, including deaths, 
will be listed separately and summarized.  Extent of exposure to the study treatment will 
be summarized using descriptive statistics.
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TABLE OF CONTENTS
Page
CLINICAL STUDY PROTOCOL .....................................................................................1
PROTOCOL APPROVAL SIGNATURE PAGE..............................................................2
PROTOCOL ACCEPTANCE PAGE ................................................................................3
TABLE OF CONTENTS ..................................................................................................16
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................23
2
BACKGROUND INFORMATION ......................................................................26
2.1
INTRODUCTION........................................................................................26
2.2
Multiple Myeloma........................................................................................27
2.3
Proteasome Background...............................................................................28
2.4
Oprozomib ...................................................................................................28
2.4.1
Preclinical Background..................................................................28
2.4.2
Oprozomib - Clinical Background..................................................30
2.4.2.1
Study 2009-003:  A Phase 1, Open-label, Dose 
Escalation Study of ONX 0912 Administered Orally 
in Patients with Advanced Refractory or Recurrent 
Solid Tumors................................................................30
2.4.2.2
Study 2011-001:  Phase 1b/2, Multicenter, Open-
label Study of the Safety and Activity of ONX 0912 
in Patients with Hematological Malignancies................31
2.4.2.3
Study 2012-001:  Phase 1b/2, Multicenter, Open-
label Study of Oprozomib and Dexamethasone in 
Patients with Relapsed and/or Refractory Multiple 
Myeloma ......................................................................32
2.4.2.4
Study OPZ003:  Phase 1b/2, Multicenter, Open-
label Study of Oprozomib and Dexamethasone in 
Combination With Lenalidomide or Oral 
Cyclophosphamide in Patients with Newly 
Diagnosed Multiple Myeloma ......................................34
2.4.3
Lenalidomide Background.............................................................35
2.4.4
Cyclophosphamide Background.....................................................35
2.4.4.1
Cyclophosphamide and Dexamethasone with 
Epoxyketone Proteasome Inhibitors..............................36
2.5
Dose Rationale.............................................................................................37
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2.5.1
Amendment 1 ................................................................................37
2.5.2
Amendment 2 ................................................................................37
2.6
Study Rationale............................................................................................38
3
STUDY OBJECTIVES..........................................................................................39
3.1
Primary Objectives.......................................................................................39
3.2
Secondary Objectives...................................................................................40
3.3
Exploratory Objectives.................................................................................40
4
STUDY DESIGN ...................................................................................................41
4.1
Type/Design of Study...................................................................................41
4.1.1
Patients Electing to Have Stem Cells Collected..............................45
4.2
Dose-Escalation Plan....................................................................................46
4.3
Minimizing Bias...........................................................................................49
4.3.1
Randomization...............................................................................49
4.3.2
Blinding.........................................................................................49
4.4
Number of Centers .......................................................................................49
4.5
Number of Subjects......................................................................................49
4.5.1
Phase 1b ........................................................................................49
4.5.2
Phase 2 ..........................................................................................49
4.6
Estimated Study Duration.............................................................................49
5
SUBJECT SELECTION .......................................................................................50
5.1
Inclusion Criteria..........................................................................................50
5.2
Exclusion Criteria.........................................................................................51
6
SUBJECT SCREENING.......................................................................................52
7
SUBJECT ENROLLMENT ..................................................................................53
8
STUDY DRUG.......................................................................................................53
8.1
Oprozomib Tablets and Oprozomib Extended Release Tablets .....................53
8.1.1
Physical Description ......................................................................53
8.1.2
Packaging and Labeling.................................................................53
8.1.3
Oprozomib ER Tablet Drug Properties...........................................54
8.1.4
Storage ..........................................................................................55
8.1.5
Accountability ...............................................................................55
8.2
Lenalidomide ...............................................................................................55
8.2.1
Physical Description ......................................................................55
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8.2.2
Packaging and Labeling.................................................................56
8.2.3
Storage ..........................................................................................56
8.2.4
Accountability ...............................................................................56
8.3
Cyclophosphamide.......................................................................................56
8.3.1
Physical Description and Formulation............................................56
8.3.2
Packaging and Labeling.................................................................56
8.3.3
Storage ..........................................................................................56
8.3.4
Accountability ...............................................................................57
8.4
Dexamethasone ............................................................................................57
8.4.1
Physical Description ......................................................................57
8.4.2
Packaging and Labeling.................................................................57
8.4.3
Storage Condition..........................................................................57
8.4.4
Accountability ...............................................................................57
9
DOSAGE AND TREATMENT ADMINISTRATION.........................................57
9.1
Oprozomib ...................................................................................................57
9.1.1
Treatment Administration..............................................................57
9.1.2
Dose-Escalation Rules ...................................................................59
9.1.3
Definition of Dose-limiting Toxicity..............................................59
9.1.4
Subject Replacement......................................................................60
9.2
Lenalidomide, Cyclophosphamide, and Dexamethasone Administration ......61
9.2.1
Lenalidomide Administration.........................................................61
9.2.2
Cyclophosphamide Administration ................................................61
9.2.3
Dexamethasone Administration .....................................................62
9.3
Dose-Modification Guidelines......................................................................62
9.3.1
Dose-Modification Guidelines for Hematologic Toxicities.............64
9.3.2
Dose-Modification Guidelines for Nonhematologic Toxicities.......66
9.3.3
Conditions Not Requiring Dose Reduction.....................................71
9.4
Dose Delays .................................................................................................71
9.5
Interruption of Treatment for Hematopoietic Stem Cell Harvest ...................71
9.6
Missed Doses ...............................................................................................71
9.7
Safety Guidance for Investigators.................................................................72
9.7.1
Lenalidomide.................................................................................72
9.7.2
Cyclophosphamide ........................................................................72
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9.7.3
Dexamethasone..............................................................................72
9.8
Concomitant Medications.............................................................................72
9.8.1
Required Concomitant Medications ...............................................73
9.8.1.1
Acid-related Medications..............................................73
9.8.1.2
Tumor Lysis Syndrome ................................................73
9.8.1.3
Anti-thrombotic Agents................................................74
9.8.2
Optional and Allowed Concomitant Medications ...........................75
9.8.2.1
Antinausea and Antiemetics .........................................75
9.8.2.2
Antidiarrheals...............................................................75
9.8.2.3
Antihypertensives.........................................................75
9.8.3
Excluded Concomitant Medications...............................................76
10
STUDY PROCEDURES........................................................................................76
10.1
Study-specific Procedures ............................................................................76
10.1.1
Vital Signs.....................................................................................76
10.1.2
Physical Examination.....................................................................76
10.1.3
Electrocardiogram..........................................................................76
10.2
Laboratory Evaluations for Safety................................................................77
10.3
Disease Response Assessments ....................................................................78
10.3.1
Tumor Response Assessment.........................................................78
10.4
Pharmacokinetic and Pharmacodynamic Measurements ...............................79
10.5
Genomic Evaluations ...................................................................................79
10.6
Platelet function assessment .........................................................................80
11
STUDY TREATMENT DISCONTINUATION AND 
DISCONTINUATION FROM THE STUDY .......................................................81
11.1
Study Treatment Discontinuation .................................................................81
11.1.1
Assessments at End of Study Treatment or Early 
Discontinuation..............................................................................82
11.1.2
Follow-up for subjects who end study treatment without 
documented progressive disease.....................................................82
11.2
Assessments at End of Study Treatment or Early Discontinuation ................82
12
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...............................83
12.1
Adverse Event Reporting..............................................................................83
12.1.1
Definitions.....................................................................................83
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12.2
Causality......................................................................................................84
12.3
Adverse Events Reporting Procedures..........................................................85
12.3.1
General..........................................................................................85
12.3.2
Disease Progression.......................................................................86
12.4
Long-Term Follow-up..................................................................................87
12.5
Serious Adverse Events Definitions..............................................................87
12.6
Serious Adverse Event Reporting and Documentation Requirements............88
12.7
Pregnancy Reporting ....................................................................................88
13
STATISTICS .........................................................................................................89
13.1
Study Endpoints...........................................................................................90
13.1.1
Primary Endpoints .........................................................................90
13.1.2
Secondary Endpoints .....................................................................90
13.1.3
Exploratory Endpoints ...................................................................90
13.2
Analysis of Study Conduct ...........................................................................90
13.3
Independent Review Committee...................................................................91
13.4
Data Monitoring Committee.........................................................................91
13.5
Analysis of Treatment Group Comparability ................................................91
13.6
Statistical Methods.......................................................................................91
13.6.1
Efficacy Analyses..........................................................................91
13.6.2
Safety Analyses .............................................................................92
13.6.3
Pharmacokinetic Analyses .............................................................93
13.6.4
Exploratory Analyses.....................................................................93
13.7
Handling of Missing Data.............................................................................94
13.8
Determination of Sample Size ......................................................................94
13.9
Interim Analysis...........................................................................................94
14
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS..............................94
14.1
Compliance Statement..................................................................................94
14.2
Institutional Review Board or Independent Ethics Committee ......................95
14.3
Informed Consent and Human Subject Protection.........................................95
14.4
Direct Access to Source Data, Source Documents, and Study Records .........96
14.5
Data Collection and Handling.......................................................................96
14.6
Confidentiality .............................................................................................97
15
REFERENCES ......................................................................................................98
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APPENDIX A  
SCHEDULE OF STUDY ASSESSMENTS FOR 5/14 DOSING 
SCHEDULE.........................................................................................101 
APPENDIX B 
SCHEDULE OF STUDY ASSESSMENTS FOR 2/7 DOSING 
SCHEDULE.........................................................................................105 
APPENDIX C 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCALE .................................................................109 
APPENDIX D 
NCI-CTCAE VERSION 4.03 .............................................................110 
APPENDIX E 
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES WITH  
NARROW THERAPEUTIC RANGE ..............................................111 
APPENDIX F 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA ..............112 
APPENDIX G 
ACTG BRIEF PERIPHERAL NEUROPATHY SCREENING 
TOOL ...................................................................................................114 
APPENDIX H 
REVLIMID PRESCRIBING INFORMATION ..............................115 
APPENDIX I 
CYCLOPHOSPHAMIDE PRESCRIBING INFORMATION ......116 
APPENDIX J 
DEXAMETHASONE PRESCRIBING INFORMATION ..............117 
APPENDIX K 
REVLIMID RISK EVALUATION AND MITIGATION 
STRATEGY (REMS)™ PROGRAM ...............................................118 
APPENDIX L 
SUMMARY OF CHANGES IN PROTOCOL OPZ003 
AMENDMENT 2 ................................................................................119 
 
List of Tables 
Table 1 
Phase 1 Response Rates for Subjects with Multiple Myeloma, by Schedule 
and Formulation .....................................................................................................31 
Table 2 
Phase 1 Response Rates for Subjects with Waldenström macroglobulinemia, 
by Schedule and Formulation ................................................................................31 
Table 3 
Dose-Escalation Scheme:  Oprozomib Tablets in Combination with 
Lenalidomide and Dexamethasone (ORd) for 5/14 Dosing Schedule 
(Original Protocol and Amendment 1) ..................................................................47 
Table 4 
Dose-Escalation Scheme:  Oprozomib Tablets in Combination with 
Lenalidomide and Dexamethasone (ORd) for 2/7 Dosing Schedule 
(Amendment 2) ......................................................................................................48 
Table 5 
Dose-Escalation Scheme:  Oprozomib ER Tablets in Combination with 
Cyclophosphamide and Dexamethasone (OCyd) for the 2/7 Dosing 
Schedule (Amendment 2) ......................................................................................48 
Table 6 
Dose-escalation Rules ............................................................................................59 
Table 7 
Dose Decrements for Oprozomib (5/14 Schedule, 
Original Protocol Amendment 1) ...........................................................................63 
Table 8 
Dose Decrements for Oprozomib (2/7 Schedule, Amendment 2) .........................63 
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Table 7
Dose Decrements for Oprozomib (5/14 Schedule, 
Original Protocol Amendment 1) .......................................................................63
Table 8
Dose Decrements for Oprozomib (2/7 Schedule, Amendment 2)........................63
Table 9
Dose Decrements for Lenalidomide ...................................................................63
Table 10
Dose Decrements for Cyclophosphamide ...........................................................63
Table 11
Dose Decrements for Dexamethasone ................................................................64
Table 12
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and 
Cyclophosphamide-related Hematologic Toxicities Post-Cycle 1.......................65
Table 13
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and 
Cyclophosphamide-Related Nonhematologic Toxicities Post-Cycle 1................67
Table 14
Treatment Guidelines for Dexamethasone-related Toxicity ................................70
Table 15
Full Chemistry Panels ........................................................................................77
Table 16
Toxicity Grading for Adverse Events not Covered in the NCI-CTCAE 
(Version 4.03)....................................................................................................83
Table 17
Date of Progression or Censoring for Progression-free Survival 
and Duration of Response ..................................................................................92
List of Figures
Figure 1
Study Schema for OPZ003................................................................................41
Figure 2
Dose Administration Schema for Oprozomib, Lenalidomide, 
Dexamethasone (ORd) 5/14 Schedule (Original Protocol and Amendment 1).....42
Figure 3
Dose Administration Schema for Oprozomib, Lenalidomide, 
Dexamethasone (ORd) 2/7 Schedule (Amendment 2).........................................43
Figure 4
Dose Administration Schema for Oprozomib, Cyclophosphamide, 
Dexamethasone (OCyd) 2/7 Schedule (Amendment 2).......................................44
Figure 5
Schedule for Stem Cell Collection......................................................................46
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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-HT3
5-hydroxytryptamine type-3
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
AUC
area under the curve
BP
blood pressure
C1D1
Cycle 1 Day 1
C1D2
Cycle 1 Day 2
C1D5
Cycle 1 Day 5
C1D8
Cycle 1 Day 8
C4D1
Cycle 4 Day 1
CBC
complete blood count
CBR
clinical benefit rate
CR
complete response
CrCl
creatinine clearance
CRd
carfilzomib, Revlimid (lenalidomide), and dexamethasone
CRR
complete response rate
CSRC
Cohort Safety Review Committee
Cyd
cyclophosphamide and dexamethasone
CYP3A
cytochrome P450 3A
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme linked immunosorbent assay
ER
Extended Release
FCBP
female(s) of childbearing potential
FDA
Food and Drug Administration
FISH
fluorescent in situ hybridization
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Abbreviation
Definition
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
GLP
Good Laboratory Practice 
GM-CSF
granulocyte macrophage-colony stimulating factor
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
IB
investigator’s brochure
IC50
50% inhibition concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGH
immunoglobulin heavy locus
IMWG
International Myeloma Working Group
IMWG-URC
International Myeloma Working Group - Uniform Response Criteria
IND
Investigational New Drug
IRB
Institutional Review Board
IV
intravenous(ly)
ISS
International Staging System
LDH
lactate dehydrogenase
LFT
liver function test
MAD
maximum administered dose
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MR
minimal response
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
nCR
near complete response
NF-Kappa B
nuclear factor kappa light chain enhancer of activated B cells
NHL
non-Hodgkin lymphoma
NSCLC
non-small-cell lung cancer
OCyd
oprozomib, cyclophosphamide, dexamethasone
OPZ
oprozomib
ORd
oprozomib, lenalidomide, dexamethasone
ORR
overall response rate
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Abbreviation
Definition
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PDn
pharmacodynamics
PFA-100
platelet function analyzer
PFS
progression-free survival
PIC
Powder in capsule
PK
pharmacokinetic(s)
PO
oral(ly)
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes
PR
partial response
qPCR
quantitative polymerase chain reaction
QTc 
corrected QT interval 
RBC
red blood cell
Rd
lenalidomide and dexamethasone
REMS
Risk Evaluation and Mitigation Strategy
RNA-Seq
whole transcriptome sequencing
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAH
subachnoid hemorrhage
sCR
stringent complete response
SD
stable disease
SFLC
serum free light chain
SPEP
serum protein electrophoresis
STD10
severely toxic dose to 10% of test animals
TLS
tumor lysis syndrome
ULN
upper limit of normal
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
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2
BACKGROUND INFORMATION
2.1
INTRODUCTION
This is a Phase 1b/2 clinical trial of the oral proteasome inhibitor, oprozomib in combination 
with dexamethasone and lenalidomide or oral cyclophosphamide, in subjects with newly 
diagnosed multiple myeloma. See Section 4 for a complete description of the study design.
The protocol has been amended twice with changes to the study design based on emerging 
safety data from other oprozomib studies. A summary of changes for each amendment is 
included in the appendix of each version of the protocol.  The primary purposes for each 
amendment are summarized below.
Amendment 1
Study Design
The OCyd treatment regimen was added to the protocol to assess the safety and 
1.
activity of the combination.  No formal comparisons between the OCyd and ORd 
arms are planned.  Resultant data will inform future trial designs. 
Dose-Modification Guidelines/Safety Guidance for the Investigator
Updated tables of dose-modification guidelines for hematologic and nonhematologic 
2.
toxicities to include guidance for cyclophosphamide related toxicities.
Added text to provide specific guidance for the treatment of tumor lysis syndrome.
3.
Added text to provide specific guidance for antinausea and antiemetics, and 
4.
antidiarrheals.
Amendment 2 
Study Design
The current dose of oprozomib on the 5/14 schedule is 150 mg.  The study was 
1.
initiated at 210 mg and the dose was reduced to 150 mg after DLTs were reported in 
the 210 and 180 mg cohorts.  The protocol has been updated throughout to reflect 
these events.  The 150 mg dose is 3 full dose levels below the single-agent maximum 
tolerated dose (MTD).
The dosing schedule was changed from 5/14 to 2/7 for subsequent cohorts in the ORd 
2.
arm and for all subjects in the OCyd arm to provide an increased margin of safety for 
subjects participating in this study.  The initial dose of oprozomib for the OCyd and 
ORd arms on the 2/7 schedule is 210 mg.  It is 3 full dose levels below the single 
agent MTD on the 2/7 schedule.
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Introduced the new Oprozomib Extended Release (ER) Tablet and the strengths to be 
3.
used in this study.
Exclusion Criteria
Added language excluding patients undergoing or expected to require plasmapheresis 
4.
during the screening process or any time during the study.
Added exclusion criterion for patients with prior clinically significant bleed in the 
5.
6 months prior to first dose of study treatment.
Dose Modification Guidelines/Safety Guidance for the Investigator
Additional safety guidance regarding Grade 3 or 4 GI hemorrhage.
6.
Added guidance for subjects receiving antihypertensive therapy about the risk for 
7.
hypotension.
Laboratory Evaluations for Safety
Platelet function assessment to understand impact of oprozomib, if any, on platelet 
8.
adherence, activation, aggregation and interaction with clotting factors.
2.2
MULTIPLE MYELOMA
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and is responsible for approximately 72,000 annual deaths 
worldwide (Ferlay 2010).  There are an estimated 11,000 deaths per year in the United States 
(US) and more than 19,000 deaths per year in Europe (American Cancer Society 2005;
Boyle 2005).  Multiple myeloma is characterized by anemia, bone destruction, monoclonal 
gammopathy, renal failure, hypercalcemia, and increased susceptibility to infections.  
The disease is systemic, and chemotherapy is indicated for management of symptomatic 
myeloma.  Current treatment options for multiple myeloma commonly include combination 
regimens using alkylators such as melphalan (Alkeran) or cyclophosphamide (Cytoxan), 
bortezomib (Velcade), carfilzomib (Kyprolis), an immunomodulatory agent including
thalidomide (Thalomid), lenalidomide (Revlimid), or pomalidomide (Pomalyst), with and 
without corticosteroids such as dexamethasone or prednisone, and other agents.  Eligible 
subjects 65 to 70 years old or younger frequently undergo consolidation therapy with 
myeloablative chemotherapy, or radiation followed by autologous stem cell transplantation.  
Although improvements in progression-free survival (PFS) and overall survival (OS) have 
occurred in the past 5 years, even with the best available approved agents, essentially all 
patients eventually relapse.  Median OS from diagnosis was reported at 3 years for high-risk 
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subjects, 4 to 5 years for intermediate-risk subjects, and 8 to 20 years for standard-risk
subjects (Mikhael 2013).
2.3
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 activity, a 
trypsin-like activity, and a caspase-like activity.
2.4
OPROZOMIB
2.4.1
PRECLINICAL BACKGROUND 
Oprozomib is a tripeptide epoxyketone-based inhibitor of the 20S proteasome that primarily 
targets the chymotrypsin-like activity.  Oprozomib (formerly ONX 0912) is a structural 
analogue of carfilzomib (Kyprolis), an intravenously administered tetrapeptide epoxyketone 
that received accelerated approval in the US for the treatment of patients with multiple 
myeloma who have received at least 2 prior therapies, including bortezomib and an 
immunomodulatory agent, and have demonstrated disease progression on or within 60 days 
of completion of the last therapy (Kyprolis Prescribing Information [Onyx Pharmaceuticals 
2012]).  Like carfilzomib, oprozomib is an irreversible and highly selective proteasome 
inhibitor that binds most potently to the chymotrypsin-like subunit of the proteasome (50% 
inhibition concentration [IC50] 50–80 nM) (Zhou 2009).  In addition, when measured against 
a broad panel of proteins containing metallo-, aspartyl-, and serine-proteases, oprozomib 
demonstrated minimal reactivity against these nonproteasomal proteases.
Exposure to oprozomib is associated with potent pro-apoptotic activity across a broad panel 
of tumor-derived cell lines in culture.  The antitumor efficacy of oprozomib has been tested 
in a variety of mouse xenograft models, including those for both solid (colorectal 
adenocarcinoma, non-small cell lung cancer [NSCLC]) and hematologic (multiple myeloma, 
non-Hodgkin lymphoma [NHL]) tumors.  Oprozomib has shown an equivalent antitumor 
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activity to carfilzomib in preclinical models where both compounds have been tested 
(Zhou 2009).
In Good Laboratory Practice (GLP)-compliant toxicity studies, oprozomib was administered 
orally for 2 complete cycles of daily dosing for 5 days with 9 days rest to rats at doses of 120, 
180, and 240 mg/m2 (20, 30, and 40 mg/kg, respectively).  Administration at 180 mg/m2
(30 mg/kg) resulted in mortality in 1 of 26 animals during the first cycle of dosing.  
Surviving animals received a second cycle of oprozomib administration without additional 
severe toxicities, and this dose was determined to be the severely toxic dose to 10% of test 
animals (STD10). Proteasome inhibition was > 90%, as measured in whole blood 1 hour after 
the first dose.  Mortality of > 10% was noted at the next highest dose level (240 mg/m2) also 
in the first cycle of dosing.  In this study, mortality was restricted to females, where exposure 
(as determined by pharmacokinetics [PK]) was 3-fold to 5-fold higher than in males on the 
first day of dosing.  The apparent cause of death could not be determined, but histologic 
analysis of the surviving animals showed mucosal hyperplasia in the small intestines.
Oprozomib was administered orally to dogs at 60, 120, and 200 mg/m2 (3, 6, and 10 mg/kg, 
respectively) using the same schedule of administration.  A dose of 120 mg/m2 (6 mg/kg) 
was determined to be the highest non-severely toxic dose (HNSTD).  Mortality or early 
sacrifice was noted in 3 of 14 animals at the highest dose (200 mg/m2).  Clinical observations 
in these animals preceding death included emesis, decreased activity, lethargy, high body 
temperatures, cold to touch, weight loss, decreased food consumption, and brown/pink nasal 
discharge and, in 1 of the animals, irregular gait.  The apparent cause of death for these 
animals was attributed to mucosal hemorrhage and atrophy of the small and large intestines,
which was associated with frequent watery diarrhea and occasionally the presence of blood 
in the stool.
In both rats and dogs, all doses of oprozomib resulted in > 80% inhibition of proteasome 
activity in whole blood as measured 1 hour after the first dose.  In both rats and dogs, 
exposure as measured by area under the curve (AUC), showed a greater than dose 
proportional increase when the dose was increased above the STD10/HNSTD.
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In a cardiovascular safety pharmacology study conducted in male and female dogs, a single 
dose of oprozomib at 120 mg/m2 was not associated with cardiovascular toxicity.  
Hypotension, beginning approximately 4 hours after dose administration was noted in all 
animals at 200 and 400 mg/m2, and was dose-dependent in severity.  In all but 1 animal, 
this was accompanied by an increase in heart rate.  There were no observed corrected 
QT intervals (QTc) prolongations in any animals.
Further information about the preclinical pharmacology and toxicology of oprozomib is 
presented in the Oprozomib Investigator’s Brochure (IB).
2.4.2
OPROZOMIB - CLINICAL BACKGROUND 
2.4.2.1
Study 2009-003:  A Phase 1, Open-label, Dose Escalation Study of 
ONX 0912 Administered Orally in Patients with Advanced Refractory or 
Recurrent Solid Tumors
Efficacy
In Study 2009-003, oprozomib, dosed as powder in capsule, was studied in solid tumor 
subjects.  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 AEs were Grade 1 and 2, manageable, and there were no apparent 
cumulative toxicities. The most common AEs were in the gastrointestinal (GI) system organ 
class. This was consistent with preclinical animal studies with oprozomib.  Dose-limiting 
toxicities (DLTs) 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 MTD for 
the once daily x 5 days dose group is 150 mg. Dose-limiting toxicities for the split daily x 5
days dosing group in Study 2009-003 included Grade 3 hypophosphatemia at 180 mg and 
Grade 5 GI bleed and Grade 3 hallucinations at 210 mg. The MTD for the split daily dosing 
group is 180 mg.
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2.4.2.2
Study 2011-001:  Phase 1b/2, Multicenter, Open-label Study of the Safety 
and Activity of ONX 0912 in Patients with Hematological 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
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.
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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 
(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.
2.4.2.3
Study 2012-001:  Phase 1b/2, Multicenter, Open-label Study of Oprozomib 
and Dexamethasone in Patients with Relapsed and/or Refractory 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 
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day in combination with dexamethasone on a bimonthly schedule with daily dosing and 
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 in combination with 20 mg of dexamethasone 
and 1 subject had a very good partial response (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 
subjects have experienced DLTs at the 210 mg dose, including 1 subject with a 
subarachnoid hemorrhage, 1 subject with Grade 3 transaminitis, and 1 subject with 
Grade 4 thrombocytopenia.  In addition, 1 subject had 3 SAEs (esophagitis, urinary 
tract infection, and pneumonia).  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.
As of 31 March 2014, ten (10) subjects experienced SAEs across both schedules.  The 
3 treatment-related SAEs were 1 subject with a subachnoid hemorrhage (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 delirium were not.
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2.4.2.4
Study OPZ003: Phase 1b/2, Multicenter, Open-label Study of Oprozomib
and Dexamethasone in Combination With Lenalidomide or Oral 
Cyclophosphamide in Patients with Newly Diagnosed Multiple Myeloma
Efficacy
No efficacy data are available at this time.
Safety
The OPZ003 Phase 1b/2 study is currently enrolling in the Phase 1b portion of the study. 
Subject enrollment has been in the ORd arm only.  No subjects have been enrolled in the 
OCyd arm.
As of 18 July 2014, ten subjects have been enrolled and 1 subject remained on study. Of the 
3 subjects enrolled at the 210 mg dose level (ORd regimen), 2 of those subjects experienced 
Grade 3 syncope.  Nausea and vomiting with dehydration and concomitant medications were 
contributing factors in 1 case.  In the other, no cause was identified.  Cardiac and neurologic 
evaluations were unremarkable.  Both syncopal events were described as related to 
oprozomib.  As such, they represented DLTs and the cohort dose was de-escalated to 
180 mg.  One subject who experienced syncope discontinued treatment, and the other 
continued after a dose reduction to 180 mg.  
No further syncopal events have been reported.  Syncope has been identified as an event of 
interest for oprozomib.
Seven subjects were enrolled in the 180 mg cohort.  Six of the 7 were DLT evaluable. Two 
subjects experienced dose limiting toxicities.  The first had Grade 3 abdominal pain with
distension in the setting of diarrhea.  The second subject developed Grade 3 hypotension in 
the setting of diarrhea and continued anti-hypertensive and cardiac rate controlling 
medication use.
The cohort dose was subsequently de-escalated to 150 mg.  No DLTs have been reported in 
this cohort as of the writing of this amendment.
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2.4.3
LENALIDOMIDE BACKGROUND
Lenalidomide is a derivative of thalidomide and has both immunomodulatory and 
anti-angiogenic properties which confer antitumor effects.  
Combining lenalidomide with high-dose dexamethasone has led to significantly improved 
efficacy outcomes compared with high-dose dexamethasone alone as measured by time to 
progression, ORR, and OS; indeed, lenalidomide and dexamethasone have become a 
standard treatment for relapsed multiple myeloma (Dimopoulos 2007; Weber 2007).  In a 
recent study of high-dose versus low-dose therapeutic dexamethasone, both with 
lenalidomide in newly diagnosed multiple myeloma (Rajkumar 2010), lenalidomide 
combined with low-dose dexamethasone (once weekly) was associated with reduced rates of 
deep vein thrombosis, infection, and other nonhematologic reactions.  There was no 
difference seen in PFS between treatment arms, however, in subjects over 65 years of age, 
low-dose therapeutic dexamethasone combined with lenalidomide was associated with 
greater OS (p-value = 0.0002).  Thus, the use of low-dose therapeutic dexamethasone is 
currently recommended in combination with lenalidomide and will be used in this study.
2.4.4
CYCLOPHOSPHAMIDE BACKGROUND
Alkylating agents such as melphalan and cyclophosphamide have been the backbone of 
multiple myeloma therapy for over 40 years.  In current practice they are widely used during 
induction therapy in subjects with newly diagnosed multiple myeloma in combination with 
steroids and 1 of the novel agents, particularly a proteasome inhibitor (Dispenzieri 2007).  
Cyclophosphamide is less stem-cell toxic than other alkylating agents, and has predictable, 
short duration myelosuppression when administered at doses currently in use in multiple 
myeloma (300–500 mg/m2) (Volpe 2003; Morgan 2011).  These properties have encouraged 
the use of oral cyclophosphamide in combination with a steroid and proteasome inhibitor in 
both front-line and relapsed and/or refractory multiple myeloma (Kropff 2007; Kropff 2009; 
Reece 2008; Reeder 2009; Reeder 2010).  The largest published experience with 
cyclophosphamide-based induction regimens was reported by Reeder (2010) who combined 
cyclophosphamide 300 mg/m2 orally (PO) on Days 1, 8, 15, and 22, with dexamethasone 
40 mg PO on Days 1 through 4, 9 through 12, and 17 through 20 or Days 1, 8, 15, and 22 and 
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bortezomib 1.3 mg/m2 intravenous (IV) on Days 1, 4, 8, and 11 or 1.5 mg/m2 IV on Days 1, 
8, 15, and 22 every 28 days for 4 cycles in transplant-eligible subjects (Reeder 2010). The 
overall response rate (PR or better) for 63 subjects enrolled in this trial was 90%, with 41% 
complete response/near complete response (CR/nCR) and 60% VGPR or better.  Weekly 
(Days 1, 8, 15, 22) bortezomib administration led to reduction in Grades 3 and 4 toxicity 
(37% versus 48%), without apparent reduction in efficacy.  
2.4.4.1
Cyclophosphamide and Dexamethasone with Epoxyketone Proteasome 
Inhibitors
The safety, tolerability, and efficacy of carfilzomib in combination with cyclophosphamide 
and dexamethasone are being evaluated in a Phase 2 study (Palumbo 2012).  
Transplant-ineligible subjects with newly diagnosed multiple myeloma received oral 
cyclophosphamide 300 mg/m2 on Days 1, 8, and 15; oral dexamethasone 40 mg on Days 1, 8, 
15, and 22; and IV carfilzomib 20 mg/m2 on Days 1 and 2 and 36 mg/m2 on Days 8, 9, 15, 
and 16 in Cycle 1, Cycle 2, and beyond, every 28 days for 9 cycles.  Median age of the 
34 enrolled subjects was 70 years; 46% had International Staging System (ISS) Stage III.  
Nineteen subjects were evaluable for response and safety after at least 4 cycles.  All subjects 
had achieved at least a PR, 74% at least a VGPR, and 42% CR/nCR including 10% stringent 
complete response (sCR).  Responses were rapid with a median time to PR of 1 month.  
At least 1 Grade 3 or 4, nonhematologic adverse event (AE) was reported in 4 subjects 
(21%).  No subjects discontinued treatment and 4 subjects (21%) required carfilzomib dose 
reduction due to AEs (Grade 4 neutropenia, Grade 3 pneumonia, Grade 3 atrial fibrillation, 
and Grade 3 renal failure).  These results are consistent with the report of the “CYCLONE”
Phase 1/2 study in patients with newly diagnosed multiple myeloma investigating a 
combination of carfilzomib with oral cyclophosphamide 300 mg/m2 on Days 1, 8, and 15; 
thalidomide 100 mg. Days 1 through 28, and dexamethasone 40 mg on Days 1, 8, 15, and 22 
in transplant-eligible subjects.  In this report, doses of carfilzomib up to 45 mg/m2 were 
safely delivered without DLTs and with a high ORR of 96% (Mikhael 2013).
These data, along with the emerging data that oprozomib has similar activity as carfilzomib, 
suggest that oprozomib, cyclophosphamide, and dexamethasone may be an active regimen
for initial treatment of multiple myeloma regardless of transplant eligibility.  However, the 
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safety, tolerability and MTD of oprozomib in this combination have not been evaluated.  
This study will investigate the MTD for oprozomib when given in combination with 
cyclophosphamide and dexamethasone.
2.5
DOSE RATIONALE
2.5.1
AMENDMENT 1
The OPZ003 study was initiated in 2013 utilizing a 3 x 3 dose escalation schema.  The 
starting dose for the oprozomib, lenalidomide, dexamethasone (ORd) and oprozomib, 
cyclophosphamide, dexamethasone (OCyd) arms was 210 mg for 5 consecutive days 
(5/14 schedule) in the Phase 1b component of the study.  This initial dose and schedule were 
selected based upon preclinical data that suggested improved antimyeloma activity with 
consecutive day dosing of epoxyketone proteasome inhibitors (Demo 2007) and clinical data 
collected for subjects exposed to oprozomib in ongoing and completed clinical studies.  
Safety results from Study 2009-003 in subjects with solid tumors, and 2011-001 in subjects 
with hematologic malignancy demonstrated acceptable tolerability profiles for once daily × 5 
bimonthly dosing schedule (5/14 schedule). The MTD for single agent oprozomib in the 
2011-001 trial was 240 mg.
In the 2011-001 trial the tolerability of the once daily × 2 weekly (2/7 schedule) and the 
5/14 schedule was similar.  In addition, antimyeloma activity (confirmed minimal response
[MR] or better) was reported with the 2/7 schedule and the 5/14 schedule, both beginning at a 
daily dose of 150 mg (Kaufman 2013).  See Section 2.4.2.
Given the activity against multiple myeloma, the acceptable safety profile demonstrated, and 
the increased experience with the 5/14 schedule compared to the 2/7 schedule, the 
5/14 schedule was chosen for the OPZ003 study.  
2.5.2
AMENDMENT 2
Two of the 3 subjects enrolled in the 210 mg cohort of the OPZ003 ORd arm experienced 
syncope, a DLT (see Section 2.4.2.4).  These DLTs prompted a dose de-escalation to the 
180 mg cohort.  Seven subjects were enrolled at the 180 mg dose level.  Two DLTs, 
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abdominal pain with distension and hypotension were observed prompting dose de-escalation 
to 150 mg on the 5/14 schedule.
The dose of oprozomib for subjects enrolled in the ORd arm will continue at 150 mg on the 
5/14 schedule unless 2 or more DLTs are reported.
Given the increased clinical experience with the 2/7 schedule in 2011-001, and the 
experience in Amendment 1 of this trial, the starting dose for subjects enrolling in the 
ORd arm under Amendment 2 will be 210 mg on the 2/7 schedule.  
The starting dose for subjects enrolled in the OCyd arm under Amendment 2 will also be 
210 mg on the 2/7 schedule.  No subjects were enrolled in the OCyd arm prior to 
Amendment 2.
Starting with Amendment 2, an ER tablet will be administered.  There are minimal changes 
between the ER formulation and the modified release formulation used in Amendment 1.  As 
such, dosing with the ER formulation will occur at the same level as the modified 
formulation.
Subjects enrolled in the original protocol or Amendment 1 will receive Oprozomib Tablets 
and may receive Oprozomib Extended Release (ER) Tablets when available.  Subjects 
enrolled under Amendment 2 will receive Oprozomib ER Tablets only.
2.6
STUDY RATIONALE
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 immunomodulatory agent 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, Phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose 
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dexamethasone in subjects with newly diagnosed multiple myeloma has demonstrated 
excellent activity and tolerability with 62% of 53 subjects achieving nCR or better and with 
only Grade 1/2 peripheral neuropathy reported in 23% of subjects (Jakubowiak 2012).  
Preliminary results from an ongoing Phase 2 study of CRd in untreated newly diagnosed 
nontransplant and transplant candidates with multiple myeloma have also been reported.  
After a median of 4 cycles of CRd completed (range 1–8) in 15 evaluable subjects, 40% of 
subjects achieved nCR or better (4 sCR and 2 nCR), 33% of subjects had VGPR (n = 5), 20% 
of subjects had PR (n = 3), and 1 subject had SD (6%).  No subjects reported ≥Grade 3 
neuropathy (Korde 2012).
Likewise, and as described above in Section 2.4.4, the combination of carfilzomib and 
cyclophosphamide also appears to have good antimyeloma activity and an acceptable safety 
profile. 
Oprozomib appears to have single-agent activity in an ongoing study (2011-001, see 
Section 2.4.2.2) of patients with hematologic malignancies, including multiple myeloma. 
Combining oprozomib with low-dose therapeutic dexamethasone, plus either 
cyclophosphamide or lenalidomide, to provide an all oral treatment regimen for the frontline 
treatment of multiple myeloma has appeal due to increased convenience.  The current study 
is designed to establish the MTD of oprozomib when combined with low-dose therapeutic 
dexamethasone and standard doses of either cyclophosphamide or lenalidomide, and to 
provide a preliminary assessment of the antimyeloma activity of these combinations.
3
STUDY OBJECTIVES
3.1
PRIMARY OBJECTIVES
The primary objectives are:
Phase 1b

To establish the MTD of oprozomib given in combination with lenalidomide and 
dexamethasone (ORd) or with cyclophosphamide and dexamethasone (OCyd)

To evaluate the safety and tolerability of the ORd and OCyd combination regimens,
as assessed by the type, incidence, severity and seriousness of AEs, and abnormalities 
in selected laboratory analytes
Phase 2
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
To estimate the antitumor activity of the ORd and OCyd combination regimens, as 
measured by overall response rate (ORR) and complete response rate (CRR)

To evaluate the safety and tolerability of the ORd and OCyd combination regimens,
as assessed by the type, incidence, severity and seriousness of AEs, and abnormalities 
in selected laboratory analytes
3.2
SECONDARY OBJECTIVES
The secondary objectives are:

To evaluate population PK parameter estimates of oprozomib, and may include its 
metabolite(s), and the variability in these estimates

To estimate the duration of response (DOR)

To estimate PFS
3.3
EXPLORATORY OBJECTIVES
The exploratory objectives are:

To evaluate PDn biomarkers that may correlate with antitumor activity

To evaluate genomic biomarkers that may predict response and resistance following 
treatment with proteasome inhibitors
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4
STUDY DESIGN
4.1
TYPE/DESIGN OF STUDY
This study is an open-label, Phase 1b/2, two-combination regimen, non-randomized, multicenter study (Figure 1).  
Figure 1
Study Schema for OPZ003
ORd Treatment Regimen
Oprozomib PO on Days 1–5 and Days 15–19 (5/14 schedule)
and 
Oprozomib PO on Days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule)
Lenalidomide 25 mg PO on Days 1–21
Dexamethasone 20 mg PO on Days 1, 2, 8, 9, 15, 16, 22, and 23
Cycles 1–24 (28 days each)
OCyd Treatment 
Regimen
Oprozomib PO on Days 
1, 2, 8, 9, 15, 16, 22 
and 23 (2/7 schedule)
Cyclophosphamide 
300 mg/m2 PO on Days 
1, 8, and 15
Dexamethasone 20 mg 
PO on Days 1, 2, 8, 9, 
15, 16, 22, and 23
Cycles 1–8 (28 days each)
3
0
D
A
Y
P
O
S
T
T
X
V
I
S
I
T
S
C
R
E
E
N
PD or 
unacceptable 
toxicity
PD or 
unacceptable 
toxicity
Oprozomib ±
Dexamethasone 
premedication (4 
mg)
Oprozomib +
Dexamethasone (premedication 
[4 mg] and low-dose [20 mg or 
10 mg])
Cycles 9–24
Oprozomib ±
Dexamethasone 
(premedication  [4 
mg] or low-dose 
[20 mg or 10 mg])
Cycles 25+
Cycles 25+
Disease Response 
Assessments
Every 4 weeks
Every 8 weeks
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The ORd combination regimen treatment cycles are 28 days in duration.  Two (2) oprozomib 
dosing schedules will be assessed during dose escalation. Subjects enrolled under the 
original protocol and Amendment 1 will receive oprozomib once daily on Days 1 through 5 
and Days 15 through 19 (referred to as the 5/14 schedule).  Subjects enrolled under 
Amendment 2 will receive oprozomib once daily on 2 consecutive days every 7 days; 
specifically on Days 1, 2, 8, 9, 15, 16, 22, and 23 (referred to as the 2/7 schedule).  All 
subjects on the ORd arm will receive lenalidomide at a dose of 25 mg will be given on 
Days 1–21 and dexamethasone at a dose of 20 mg will be given on Days 1, 2, 8, 9, 15, 16, 
22, and 23 of every 28-day cycle (Figure 2 and Figure 3).
Figure 2
Dose Administration Schema for Oprozomib, Lenalidomide, 
Dexamethasone (ORd) 5/14 Schedule (Original Protocol and Amendment 1)
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Figure 3
Dose Administration Schema for Oprozomib, Lenalidomide, 
Dexamethasone (ORd) 2/7 Schedule (Amendment 2)
The ORd combination will be administered until progression of disease, unacceptable 
toxicity, or for 24 cycles (approximately 24 months), whichever occurs first.  Dexamethasone 
will be administered at a dose of 20 mg/day, as described above, through the first cycle, after 
which the dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion 
of the investigator.  Subjects who complete 24 cycles of treatment and who demonstrate a 
response of stable disease or better will continue oprozomib, with or without dexamethasone 
premedication (4 mg/day) until progression of disease or unacceptable toxicity.  
Lenalidomide will be administered for a maximum of 24 cycles.  
The OCyd regimen treatment cycles are 28 days in duration.  One oprozomib dosing 
schedule will be assessed during dose escalation.  All study subjects will receive oprozomib 
on 2 consecutive days every 7 days; specifically on Days 1, 2, 8, 9, 15, 16, 22, and 23
(referred to as the 2/7 schedule).  Cyclophosphamide at a dose of 300 mg/m2 will be given on 
Days 1, 8, and 15 and dexamethasone at a dose of 20 mg will be given on Days 1, 2, 8, 9, 15, 
16, 22, and 23 of every 28-day cycle (Figure 4). 
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Dexamethasone will be taken at a dose of 20 mg/day, as described above, through the first 
cycle, after which the dose may be decreased to 10 mg/day in subjects > 75 years of age, at 
the discretion of the investigator.
Figure 4
Dose Administration Schema for Oprozomib, Cyclophosphamide, 
Dexamethasone (OCyd) 2/7 Schedule (Amendment 2)
The OCyd combination will be administered until progression of disease, unacceptable 
toxicity, or for 8 cycles (approximately 8 months), whichever occurs first.  Subjects who 
complete 8 cycles of treatment and have stable disease or better will continue on oprozomib, 
with dexamethasone premedication.  Dexamethasone dosing, premedication and low-dose 
(e.g., 20 mg or 10 mg), should continue for a total of 24 cycles or until progression of disease 
or unacceptable toxicity.  Subjects who complete 24 cycles of oprozomib therapy (total) 
without evidence of progression may continue therapy with or without dexamethasone, 
premedication or low-dose.  A taper of dexamethasone after 24 cycles may be utilized as per 
institutional guidelines.  Cyclophosphamide will be administered for a maximum of 8 cycles.  
Both the Phase 1b and Phase 2 portions of this trial will enroll patients with newly diagnosed,
symptomatic multiple myeloma for whom a hematopoietic stem cell transplant is not planned 
or scheduled during the study, or are considered ineligible for hematopoietic stem cell 
transplant at the discretion of the investigator.  
Week 1
Week 2
Week 3
Week 4
Dexamethasone dosing Days 1, 2, 8, 9, 15, 16, 22, and 23
P
Cyclophosphamide dosing Days 1, 8, and 15
Oprozomib dosing Days 1, 2, 8, 9, 15, 16, 22, and 23
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Subjects in either treatment cohort who complete at least 4 cycles of study treatment and 
achieve a confirmed response (i.e., PR, VGPR, CR, or sCR) may, after discussion with the 
Onyx study medical monitor, suspend study treatment for up to 6 weeks to undergo a 
hematopoietic stem cell harvest.  Stem cell mobilization will be conducted using a 
noncytotoxic regimen such as granulocyte colony-stimulating factor (G-CSF).  These 
subjects may then resume study treatment until progression of disease, unacceptable toxicity, 
or for a total of 24 cycles of treatment with lenalidomide or a total of 8 cycles of treatment 
with cyclophosphamide, followed by oprozomib treatment with low-dose dexamethasone 
(20 mg or 10 mg) for subjects free from progression, as described above.   
In the Phase 1b portion, subjects will be enrolled in escalating or dose-de-escalating dose 
cohorts in each combination regimen (see Section 4.2 and Table 3, Table 4, and Table 5 for 
doses/cohorts, and see Section 9.1.2 for methods of dose escalation to the MTD).  Dose 
escalation will proceed only after the safety and tolerability of the previous dose level has 
been assessed as acceptable by the Cohort Safety Review Committee (CSRC) comprised of 
Onyx’s study medical monitor, Onyx’s drug safety representative, and the investigators, or 
until a MTD has been determined.   
In the Phase 2 portion, oprozomib will be given in combination with dexamethasone and 
either lenalidomide or cyclophosphamide at the recommended Phase 2 dose (RP2D), as 
defined in the Phase 1b portion of the study.  The RP2D may or may not be the same as the 
MTD, and will be assessed on the basis of the totality of safety and PK/PDn data.   
4.1.1 
PATIENTS ELECTING TO HAVE STEM CELLS COLLECTED 
Subjects enrolling in the OPZ003 study must be newly diagnosed and require treatment as 
per the 2013 National Comprehensive Cancer Network (NCCN) guidelines.  Subjects 
scheduled for or planning to proceed with transplant in the front-line setting should not be 
enrolled.  However, subjects may have their stem cells collected for future salvage transplant.  
The schema below (Figure 5) depicts the schedule for subjects electing to bank their stem 
cells. 
In the event that a subject who had not previously intended to proceed to front-line transplant 
elects to proceed, that subject will be discontinued from the study (see Section 11). 
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Figure 5 Schedule for Stem Cell Collection  
 
ASCT = autologous stem cell transplantation; Cyd = cyclophosphamide and dexamethasone. OPZ = oprozomib; PD = 
progressive disease; PR = partial response; Rd = lenalidomide and dexamethasone. 
 
4.2 
DOSE-ESCALATION PLAN 
In the Phase 1b portion of the study, oprozomib doses will be escalated in sequential groups 
of 3 subjects for each combination regimen, with expansion to up to 6 subjects if a DLT is 
observed in 1 of the first 3 subjects.  The doses of lenalidomide, cyclophosphamide, and 
dexamethasone will remain fixed in all dose cohorts.   
Enrollment in the initial cohort (Table 3) for the ORd arm was entered at a daily dose level of 
210 mg on the 5/14 schedule.  Two DLTs (syncope) were observed in the first 3 subjects and 
the cohort dose was decreased by 1 dose level to 180 mg of oprozomib.  The dosing cohort 
was de-escalated to 150 mg after 2 DLTs (abdominal pain and hypotension) in 6 DLT 
evaluable subjects were reported at the 180 mg dosing level.  With the introduction of the ER 
Tablet with Amendment 2, there will be no further attempt at dose escalation in the 5/14 
schedule with the tablet formulation.  
The starting dose for subjects enrolled in the ORd and OCyd arms under Amendment 2 will 
be 210 mg on the 2/7 schedule (Table 4 and Table 5).  The dose of oprozomib for subsequent 
cohorts will be escalated or de-escalated by 30-mg increments until the MTD is established.  
The maximum dose to be tested has not been defined.  It is anticipated that dosing will not 
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exceed the oprozomib single agent MTD.  Biweekly investigator calls and CSRC meetings, 
during which safety data will be reviewed from this and other oprozomib studies will occur 
before all cohort dose escalation decisions and implementation.  Additional details regarding 
dose escalation can be found in the Cohort Management Plan.  Details on subject 
replacement are provided in Section 9.1.4.  The MTD will be defined as the highest dose in 
which a DLT is observed in fewer than 2 of 6 patients (Kummar 2006).  At least 6 patients 
must be treated at the MTD for a minimum of 1 cycle to establish this dose as tolerated. 
Table 3 
Dose-Escalation Scheme:  Oprozomib Tablets in Combination with 
Lenalidomide and Dexamethasone (ORd) for 5/14 Dosing Schedule 
(Original Protocol and Amendment 1) 
Cohorts 
Oprozomib Daily 
Dose (mg)a, b 
Lenalidomide 
Doses (mg) 
Dexamethasone 
Doses (mg) 
-102 
150 
25 
20 
-101c 
180 
25 
20 
101  
210 
25 
20 
102 
240 
25 
20 
103 
270 
25 
20 
104 
300 
25 
20 
a Subjects enrolled in the Phase 1b prior to the availability of Oprozomib ER 
Tablets, will initiate treatment with oprozomib tablets.  These subjects may 
have their oprozomib tablets replaced with Oprozomib ER Tablets after they 
have completed the 1st cycle of ORd treatment and when the Oprozomib ER 
Tablets are available.  
b Re-escalation of oprozomib dosing in the ORd arm may occur if significant 
differences in the pharmacokinetic profile of the extended and modified 
release formulations are observed.  In this case, enrollment would start at 
150 mg or the MTD established with the ER formulation and subsequent 
cohorts of 3-6 subjects enrolled with doses escalated by 30 mg until the MTD 
(the highest dose at which a DLT is observed in less than 2 of 6 evaluable 
subjects) with the new formulation is defined. 
c DLTs were observed in 2 subjects in the 101 cohort at a dose level of 210 mg, 
and in the -101 cohort at a dose level of 180 mg.  Dosing will proceed at 
150 mg as agreed with the Cohort Safety Review Committee (CSRC).  The 
number of subjects may be expanded to include up to 6 evaluable subjects. 
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Table 4
Dose-Escalation Scheme: Oprozomib Tablets in Combination with 
Lenalidomide and Dexamethasone (ORd) for 2/7 Dosing Schedule (Amendment 2)
Cohorts
Oprozomib Daily 
Dose (mg)a,b
Lenalidomide 
Doses (mg)
Dexamethasone 
Doses (mg)
-202
150
25
20
-201 a
180
25
20
201 b
210
25
20
202
240
25
20
203
270
25
20
204
300
25
20
205
330
25
20
206
360
25
20
a
If DLTs are observed in 2 or more subjects at the first dose level of 210 mg, 
dosing of Cohort -201 will proceed at 180 mg, or a lower dose as agreed with 
the Cohort Safety Review Committee (CSRC) and may be expanded to 
include up to 6 evaluable subjects.
b
Cohorts of 3–6 subjects will continue to be enrolled with doses escalated by 
30 mg until the MTD (the highest dose at which a DLT is observed in less 
than 2 of 6 evaluable subjects) is defined.
Table 5
Dose-Escalation Scheme: Oprozomib ER Tablets in Combination with 
Cyclophosphamide and Dexamethasone (OCyd) for the 2/7 Dosing Schedule
(Amendment 2)
Cohorts
Oprozomib
ER Tablets
Daily Dose (mg)
Cyclophosphamide
Doses (mg/m2)
Dexamethasone 
Doses (mg)
-302
150
300
20
-301a
180
300
20
301b
210
300
20
302
240
300
20
303
270
300
20
304
300
300
20
305
330
300
20
a If DLTs are observed in 2 or more subjects at the first dose level of 210 mg, 
dosing of Cohort -301 will proceed at 180 mg, or a lower dose as agreed with 
the Cohort Safety Review Committee (CSRC) and may be expanded to include 
up to 6 evaluable subjects.
b Cohorts of 3–6 subjects will continue to be enrolled with doses escalated by 
30 mg until the MTD (the highest dose at which a DLT is observed in less than 
2 of 6 evaluable subjects) is defined.
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4.3
MINIMIZING BIAS
4.3.1
RANDOMIZATION
This is an open-label study.  Subjects will be assigned to dose levels in a sequential manner
(see Section 4.1).
4.3.2
BLINDING
Not applicable; this is an open-label study.  
4.4
NUMBER OF CENTERS
Approximately 20 study centers in the US will be recruited for participation in this study.  
4.5
NUMBER OF SUBJECTS
Total enrollment of up to approximately 134 evaluable subjects is planned for this study, 
including up to approximately 64 evaluable subjects for the Phase 1b portion of the study
(40 and 24 for ORd and OCyd, respectively) and approximately 70 subjects for the Phase 2 
portion of the study (35 subjects for each combination regimen).  
4.5.1
PHASE 1b 
The estimated sample size of up to 40 subjects for the ORd combination regimen and up to
24 subjects for the OCyd combination regimen is based upon standard 3 + 3 dose-escalation 
rules (see Section 9.1.2) and the expectation that 2–6 dosing cohorts of 3–6 subjects per 
cohort will be required to establish the MTD for each treatment regimen.
4.5.2
PHASE 2
Enrollment of 35 additional subjects in each combination regimen during the Phase 2 portion 
of the study is based upon the goal of ruling out an ORR < 85% and a CRR < 50% based 
upon the approximate lower 1-sided 90% confidence interval. The same assumptions are 
used in determining the sample size for each combination regimen. 
4.6
ESTIMATED STUDY DURATION
The total study duration is expected to be approximately 59 months based upon the 
assumptions that approximately 35 months may be required to enroll all subjects 
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(approximately 23 months to enroll Phase 1b subjects and approximately 12 months to enroll 
Phase 2 subjects) and that the average time on study will be approximately 24 months.  
5
SUBJECT SELECTION
Up to approximately 134 patients with newly diagnosed, symptomatic multiple myeloma for 
which a hematopoietic stem cell transplant is not planned or scheduled during the study or 
are considered ineligible for hematopoietic stem cell transplant at the discretion of the 
investigator, and are considered to be appropriate for this clinical study by their treating 
physicians may enroll.  
5.1
INCLUSION CRITERIA
1. Newly diagnosed multiple myeloma patients for whom treatment is indicated per the 
NCCN guidelines, and for whom a hematopoietic stem cell transplant is not planned 
or scheduled during the study or are considered ineligible for hematopoietic stem cell 
transplant, with 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 hour
c.
Serum free light chain (SFLC):  Involved SFLC level ≥10 mg/dL provided 
SFLC ratio is abnormal
2. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2
3. Males and females ≥ 18 years of age
4. Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal 
(ULN), aspartate aminotransferase (AST) ≤3 times ULN, and alanine 
aminotransferase (ALT) ≤3 times ULN (Note:  Patients with documented Gilbert 
Syndrome may be enrolled with an elevated unconjugated bilirubin after discussion 
with the Onyx study medical monitor)
5. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 7.0 g/dL, and platelet 
count ≥75 × 109/L
a.
Patients must not have received platelet transfusions for at least 1 week prior to 
Screening
b. Screening ANC must be independent of granulocyte colony-stimulating factor
(G-CSF) or granulocyte/macrophage-colony-stimulating factor (GM-CSF) 
support for at least 1 week and of pegylated G-CSF support for ≥ 2 weeks
c.
Patients may receive red blood cell (RBC) transfusions or receive supportive 
care with erythropoietin or darbepoetin in accordance with institutional 
guidelines
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6. Creatinine clearance (CrCl) rate of ≥50 mL/min, either measured or calculated using 
the formula of Cockcroft and Gault [(140 – age) × mass (kg) / (72 × serum 
creatinine mg/dL)].  Multiply result by 0.85, if female.  
7. Patients must sign written informed consent form (ICF) in accordance with federal, 
local, and institutional guidelines
8. For both treatment regimens (ORd and OCyd):  Females of childbearing potential 
(FCBP) must agree to ongoing pregnancy testing and to practice contraception as
outlined in the Revlimid REMS Guide (Appendix K).  Two effective contraceptive 
methods must be used by FCBP for at least 4 weeks prior to start of lenalidomide or 
cyclophosphamide therapy, during therapy, and during dose interruptions, and for 
3 months following the discontinuation of oprozomib.  Postmenopausal females 
(> 45 years old and without menses for > 24 consecutive months) and surgically 
sterilized females are exempt from these requirements.
9. For both treatment regimens (ORd and OCyd):  Male subjects must agree to practice 
contraception as outlined in the Revlimid Risk Evaluation and Mitigation Strategy 
(REMS) Guide (Appendix K).  Male subjects receiving lenalidomide or 
cyclophosphamide must use an effective method of contraception during any sexual 
contact with FCBP during the study, and for 3 months following the discontinuation 
of oprozomib, even if the subject has undergone a successful vasectomy.
5.2
EXCLUSION CRITERIA
1. Radiation therapy within 2 weeks prior to first dose
2. Any prior systemic antimyeloma therapy except oral steroids (dexamethasone up to a 
total dose of 160 mg or equivalent within 14 days prior to the first dose of study 
treatment).  Use of topical or inhaled steroids is acceptable.  
3. Participation in an investigational therapeutic study within 3 weeks prior to first dose
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. Major surgery within 3 weeks prior to first dose
6. Clinically significant GI bleed in the 6 months prior to Cycle 1 Day 1 (C1D1) first 
dose
7. 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 prior to first dose
8. A history of deep vein thrombosis or pulmonary embolism, with contraindication to 
anticoagulation and antiplatelet options
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9. Active infection requiring systemic antibiotics, antivirals, or antifungals within 
2 weeks prior to first dose
10. Known or suspected human immunodeficiency virus (HIV) infection or subjects who 
are HIV seropositive
11. Active hepatitis A, B, or C infection
12. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of first 
dose
13. Other malignancy within the past 3 years except those considered cured by surgical 
resection including some cases of:
a.
Adequately treated basal or squamous cell carcinoma of the skin
b. Thyroid cancer
c.
Carcinoma in situ of the breast or cervix
d. Prostate cancer with Gleason Score of 6 or less with stable prostate-specific 
antigen levels
14. Plasma cell leukemia
15. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes)
16. Known amyloidosis 
17. Uncontrolled diabetes or hypertension
18. Female subjects who are pregnant or nursing
19. Any clinically significant psychiatric or medical condition that in the opinion of the 
investigator could increase patient risk, interfere with protocol adherence, or a 
subject’s ability to give informed consent
6
SUBJECT SCREENING
A signed and dated ICF will be obtained before any screening procedures are performed.  
Evaluations obtained as part of routine medical care and performed prior to obtaining 
informed consent may be used in place of the study-specific evaluations, provided they meet 
the time windows described in the Schedule of Assessments (Appendix A and Appendix B).  
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 when the 
subject undergoes the first study-specific screening assessment, and must be completed 
within 21 days.  The window of assessment for bone marrow aspirate and biopsy in the 
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Phase 1b is 8 weeks and is the only exception to the 21-day screening assessment window.  
In the Phase 2, the bone marrow assessments must be performed within 28 days prior to
C1D1 and is the only exception to the 21-day screening assessment window.
7
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 Onyx study medical monitor will review the 
subject’s information before enrollment.  Only subjects who are approved by the Onyx study 
medical monitor or designee will be allowed to enroll into the study.  A minimum of 
24 hours during weekdays (Monday through Friday) will be required for the Onyx study 
medical monitor 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 Onyx study medical monitor approves the patient for enrollment. The logistics of 
cohort assignment are detailed in the Cohort Management Plan.
8
STUDY DRUG
8.1
OPROZOMIB TABLETS AND OPROZOMIB EXTENDED RELEASE 
TABLETS
8.1.1
PHYSICAL DESCRIPTION
Oprozomib is a synthetic small molecule peptide epoxyketone.  The molecular formula is 
C25H32N4O7S and the molecular weight is 532.61 (Oprozomib IB).  It specifically functions 
as an inhibitor of the chymotrypsin-like activity of the 20S proteasome, which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis.
8.1.2
PACKAGING AND LABELING
Oprozomib will be provided as a tablet for oral administration.  Subjects enrolled under the 
original protocol or Amendment 1 will receive Oprozomib Tablets containing 60, 90, or 
120 mg of oprozomib drug substance.  Subjects enrolled under Amendment 2 will receive 
Oprozomib ER Tablets containing 120, 150, 180, 210, 240, or 270 mg oprozomib drug 
substance. Oprozomib Tablets and Oprozomib ER Tablets are intended to have an average 
release greater than or equal to 75% (Quantity) of the total dose of oprozomib over 8 hours.
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Oprozomib Tablets are white to off-white, film-coated, round biconvex tablets and are 
manufactured at 3 dosage strengths:

Oprozomib 60 mg tablets are debossed with “1” on one side and contain
60 mg of oprozomib

Oprozomib 90 mg tablets are debossed with “3” on one side and contain
90 mg of oprozomib

Oprozomib 120 mg tablets debossed with “5” on one side and contain
120 mg of oprozomib
Oprozomib ER Tablets are white to off-white, film-coated, tablets manufactured at 
6 dosage strengths:

Oprozomib 120 mg tablets are debossed with “G” on one side and contain 
120 mg of oprozomib.

Oprozomib 150 mg tablets are debossed with “H” on one side and contain 
150 mg of oprozomib.

Oprozomib 180 mg tablets are debossed with “I” on one side and contain
180 mg of oprozomib.

Oprozomib 210 mg tablets are debossed with “J” on one side and contain 
210 mg of oprozomib.

Oprozomib 240 mg tablets are debossed with “K” on one side and contain 
240 mg of oprozomib

Oprozomib 270 mg 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 6 dosage strengths.
8.1.3
OPROZOMIB ER TABLET DRUG PROPERTIES
The Oprozomib ER Tablet has been developed to have a more consistent dissolution profile.
There are minimal changes in the tablet coating and ratio of current excipients; however, 
there is no change to the ratio of active pharmaceutical ingredient to excipients.  The 
Oprozomib ER Tablet is designed to have a dissolution profile with lower variability that 
targets the current Oprozomib Tablet profile.  In addition, multiple tablets make up the 
current dose levels and the new tablet will be generally administered as a single tablet.  
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Given the minimal changes, the new Oprozomib ER Tablet is not expected to result in altered
exposure or additional adverse events related to formulation.  
8.1.4
STORAGE
Oprozomib must be stored at room temperature (15°C–30°C; 59°F–86°F) in a securely
locked area to which access is limited to appropriate study personnel.
8.1.5
ACCOUNTABILITY
Onyx and the investigator will maintain records of each shipment of investigational product.  
The records will document shipment dates, method of shipment, batch numbers, and number 
of bottles contained in the shipment.  On receipt of the investigational product, the designated 
recipient at the study site will inspect the shipment, verify the number and condition of the 
drug product, and prepare an inventory or drug accountability record.  Drug accountability 
records must be readily available for inspection by representatives of Onyx and by regulatory 
authorities.  Further instructions are provided in the Pharmacy Manual.
Instructions for the destruction and return of unused drug supply are also provided in the 
Pharmacy Manual.
8.2
LENALIDOMIDE
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic 
and antineoplastic properties. The empirical formula for lenalidomide is C13H13N3O3, and 
the molecular weight is 259.3 (Revlimid Prescribing Information, Appendix H).
8.2.1
PHYSICAL DESCRIPTION
Lenalidomide is an off-white to pale-yellow solid powder.  It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents.  Lenalidomide is more soluble in 
organic solvents and low pH solutions.  Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/mL.  Lenalidomide has an asymmetric carbon 
atom, can exist as the optically active forms S(–) and R(+), and is produced as a racemic 
mixture with a net optical rotation of zero.  Lenalidomide is available in 5 mg, 10 mg, 15 mg, 
and 25 mg capsules for oral administration.  Each capsule contains lenalidomide as the active 
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ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate.  The 5 mg and 25 mg capsule 
shells contain gelatin, titanium dioxide and black ink.  The 10 mg capsule shell contains 
gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.  The 15 mg 
capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink (Appendix H).
8.2.2
PACKAGING AND LABELING 
Revlimid (lenalidomide) is a commercially available drug supplied as 5 mg, 10 mg, 15 mg, 
and 25 mg capsules for oral administration only (Appendix H).
8.2.3
STORAGE
Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) (Appendix H).
8.2.4
ACCOUNTABILITY
Bottles of lenalidomide will contain a sufficient number of capsules to last for 1 cycle of 
dosing.  Sites will be required to record and document patient compliance regarding 
lenalidomide dosing. Please refer to the Pharmacy Manual for additional details.
8.3
CYCLOPHOSPHAMIDE
8.3.1
PHYSICAL DESCRIPTION AND FORMULATION
Cyclophosphamide is an alkylating agent (Cyclophosphamide Prescribing Information,
Appendix I).
8.3.2
PACKAGING AND LABELING
Cyclophosphamide is a commercially available drug, available both as tablets for PO
administration and as various sterile formulations for parenteral administration (Appendix I).  
Only the tablet formulation will be used in this protocol.
8.3.3
STORAGE
Cyclophosphamide is to be stored at controlled room temperature. Do not store above 25°C.
Consult the package insert for additional storage and usage instructions (Appendix I).
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8.3.4
ACCOUNTABILITY
Sites will be required to record and document patient compliance regarding 
cyclophosphamide dosing.  Please refer to the Pharmacy Manual for additional details.
8.4
DEXAMETHASONE
8.4.1
PHYSICAL DESCRIPTION
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, 
crystalline powder (Dexamethasone Prescribing Information, Appendix J).  The empirical 
formula and molecular weight is C22H29FO5 and 392.5, respectively.  
8.4.2
PACKAGING AND LABELING
Dexamethasone is a commercially available drug, available both as tablets for oral 
administration and as various sterile formulations for parenteral administration (Appendix J).
8.4.3
STORAGE CONDITION
Dexamethasone is to be stored at controlled room temperature 20°C–25°C (68°F–77°F).  
Consult the package insert of the respective product for additional storage and usage 
instructions (Appendix J).
8.4.4
ACCOUNTABILITY
Sites will be required to record and document subject compliance regarding dexamethasone 
dosing.  Please refer to the Pharmacy Manual for additional details.
9
DOSAGE AND TREATMENT ADMINISTRATION
9.1
OPROZOMIB
9.1.1
TREATMENT ADMINISTRATION
Oprozomib ER Tablets will be administered in single daily doses (Table 3, Table 4 and
Table 5 in the following manner:  
It is recommended that subjects take oprozomib with approximately 8 ounces of water at 
approximately the same time of day with food.  When oprozomib is given on the same day 
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with other treatments, dexamethasone should be administered 30 minutes before oprozomib, 
lenalidomide and cyclophosphamide.  Subjects may take lenalidomide or cyclophosphamide 
following oprozomib administration at investigator’s discretion; however it is recommended
that they take their study drugs at approximately the same time each day.  On days when
oprozomib is not administered, subjects should take lenalidomide or cyclophosphamide at 
approximately the same time of the day for consistency.
For subjects receiving the ORd treatment regimen under Amendment 1, oprozomib will be 
administered orally, once daily for 5 consecutive days every other week; specifically on 
Days 1 through 5, and 15 through 19 (5/14 schedule) of each 28-day treatment cycle.  
Subjects receiving ORd under Amendment 2 will receive oprozomib 2 consecutive days 
every 7 days; specifically on Days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day 
treatment cycle (Figure 1).
For subjects receiving the OCyd treatment regimen, oprozomib will be administered orally,
once daily on 2 consecutive days every 7 days; specifically on Days 1, 2, 8, 9, 15, 16, 22, and 
23 (2/7 schedule) of each 28-day treatment cycle (Figure 1). 
Treatment with oprozomib will continue until disease progression, unacceptable toxicity, or 
study treatment discontinuation for any reason (see Section 11).
Subjects who permanently discontinue lenalidomide or cyclophosphamide for reasons other 
than disease progression may continue treatment with oprozomib and dexamethasone until 
disease progression as described above.  After 24 months, the dose of dexamethasone will be 
decreased to premedication doses (4 mg).  A dexamethasone taper may be utilized as per
institutional guidelines.  
Subjects receiving the ORd treatment regimen, who permanently discontinue oprozomib for 
reasons other than disease progression following the completion of Cycle 1, may continue 
treatment with lenalidomide and dexamethasone until disease progression or for a maximum 
of 24 months, whichever occurs first.  Subjects who discontinue both lenalidomide and 
oprozomib may not continue treatment with dexamethasone alone.  Subjects receiving the 
OCyd treatment regimen who permanently discontinue oprozomib for reasons other than 
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disease progression following the completion of Cycle 1, may continue treatment with 
cyclophosphamide and dexamethasone until disease progression or for a maximum of 
8 months, whichever occurs first.  Subjects who discontinue both cyclophosphamide and 
oprozomib may not continue treatment with dexamethasone alone.
Guidelines for dose modification are provided in Section 9.3.  Details on the study design are 
provided in Section 4.1.
9.1.2
DOSE-ESCALATION RULES
The planned and contingent dose levels are provided in Section 4.2 (Table 3, Table 4, and
Table 5 and dose-escalation rules are provided in Table 6.  Additional details can be found in 
the Cohort Management Plan. 
Table 6
Dose-escalation Rules
No. of Evaluable Subjects 
with Treatment-related 
DLT at a Given Dose Level
Dose-Escalation Rules
0 of 3
New cohort of 3 subjects treated at the next higher dose level.
1 of 3
Up to 3 more subjects are treated at that same dose level.
≥2 of 3
Dose escalation stops.  Three more subjects will be added to the preceding
dose level, unless 6 subjects have already been treated at that dose level.
1 of 6
New cohort of 3 subjects treated at the next higher dose level.
≥2 of 6
Dose escalation stops.  Additional subjects may be treated at the preceding
dose level, for a minimum of 6 subjects treated at that dose level.
Highest dose with < 2 of 6
Maximum tolerated dose
DLT = dose limiting toxicity.
Source:  Modified from Simon 1997.
Intrasubject dose escalation to the MTD or RP2D may be permitted once that dose has been 
determined and after a discussion has occurred between the treating physician and Onyx 
study medical monitor.  
9.1.3
DEFINITION OF DOSE-LIMITING TOXICITY
Subjects will be evaluated for DLT according to the National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03 (see Appendix D).  
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During the Phase 1b portion, assessment of DLTs will occur during the first 28 days of 
treatment (Cycle 1).  For the purposes of this study, a DLT is defined as any of the following 
treatment-related events occurring in the first 28 days of treatment:
Nonhematologic DLT:

Any ≥ Grade 3 nonhematologic toxicity with the following exceptions or 
qualifications:
o
≥ Grade 3 nausea, vomiting, diarrhea, or constipation will be considered a DLT 
only if lasting > 7 days, despite optimal supportive care, including (at a 
minimum), a 5-hydroxytryptamine type-3 (5-HT3) antagonist and aprepitant for 
nausea/ vomiting and (e.g., Imodium), and diphenoxylate/atropine 
(e.g., Lomotil) for diarrhea
o
Asymptomatic Grade 3 hypophosphatemia is not considered a DLT
o
Grade 3 hyperglycemia or toxicity solely due to dexamethasone is not 
considered a DLT (see dose reduction guidelines for dexamethasone in 
Section 9.3.2)
o
Grade 3 fatigue lasting < 14 days is not considered a DLT
o
Grade 3 rash attributed specifically to lenalidomide is not a DLT 
Hematologic DLT:

Grade 4 neutropenia:  ANC < 0.5 × 109/L lasting ≥7 days, despite myeloid growth 
factor support

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)

Grade 4 thrombocytopenia lasting ≥ 7 days or

Grade 4 thrombocytopenia lasting < 7 days with > Grade 2 clinically significant 
bleeding or < 10,000 platelets requiring platelet transfusion, or 

Grade ≥3 thrombocytopenia with clinically significant bleeding or requiring platelet 
transfusion.
Note:  Grade 4 anemia will not be considered a DLT, but should be treated with supportive 
measures in accordance with institutional guidelines.
9.1.4
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:
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
A minimum of 8 of 10 planned doses of oprozomib must be received on the 
5/14 schedule

A minimum of 7 of 8 planned doses of oprozomib must be received on the 
2/7 schedule

A minimum of 6 of 8 planned doses of dexamethasone must be received 

All 3 planned doses of cyclophosphamide must be received (OCyd combination 
regimen only)

A minimum of 17 of 21 planned doses of lenalidomide must be received (ORd 
combination regimen only)
Subjects not meeting all of the above criteria or assessed as unevaluable will be replaced. 
Subjects who do not meet the criteria above because of a DLT will be considered 
DLT-evaluable.  Subjects who discontinue study treatment for any reason after Cycle 1 will 
not be replaced.  
Guidelines for withholding study treatment, including treatment delays, reintroduction, and 
discontinuation, are described in Section 9.3. 
9.2
LENALIDOMIDE, CYCLOPHOSPHAMIDE, AND DEXAMETHASONE 
ADMINISTRATION
9.2.1
LENALIDOMIDE ADMINISTRATION
Lenalidomide will be administered orally at a dose of 25 mg with or without food at 
investigator and subject discretion, on Days 1 through 21 of each 28-day cycle for a 
maximum of 24 cycles (approximately 24 months).  Subjects may take lenalidomide 
following oprozomib, however, it is recommended that they take lenalidomide at 
approximately the same time each day (Refer to Section 9.1.1 for details on oprozomib 
treatment administration).  On days when oprozomib is not administered, subjects should
take lenalidomide at approximately the same time of the day for consistency.
9.2.2
CYCLOPHOSPHAMIDE ADMINISTRATION
Cyclophosphamide will be administered orally at 300 mg/m2 (up to a maximum of 600 mg)
with or without food at investigator and subject discretion, on Days 1, 8, and 15 of each 
28-day cycle for a maximum of 8 cycles of therapy (approximately 8 months).  Subjects may 
take cyclophosphamide following oprozomib, however it is recommended that they take 
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cyclophosphamide at approximately the same time each day (Refer to Section 9.1.1 for 
details on oprozomib treatment administration).  On days when oprozomib is not 
administered, subjects should take cyclophosphamide at approximately the same time of the 
day for consistency.
9.2.3
DEXAMETHASONE 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 when both oprozomib and dexamethasone are administered
(i.e., on Days 1, 2, 8. 9, 15, 16, 22, and 23), dexamethasone should be taken at least 
30 minutes prior to oprozomib.  
Note:  Dexamethasone will be taken at a dose of 20 mg/day through the first cycle, after 
which the dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion 
of the investigator.  Dexamethasone dosing (premedication and low-dose) as per the schedule 
above in combination with oprozomib should be continued for subjects who demonstrate a 
response of stable disease or better for 24 cycles for both the ORd and OCyd treatment 
regimens.  After 24 cycles, this treatment may be continued or tapered at the discretion of the 
investigator and per institutional guidelines. 
9.3
DOSE-MODIFICATION GUIDELINES
The following sections and tables summarize dose modifications for oprozomib, 
lenalidomide, cyclophosphamide, and dexamethasone to manage possible toxicity.  
Administration of oprozomib, lenalidomide, or cyclophosphamide will be discontinued in the 
event of a treatment-related toxicity that, in the opinion of the investigator, warrants 
permanent discontinuation.  Interruption of oprozomib dosing for > 4 weeks for any reason 
will result in permanent discontinuation of oprozomib.  No dose reductions of oprozomib are 
allowed in Cycle 1.  The subject will remain on protocol treatment as long as oprozomib,
lenalidomide, or cyclophosphamide is being administered (either alone or in combination 
with dexamethasone).  Monotherapy with dexamethasone is not allowed.  
Dose modifications made during the first cycle of treatment for either combination regimen 
in the Phase 1b portion of this study should be discussed with the Onyx study medical 
monitor.
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Dose reduction levels for oprozomib, lenalidomide, and cyclophosphamide are provided in
Table 7, Table 8, and Table 9, respectively.
Table 7
Dose Decrements for Oprozomib
(5/14 Schedule, Original Protocol Amendment 1)
Nominal Dose
Reduced Oprozomib Doses
Dose -1
Dose -2
Assigned Cohort Dose
Nominal dose – 30 mg
Nominal dose – 60 mg
Table 8
Dose Decrements for Oprozomib (2/7 Schedule, Amendment 2)
Nominal Dose
Reduced Oprozomib Doses
Dose -1
Dose -2
Assigned Cohort Dose
Nominal dose – 30 mg
Nominal dose – 60 mg
Table 9
Dose Decrements for Lenalidomide
Nominal Dose
Reduced Lenalidomide Doses
Dose -1
Dose -2
Dose -3
25 mg
15 mg
10 mg
5 mg
Note: Dose adjustments should, in general, follow the Revlimid Prescribing Information 
(Appendix H).
Table 10
Dose Decrements for Cyclophosphamide
Nominal Dose
Reduced Cyclophosphamide Doses
Dose -1
Dose -2
300 mg/m2
200 mg/m2
100 mg/m2
Note: Dose adjustments should, in general, follow the Cyclophosphamide Prescribing 
Information (Appendix I).
Dose-modification guidelines for specific hematologic toxicities are outlined in Section 9.3.1
and for nonhematologic toxicities in Section 9.3.2.  In addition to dose reductions, 
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administration of oprozomib, lenalidomide, and cyclophosphamide may be temporarily 
interrupted in the event of a treatment-related toxicity, at the investigator’s discretion.
If the dose of lenalidomide, cyclophosphamide, or oprozomib is reduced, the reduced dose 
level will be continued on Day 1 of the next, 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.
Dose reduction levels are defined for dexamethasone in Table 11.
Table 11
Dose Decrements for Dexamethasone
Nominal Dose
Reduced Dexamethasone Doses
Dose -1
Dose -2
20 mg
12 mg
8 mg
Cycle 2:  Age > 75 and nominal 
dose is 10 mg post-Cycle 1
8 mg
4 mg
Dexamethasone will be permanently discontinued after 2 dose reductions in the event of 
continued, unacceptable, dexamethasone-related toxicity.  At the investigator’s discretion, 
dexamethasone may be tapered prior to complete discontinuation according to institutional 
practice.  The subject may continue on treatment with the other protocol-specified drug(s).  
Guidelines for dexamethasone dose modifications are summarized in Table 11.
9.3.1
DOSE-MODIFICATION GUIDELINES FOR HEMATOLOGIC 
TOXICITIES
Dose-modification guidelines for hematologic toxicities are outlined in Table 12.
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Table 12
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and Cyclophosphamide-related 
Hematologic Toxicities Post-Cycle 1
Toxicity
Recommended Actiona
Oprozomib
Lenalidomide
Cyclophosphamide
Toxicity on Day 1 of Cycle
Platelets < 25 × 109/L 
Hold dose until recovery to ≥25 × 109/L
restart at previous dose
Hold dose, follow CBC 3 times per week
Hold prophylactic anticoagulation until 
platelets return to ≥30 × 109/La, then 
resume at 1 dose decrement
Hold dose until recovery to ≥25 × 109/L
restart at 1 dose decrement 
ANC < 1.0 × 109/L
Hold dose
Add myeloid growth factorb
With resolution to ≥1.0 × 109/L, restart at 
previous dose
Hold dose
Add myeloid growth factorb
With resolution to ≥1.0 × 109/L, restart at 
previous dose
Hold dose
Add myeloid growth factorb
With resolution to ≥1.0 × 109/L, restart at 
1 dose decrement 
Toxicity on Subsequent Days of Cycle
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 dose; follow CBC 3 times per week
Add myeloid growth factorb
With resolution of fever and ANC ≥ 1.0 × 109/L, restart at 1 dose decrement
ANC < 0.75 × 109/L (Grade 3)
Hold dose
Add myeloid growth factorb
With resolution to ≥ 1.0 × 109/L, restart at 
previous dose
Hold dose; follow CBC 3 times per week
Administer myeloid growth factorb
Resume at full dose when 
ANC ≥ 1.0 × 109/L
(Resume at 1 dose decrement for each 
subsequent decrease to < 0.75 × 109/L)
Hold dose
Add myeloid growth factorb
With resolution to ≥1.0 × 109/L, restart at 1 
dose decrement
ANC < 0.5 × 109/L (Grade 4)
Hold dose; follow CBC 3 times per week 
Add myeloid growth factorb
Resume at full dose if ANC rises to 
≥0.5 × 109/L within 7 days
Resume at 1 dose decrement if ANC returns 
to ≥0.5 × 109/L after ≥7 days.
Hold dose; follow CBC 3 times per week 
Add myeloid growth factorb  
When ANC ≥ 1.0 × 109/L, resume at 1 dose 
decrement
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Table 12
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and Cyclophosphamide-Related 
Hematologic Toxicities Post-Cycle 1 (cont'd)
Toxicity
Recommended Actiona
Oprozomib
Lenalidomide
Cyclophosphamide
Toxicity on Subsequent Days of Cycle (continued)
Platelets 25 to < 50 × 109/L 
without ≥Grade 2 bleeding/hemorrhage
Full dose
Hold dose, follow CBC weekly
Hold prophylactic anticoagulation until 
platelets return to ≥ 30 × 109/L.
When platelets reach 50 x 109/L, then 
resume at 1 dose decrement.
Hold dose until platelets return to 
≥50 × 109/L, then resume at 1 dose 
decrement
Platelets 25 to < 50 × 109/L with ≥Grade 2
bleeding/hemorrhage 
Hold dose until platelets return to 
≥50 × 109/L and/or bleeding is controlled, 
then resume at 1 dose decrement
Hold dose, follow CBC weekly
Hold prophylactic anticoagulation until 
platelets return to ≥ 30 × 109/L.
When platelets reach 50 × 109/L, then 
resume at 1 dose decrement.
Hold dose until platelets return to 
≥50 × 109/L and/or bleeding is controlled, 
then resume at 1 dose decrement
Platelets < 25 × 109/L or any degree of 
thrombocytopenia with ≥Grade 2 
bleeding/hemorrhage 
Hold dose until platelets return to 
≥50 × 109/L and/or bleeding is controlled, 
then resume at 1 dose decrement
Hold dose, follow CBC weekly
Hold prophylactic anticoagulation until 
platelets return to ≥30 × 109/L.
When platelets reach 50 × 109/L, then 
resume at 1 dose decrement
Hold dose until platelets return to 
≥50 × 109/L and/or bleeding is controlled, 
then resume at 1 dose decrement
ANC = absolute neutrophil count; CBC = complete blood count.
a The maximum allowed dose interruption is 4 weeks.
b Myeloid growth factors include filgrastim or sargramostim.
9.3.2
DOSE-MODIFICATION GUIDELINES FOR NONHEMATOLOGIC TOXICITIES
Dose-modification guidelines for nonhematologic toxicities are outlined below in Table 13.
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Table 13
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and 
Cyclophosphamide-Related Nonhematologic Toxicities Post-Cycle 1
Nonhematologic Toxicities, All Days and Cycles
Symptom
Findings
Recommended Actiona
Oprozomib
Lenalidomide
Cyclophosphamide
Tumor Lysis Syndrome 
(TLS)
Generally recognized as 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 lenalidomide/cyclophosphamide until all abnormalities in serum chemistries have 
resolved to baseline; resume at full doses.  See Section 9.8.1.2 for specific prophylaxis and treatment 
guidelines for TLS.
Neuropathy
Grade 2 neuropathy with pain or > Grade 
3 neuropathy
Hold dose until toxicity resolve to 
≤Grade 1 or has returned to 
baseline.  Resume study drug at 
1 dose decrement.
Hold dose until toxicity resolve to 
≤Grade 1 or has returned to 
baseline.
Resume study drug at 1 dose 
decrement.
Full dose
Infection
Grade 3 or 4
Hold both oprozomib and lenalidomide/cyclophosphamide 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. 
Nausea, vomiting, 
diarrhea, or constipation
> Grade 3 without optimal supportive 
care as defined by use of both a 5HT3
antagonist and antiemetic (aprepitant)
Continue full-dose therapy.
Institute optimal supportive care.
> Grade 3 with optimal supportive care as 
defined by use of both a 5HT3 antagonist 
and antiemetic (aprepitant)
Oprozomib-related:  Hold dose 
until toxicity resolve to < Grade 1 
or has returned to baseline.  
Resume study drug at 1 dose 
decrement.
Hold dose until toxicity resolve to < Grade 1 or has returned to baseline.  
Resume study drug at full dose.
If recurs after oprozomib dose reduction, hold dose until toxicity 
resolve to < Grade 1 or has returned to baseline.  Resume study drug at 
1 dose decrement.
Fatigue
Grade 3 fatigue lasting < 14 days
Full dose
If recurs after oprozomib dose 
reduction, hold dose until toxicity 
resolves to < Grade 1 or has 
returned to baseline.
Resume study drug at 1 dose 
decrement.
Full 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 13
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and Cyclophosphamide-Related
Nonhematologic Toxicities Post-Cycle 1 (cont'd)
Nonhematologic Toxicities, All Days and Cycles
Symptom
Findings
Recommended Actiona
Oprozomib
Lenalidomide
Cyclophosphamide
Renal Dysfunction
CrCl 30 to < 50 mL/min (Grade 2)
Full dose
Reduce dose to 10 mg once daily.
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 reduction in CrCl 
reappears, then hold dose until 
CrCl recovers to ≤Grade 2 and 
reduce dose to 15 mg every 
48 hours.  
Hold dose until resolution to 
≤Grade 2 or baseline, then resume 
at full dose
CrCl 0 to <15 mL/min (Grade 4)
Discontinue 
Discontinue
Discontinue
Elevation in Liver 
Function Tests (LFTs) 
≥ Grade 3 (AST, ALT, or total bilirubin)b
Hold dose until resolves to 
baseline.
Resume at one dose decrement.  
Hold dose until resolution, then 
resume at full dose
Hold dose until resolution to 
≤Grade 1 or baseline, then resume 
at full dose
Hemorrhagic Cystitis
Grade 1 or 2
Continue full dose
Continue full dose
Hold dose until resolution, then 
resume at 1 dose decrement
Grade 3 or 4
Continue full dose
Continue full dose
Discontinue; do not resume.
Other Nonhematologic 
Toxicity
Assessed as cyclophosphamide-related 
and ≥Grade 3
Full dose
Not Applicable
Hold cyclophosphamide dose
Follow at least weekly
If the toxicity resolves to ≤Grade 
1 or baseline, restart at 1 dose 
decrement
Other Nonhematologic 
Toxicity
Assessed as oprozomib-related and 
≥Grade 3
Hold oprozomib dose until toxicity 
resolves to ≤Grade 1 or baseline; 
restart at 1 dose decrement
Full dose
Full dose
Other Nonhematologic 
Toxicity
Assessed as lenalidomide-related and 
≥Grade 3
Full dose
Hold lenalidomide dose until 
toxicity resolves to ≤Grade 1 or 
baseline; restart at 1 dose 
decrement
No Applicable
Grades 1 or 2 GI 
hemorrhage
Assessed as oprozomib-related
DELAY until Grade 0 
DECREASE one dose level for 
Grade 2
Hold lenalidomide dose until 
toxicity resolves to ≤Grade 1 or 
baseline
Hold lenalidomide dose until 
toxicity resolves to ≤Grade 1 or 
baseline
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Table 13
Dose-Modification Guidelines for Oprozomib-, Lenalidomide-, and Cyclophosphamide-Related
Nonhematologic Toxicities Post-Cycle 1 (cont'd)
Nonhematologic Toxicities, All Days and Cycles
Symptom
Findings
Recommended Actiona
Oprozomib
Lenalidomide
Cyclophosphamide
Grades 3 or 4 GI 
Hemorrhagec
Assessed as oprozomib-related
Discontinue.
Full dose when AE resolves to 
< Grade 2 at physician discretion.
Full dose when AE resolves to 
< Grade 2 at physician discretion.
5-HT3= 5-hydroxytryptamine type-3; adverse events = AE; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine 
clearance; eCRF = electronic case report form; GI = gastrointestinal; LDH = lactate dehydrogenase; LFTs = liver function tests; TLS = tumor lysis syndrome; ULN = upper limit of 
normal
a The maximum allowed dose interruption is 4 weeks.
b If AST, or ALT is ≥ 3 × ULN, the “evaluation of treatment emergent liver abnormalities” eCRF should be completed.
c Subjects who develop Grade 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.
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Table 14
Treatment Guidelines for Dexamethasone-related Toxicity
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1 or 2 (requiring 
medical management)
Treat with H2 blockers, sucralfate, and/or a proton pump 
inhibitor such as omeprazole (if not already on proton pump 
inhibitor therapy).  If symptoms persist despite above 
measures, decrease dexamethasone dose by 1 dose level.
Gastrointestinal
> Grade 3 (requiring
hospitalization or surgery)
Hold dexamethasone until symptoms are adequately 
controlled.  Restart dexamethasone at 1 dose decrement 
along with concurrent therapy with H2 blockers, sucralfate, 
and/or a proton pump inhibitor such as omeprazole.  
If symptoms persist despite above measures, discontinue 
dexamethasone permanently.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone permanently.  
Cardiovascular
Edema > Grade 3 (limiting 
function and unresponsive 
to therapy or anasarca)
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.
Neurology
Confusion or mood 
alteration > Grade 2 
(interfering with function ± 
interfering with activities of 
daily living)
Hold dexamethasone until symptoms resolve.  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)
Decrease dexamethasone by 1 dose level.  If weakness 
persists, decrease dose by 1 more dose level.  Discontinue 
dexamethasone permanently if symptoms persist.
Metabolic
Hyperglycemia ≥Grade 3
Treatment with insulin or other hypoglycemic agents as 
needed.  If uncontrolled despite above measures, decrease 
dose by 1 dose level until levels are satisfactory.
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, discontinue dexamethasone permanently. 
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9.3.3
CONDITIONS NOT REQUIRING DOSE REDUCTION
The following conditions are exceptions to the above-described dose-modification
guidelines.  Oprozomib, lenalidomide, cyclophosphamide, and dexamethasone do not need to 
be held in the following cases:

Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days with
optimal treatment with antiemetics or antidiarrheal agents)

Grade 3 fatigue (unless persisting for > 14 days)

Alopecia

Asymptomatic Grade 3 hypophosphatemia lasting less than 24 hours

Grade 3 dexamethasone-related hyperglycemia
9.4
DOSE DELAYS
Dosing delays are not permitted in Cycle 1.  If the initiation of Cycle 2 or later must be 
adjusted for reasons unrelated to toxicity (e.g., holidays or subject requests), the cycle should 
be started no later than 7 days after the originally scheduled next cycle. Schedule 
adjustments can only be made at the beginning of each cycle and cannot be made midcycle.
9.5
INTERRUPTION OF TREATMENT FOR HEMATOPOIETIC STEM CELL 
HARVEST
Subjects who complete at least 4 cycles of study treatment and achieve confirmed response 
(i.e., a PR, VGPR, CR, or sCR may, after discussion with the Onyx study medical monitor), 
suspend study treatment for up to 6 weeks to undergo a hematopoietic stem cell harvest.  
See Section 4.1 for additional information.
9.6
MISSED DOSES
Subjects in the Phase 1b portion of the study may not miss any of the planned doses of 
cyclophosphamide, or more than 4 planned doses of lenalidomide, or 2 planned doses of 
oprozomib for the 5/14 schedule or 1 planned dose of oprozomib for the 2/7 schedule, or 
2 planned doses of dexamethasone in Cycle 1.  Subjects who miss more doses than allowed 
during Cycle 1 will not be evaluable and will be replaced.  A missed dose occurs when the 
subject does not take the dose on the planned calendar day. The missed dose will not be made 
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up.  If a subject misses more than 28 consecutive days after completing Cycle 1 for reasons 
other than a hematopoietic stem cell harvest, the subject will permanently discontinue study 
treatment (see Section 9.3 for interrupted oprozomib dosing > 4 weeks).
9.7
SAFETY GUIDANCE FOR INVESTIGATORS
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.

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.

Syncope, hypotension (including orthostatic hypotension), and dehydration have been
reported for subjects treated with oprozomib.  Blood pressure monitoring as detailed
in Appendix A and Appendix B is required.

Tumor lysis syndrome has been reported for subjects treated with oprozomib.
Hydration and allopurinol prophylaxis is recommended for renally impaired subjects
and those with a high tumor burden. For specific recommendations, see Section 9.8.1.
See Section 9.3 for additional dose adjustment guidelines required for specific hematologic 
and nonhematologic toxicities. 
9.7.1
LENALIDOMIDE
See lenalidomide prescribing information for additional details (Appendix H).
9.7.2
CYCLOPHOSPHAMIDE
See cyclophosphamide prescribing information for additional details (Appendix I)
9.7.3
DEXAMETHASONE
See dexamethasone prescribing information for additional details (Appendix J).
9.8
CONCOMITANT MEDICATIONS
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  All concomitant medications must be recorded on the 
subject’s electronic case report form (eCRF) from informed consent to 30 days following the 
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last dose of study drug.  Blood or blood products are not considered concomitant medications 
and must be recorded on the appropriate eCRF.
In vitro tests indicating that the time-dependent inhibitory effect of oprozomib on human 
cytochrome P450 3A (CYP3A) is weak (Kinact to KI was only 1.4 mL/min/mcmol).  
However, 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 
as a precaution.  Cytochrome P450 3A substrates with narrow therapeutic range refer to 
drugs whose exposure-response indicates that increases in their exposure levels by the 
concomitant use of CYP3A inhibitors may lead to serious safety concerns.  Examples of 
sensitive CYP3A substrates with narrow therapeutic range can be found in Appendix E. 
Investigators should consider switching to an alternative drug, or be alert to the need for dose 
adjustment.
9.8.1
REQUIRED CONCOMITANT MEDICATIONS
Required medications are: TLS prophylaxis, proton pump inhibitors such as omeprazole or 
lansoprazole, anti-thrombotic agents for those on the ORd arm such as aspirin (or other 
anticoagulant or antiplatelet medication such as clopidogrel bisulfate, low-molecular-weight 
heparin, or warfarin) while taking lenalidomide.
Supportive medications for nausea, vomiting and diarrhea are strongly recommended; details 
are provided in Section 9.8.2.
9.8.1.1
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.
9.8.1.2
Tumor Lysis Syndrome
For subjects at risk for TLS (Sezer 2006), the following are required:
Monitoring and Prophylaxis Guidelines:  Oral hydration of 1.5 to 2 liters per 24 hours 
should be instituted in all subjects 24 to 48 hours prior to initiation of therapy in every cycle, 
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and continued throughout days of 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 ISS Stage II/III or rapidly increasing M-protein or 
light chains) or compromised renal function (CrCl < 50 cc/min).  These subjects may be at 
elevated risk for TLS and should be closely monitored.  Uric acid levels should be 
normalized prior to initiation of treatment, if appropriate. 
Subjects with laboratory abnormalities prior to dosing that are consistent with lysis of tumor 
cells should not receive the scheduled dose prior to institution of the aforementioned 
preventative measures.
TLS Laboratory Abnormalities:  Subjects with laboratory abnormalities prior to dosing 
that are consistent with lysis of tumor cells (e.g., as defined by increases of 3 of the 
4 categories:  [1] a 2-fold increase of lactate dehydrogenase [LDH] above the ULN, [2] 
increases in serum creatinine, uric acid, or phosphorus > 50% over baseline, [3] potassium 
> 30% above the ULN; or [4] decreases from baseline of calcium > 20% in the absence of 
concomitant bisphosphonate therapy) (Sezer 2006) should not receive the scheduled dose
prior to institution of the aforementioned preventative measures.
Treatment Guidelines:  If TLS occurs, cardiac rhythm, fluid and serial laboratory 
monitoring should be instituted.  Correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, 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, subject can resume treatment at the initial dose level.
All cases of TLS must be reported to Onyx Therapeutics as an SAE as outlined in the 
protocol.
9.8.1.3
Anti-thrombotic Agents
Antithrombitic agents are required for those on the ORd arm such as aspirin (or other 
anticoagulant or antiplatelet medication such as clopidogrel bisulfate, low-molecular-weight 
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heparin, or warfarin) while taking lenalidomide is required (refer to the Revlimid Prescribing 
Information, Appendix H for more information).
9.8.2
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS
At least 24 hours prior to Cycle 1 Day 1 and for the duration of the study, the following 
medications are strongly recommended per published guidelines and institutional standards 
of care (Bhatt 2008; Bladé 2011; Lonial 2005; Palumbo 2011; Zangari 2008).

Herpes zoster prophylaxis, with acyclovir, valacyclovir, or equivalent antiviral while 
taking oprozomib

Bisphosphonate therapy such as pamidronate or zoledronic acid for skeletal 
prophylaxis
9.8.2.1
Antinausea and Antiemetics
It is strongly recommended that subjects be premedicated with a 5-HT3 inhibitor, such as 
ondansetron or granisetron, at the first onset of nausea and/or vomiting prior to oprozomib 
dosing 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 be used if needed.
9.8.2.2
Antidiarrheals
Grade 1 diarrhea is defined as an increase over baseline of < 4 stools per day or mild increase 
in ostomy output compared with baseline.  For subjects developing any grade of diarrhea, 
Imodium is strongly recommended at the onset of symptoms.  For subjects with persistent 
diarrhea despite the use of Imodium, the addition of 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.
9.8.2.3
Antihypertensives
Dehydration, hypotension and syncope have been reported in subjects treated with 
oprozomib monotherapy and combination therapy.  It is strongly recommended that subjects 
utilizing antihypertensives have their volume status, blood pressure, and antihypertensive 
therapy dosing monitored closely while on protocol directed therapy (see Appendix A and 
Appendix B).
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9.8.3
EXCLUDED CONCOMITANT MEDICATIONS
Concurrent therapy with an approved or investigative anticancer therapeutic is not allowed.
During the study, concurrent glucocorticoid therapy (in addition to dexamethasone) is only 
permitted to treat a concurrent medical condition (e.g., asthma, inflammatory bowel disease, 
or as an antiemetic, etc.) after consultation with the Onyx study medical monitor.
10
STUDY PROCEDURES
All protocol-required tests and observations, along with their chronology, are outlined in the 
Schedule of Assessments (Appendix A and Appendix B).  On-treatment tests and 
observations are summarized below.
10.1
STUDY-SPECIFIC PROCEDURES
10.1.1
VITAL SIGNS
Vital signs measurements include blood pressure, pulse rate, and temperature. Orthostatic 
blood pressure (BP) should be assessed for subjects with evidence of dehydration.  At the 
investigator’s discretion, vital signs monitoring may be extended beyond the time periods 
specified in the Schedules of Assessments (Appendix A and Appendix B). 
10.1.2
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 exam including an 
assessment for peripheral neuropathy (Appendix G). Rectal and pelvic examinations are 
optional.  Eastern Cooperative Oncology Group Performance Status (assessed at the time of 
the physical exam) will be collected (Appendix C).
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.
10.1.3
ELECTROCARDIOGRAM
Twelve-lead electrocardiograms (ECGs) including corrected QT interval (QTc) will be 
performed locally.
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10.2
LABORATORY EVALUATIONS FOR SAFETY
The schedule for laboratory evaluations for safety is outlined in Appendix A and
Appendix B.  The laboratory tests included in the full chemistry panel are defined in
Table 15.
Table 15
Full Chemistry Panels
Full Chemistry Panel
Sodium
Potassium
Calcium
Alkaline phosphatase
Blood urea nitrogen
Uric acid
Lactate dehydrogenase
Creatinine
Chloride
Bicarbonate
Glucose
Total protein
Albumin
Total bilirubin
Alanine aminotransferase
Aspartate aminotransferase
Phosphorous
Magnesium
Calculate or measure creatinine clearance rate
The complete blood count (CBC) with differential includes the following:  hemoglobin, 
hematocrit, white blood cell (WBC) count with complete manual or automated differential 
(total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute 
counts), RBC count, and platelet count.
Coagulation tests include the following:  prothrombin time, activated partial thromboplastin 
time, and international normalized ratio.
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An assessment of platelet adherence, activation, aggregation, and interaction with 
coagulation factors will be conducted utilizing the platelet function analyzer (PFA-100) and 
flow cytometry.  These assessments will be conducted in a subgroup of subjects enrolled in 
the OCyd arm of the Phase 1 or Phase 2 trial.  See Section 10.6 for details of the assessment 
and eligible subject requisites.  See Appendix A and Appendix B for the schedule of these 
assessments.
For both treatment regimens (ORd and OCyd), a serum pregnancy test must be performed 
within 1 day prior to dosing for females of childbearing potential only.  Results must be 
negative prior to dosing.
10.3
DISEASE RESPONSE ASSESSMENTS
The schedule of disease assessments is provided in Appendix A and Appendix B.  Disease 
response will be assessed by the investigator.  Disease response assessments will be 
performed at the end of every 4-week cycle for 24 cycles of ORd or OCyd treatment, and 
will continue every 8 weeks thereafter, until confirmed progressive disease (PD) (see 
Figure 1, Figure 2, and Figure 4 for details on the duration of cyclophosphamide dosing) or 
the start of alternative, nonprotocol antimyeloma therapy.   Response assessment will be 
according to the International Myeloma Working Group - Uniform Response Criteria 
(IMWG-URC) (Appendix F). 
10.3.1
TUMOR RESPONSE ASSESSMENT
The following confirmation assessments are required for all response categories (sCR, CR, 
VGPR, and PR; refer to definitions in Appendix F):

All response categories require 2 consecutive assessments made at any time before
initiation of any new therapy

All response categories require no evidence of progression including new bone
lesions if radiographic studies were performed

Confirmation of CR or sCR requires bone marrow biopsy or aspirate slides (a
confirmatory bone marrow sample is not required)

Extramedullary plasmacytoma evaluation (if present at screening)
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10.4
PHARMACOKINETIC AND PHARMACODYNAMIC MEASUREMENTS
A sparse sampling strategy will be employed for PK sample collection from all subjects for 
both study phases.  Blood samples for determination of plasma concentrations of oprozomib 
and metabolite(s) will be collected from subjects at 2 postdose time points in Cycle 1 Day 1, 
and 1 predose and 2 postdose time points on Cycle 3 Day 1 and Cycle 5 Day 1.  Specific 
sampling times and volumes are detailed in the Laboratory Manual.  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.  Samples may also be used for biomarker assessment.  
Population-based PK analyses will be performed for oprozomib, and may include its 
metabolite(s).  The following PK parameters may be calculated: apparent clearance and 
volume of distribution.
Blood samples for the measurement of proteasome activity in whole blood and peripheral 
blood mononuclear cells (PBMCs) will be collected for all subjects in the Phase 1b portion of 
the study predose and 2 at postdose time points on Cycle 1 Day 1 and Cycle 2 Day 1, and 
predose on Cycle 1 Day 2.  Please refer to the Laboratory Manual for collection times and 
volumes, and processing and shipping of PDn samples.  A fluorogenic substrate assay or 
enzyme-linked immunosorbent assay will be used to measure proteasome activity in whole 
blood and PBMCs.  
10.5
GENOMIC EVALUATIONS
Analysis of genomic biomarkers that may predict for response and resistance following 
treatment with proteasome inhibitors will be performed on all subjects from both phases of 
the study who consent to optional genomic biomarker analysis.  Analysis of biomarkers will 
include analysis of saliva, blood, and a bone marrow aspirate sample at Baseline, prior to 
dosing on Cycle 1 Day 1.  Additional bone marrow samples for biomarkers may be collected 
at the End of Study Treatment visit from all subjects who consent.  End of Study Treatment 
is defined as at disease progression or the end of protocol-defined therapy if end of treatment 
is due to PD.
Bone marrow samples will be collected at Baseline, prior to dosing on Cycle 1 Day 1 for 
isolation of CD138+ cells.  One bone marrow aspirate can be split and used for both a) the 
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central verification of diagnosis and FISH studies (clinical assessment), and b) CD138+ cell 
isolation (biomarker assessment).  Saliva and a blood sample will also be collected at 
Baseline and will serve as a source of normal deoxyribonucleic acid (DNA) for 
determination of tumor-specific genomic alterations.  In addition, a bone marrow aspirate 
will be collected at disease progression for isolation of CD138+ cells.
Whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome 
sequencing (RNA-Seq), and/or other forms of nucleic acid and protein quantification will be 
conducted on isolated tumor (CD138+) cells from bone marrow samples taken at Basline and 
disease progression. In addition, WGS or WES will be performed on a normal tissue sample 
(e.g., saliva or CD3+ T-cells isolated PBMCs) in order to distinguish germline from 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 
immunoglobulin production and protein homeostasis, i.e., IGH, as well as in genes regulated 
by or involved in the activation of nuclear factor kappa light chain enhancer of activated B 
cells (NF-Kappa B) transcription factors.
Immunoglobulin levels in tumor cells will be quantified by qPCR, or immunocytochemistry,
and/or other protein or gene expression 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 outlined in Appendix A and Appendix B.
10.6
PLATELET FUNCTION ASSESSMENT
Platelet function assessments will be conducted in the 10 to 20 subjects enrolled in the OCyd 
arm for whom the platelet function tests below may be performed.  Assessments of platelet 
adherence, activation, aggregation, and interaction with coagulation factors will be conducted 
utilizing the PFA-100 (N = 10).
Subjects participating in this study component:

May not be treated with antiplatelet agents, aspirin or nonsteroidal anti-inflammatory
drugs in the 2 weeks prior to assessment.

Must have a screening and pretest value for platelets of ≥ 100,000/mm3.
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
Must have hematocrit of 28%
The PFA-100 test will be conducted according to the sites’ SOPs on Cycle 1 Day 1 (C1D1)
(prior to protocol mandated dosing), Cycle 1 Day 2 (C1D2), Cycle 4 Day 1 (C4D1), and 
30 days after the completion of oprozomib therapy.
11
STUDY TREATMENT DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY
11.1
STUDY TREATMENT DISCONTINUATION
Subjects will be monitored for AEs for 30 days after the last dose of study treatment
(i.e., oprozomib, lenalidomide/cyclophosphamide or dexamethasone).
Subjects may discontinue study treatment for the following reasons:

Disease progression

Unacceptable toxicity

Noncompliance with study procedures

Treatment with prohibited concomitant medications; details provided in Section 9.8.3

Intercurrent illness that interferes with study assessments

Female subject who becomes pregnant, in which case treatment must be immediately
discontinued
Onyx Therapeutics, or designee must be notified within 24 hours if a subject discontinues all
study treatment. 
If the reason for discontinuation is the occurrence of an AE, the subject will be followed by 
the investigator until such event(s) resolve, stabilize, and according to the investigator’s 
judgment, there is no need for further follow-up.  Subjects who discontinue study treatment 
for reasons other than disease progression may continue on study until disease progression or 
death.  The reason for discontinuation from study treatment will be documented on the eCRF.
In the Phase 1b portion of the study, additional subjects may be enrolled to account for 
subjects who have not had adequate safety evaluations.
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11.1.1
ASSESSMENTS AT END OF STUDY TREATMENT OR EARLY 
DISCONTINUATION
For subjects who discontinue treatment before PD occurs (such as for an AE, noncompliance, 
etc.), disease response assessments will be performed every 4 weeks during the first 
24 months of the study and every 8 weeks thereafter, until confirmed PD, or the start of
alternative, nonprotocol antimyeloma therapy.
11.1.2
FOLLOW-UP FOR SUBJECTS WHO END STUDY TREATMENT 
WITHOUT DOCUMENTED PROGRESSIVE DISEASE
Subjects who have ended study therapy without evidence of progression enter active 
follow-up after completing their End of Study Treatment visit.  They will be followed for 
progression-free survival.  

Disease response assessments will be performed every 4 weeks through 24 months
post C1D1, and then every 8 weeks thereafter, until progression or initiation of new 
antimyeloma therapy whichever occurs first  

Subjects who have consented to evaluate their genomic biomarkers and End of Study 
Treatment prior to progression will have a bone marrow aspirate collected for 
genomic analysis at the time of progression or the start of new antimyeloma therapy, 
whichever comes first
Active 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.  
11.2
ASSESSMENTS AT END OF STUDY TREATMENT OR EARLY 
DISCONTINUATION
For subjects who discontinue treatment before PD occurs (such as for an AE, noncompliance, 
etc.), disease response assessments will be performed every 4 weeks during the first 
24 months of the study and every 8 weeks thereafter, until confirmed PD, or the start of
alternative, nonprotocol antimyeloma therapy.
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12
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
12.1
ADVERSE EVENT REPORTING
12.1.1
DEFINITIONS
An AE is any untoward medical occurrence in a study subject administered an investigational 
product(s) regardless of the causal relationship with treatment.
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 pre-existing condition that occurs after the subject signs the 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 16 below should be used.
Table 16
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
GRADE 3 – Severe
Medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living
GRADE 4 – Life-threatening
Life-threatening consequences; urgent intervention indicated
GRADE 5 – Fatal
Death related to AE
AE = Adverse event; NCI CTCAE = National Cancer Institute - Common Terminology Criteria for 
Adverse Events.
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An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
current IB or prescribing information for a marketed compound 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 
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 pre-existing in nature and part of the subject’s medical history.
Abnormal laboratory findings should be reported as AEs if medical intervention or corrective 
action (e.g., 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.
12.2
CAUSALITY
A suspected adverse reaction 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.  An adverse reaction means any AE caused 
by a drug.  The relationship of the AE to the study drug should be assessed using the 
following criteria: 
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.
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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, concomitant medical, study or nonstudy procedure; and/or

The time 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, lenalidomide,
cyclophosphamide, and dexamethasone.
12.3
ADVERSE EVENTS REPORTING PROCEDURES
12.3.1
GENERAL
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing 
condition or laboratory finding) with an onset date after the subject signs 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 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 the informed consent through 
30 days after receiving the last dose of study drug(s).  If initiation of new anticancer therapy 
occurs within 30 days 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 which are assessed to have a reasonable 
possibility of being associated with study drug.  If the subject discontinues participation in 
the study prior to receiving study drug, AEs will not be reported through the End of Study 
Treatment visit as the subject will not be completing the End of Study Treatment visit.
All AE severity changes will be recorded on the AE CRF as separate events. 
All AEs that are considered related to study drug and all SAEs regardless of relationship to 
study drug, must be followed to resolution or stabilization if improvement is not expected. 
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AEs which 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.
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 Food and Drug Administration (FDA) Form 1572.
12.3.2
DISEASE PROGRESSION
Signs and symptoms related to disease progression (e.g., pathologic fracture in a subject with 
progressive multiple myeloma) should be reported in the appropriate case report form as an 
AE or as an SAE (if the event in question meets the criteria for seriousness). Verbatim terms 
such as “disease progression”, “progressive disease”, etc., should not be reported as AEs or 
SAEs unless the investigator considers the progression to be atypical and/or accelerated.
Similarly, deaths occurring as a result of disease progression or until 30 days after the last 
dose of study drug should be reported on the eCRF intended to capture death information and 
should not be reported as SAEs.  In cases of clinical deterioration due to the primary 
hematologic malignancy, every effort should be made to document disease progression in 
accordance with IMWG-URC (Appendix F). 
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12.4
LONG-TERM FOLLOW-UP
After completion of the End-of-Study-Treatment visit, subjects who have ended study 
therapy prior to progression enter long-term follow-up.  They will be followed for 
progression-free survival.  

Disease response assessments will be performed every 4 weeks through 24 months
post C1D1, and then every 8 weeks thereafter, until progression or initiation of next
therapy, whichever occurs first.

Subjects who have consented to evaluate their genomic biomarkers and End of Study
Treatment prior to progression will have a bone marrow aspirate collected for
genomic analysis at the time of progression or the start of new antimyeloma therapy,
whichever comes first.
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.  
12.5
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 (i.e., it does not include a reaction that, had it occurred in a more severe
form, might have caused death)

Requires inpatient hospitalization or prolongation of an existing hospitalization
(except scheduled hospitalizations for a nonacute, unrelated cause such as elective
surgery)

Results in persistent or significant disability/incapacity (i.e., 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

Important medical events that may not result in death, be life-threatening, or require
hospitalization, may be considered an SAE when, based upon appropriate medical
judgment, jeopardizes the subject and may require medical or surgical intervention to
prevent 1 of the outcomes listed in this definition.
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12.6
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. 
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 for 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.
12.7
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 last dose of study drug received, although not 
considered an SAE, must be reported to Onyx Drug Safety within 24 hours of the 
investigator, designee, or site personnel learning of the event on a Pregnancy Reporting 
Form.  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 informed consent/authorization form for the pregnant partner prior to 
the collection of any pregnancy data.  The investigator will follow the subject or the partner 
of the male subject’s pregnancy until completion or termination of the pregnancy. 
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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 above.  
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 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.  Serious AEs that may occur for these infants will be reported to Onyx 
Drug Safety.
13
STATISTICS
The final analysis will be based upon subject data collected through study discontinuation or 
at the end of maximal treatment duration plus 30 days of safety follow-up, whichever occurs 
first.  Analyses will be based upon the Safety population, defined as subjects receiving 
treatment with any amount of the treatment regimen (oprozomib and dexamethasone with 
either lenalidomide or cyclophosphamide) under study. Additional efficacy analyses will be 
performed using the Response Evaluable population, defined as subjects who are included in 
the Safety population, and have a baseline disease assessment and at least 1 post-baseline 
disease assessment, or dropped out due to AE or other reasons prior to first post-baseline 
tumor assessment.  
All summaries will be presented for each combination regimen by the assigned dose cohort 
level, the combined MTD dose level, as well as for the overall safety population
(i.e., subjects who elect to escalate to the RP2D will be analyzed according to their original 
cohort assignment).
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13.1
STUDY ENDPOINTS
13.1.1
PRIMARY ENDPOINTS
The safety endpoints for the Phase 1b and Phase 2 portions of this study are:

Incidence, nature, and severity of AEs, SAEs, and DLTs (Phase 1b only) of
oprozomib, given in combination with dexamethasone, and either lenalidomide or
cyclophosphamide, as well as changes from baseline in selected laboratory analytes,
vital signs and ECG findings.
The primary efficacy endpoints for the Phase 2 portion of this study are:

Overall response, defined as a best overall response of sCR, CR, VGPR, or PR
according to the IMWG-URC (see Appendix F).

Complete response, defined as a best overall response of either sCR or CR.
13.1.2
SECONDARY ENDPOINTS
The secondary endpoints of this study are:

Population-based PK parameters including, but not limited to, clearance and volume
of distribution will be determined.

Duration of response, defined as the time from first evidence of PR or better to
confirmation of disease progression or death due to any cause.

PFS, defined as the time from the start of treatment to disease progression or death
(due to any cause), whichever comes first.
13.1.3
EXPLORATORY ENDPOINTS
The exploratory endpoints of this study are:

Pharmacodynamic analyses of proteasome inhibition will be determined.

Analyses to potentially identify genetic and gene expression biomarkers that may
predict response and will be conducted.
13.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol violations, and discontinuations from the study will be 
summarized for each combination regimen by the assigned dose cohort, the combined MTD 
dose level, and for all subjects.
Demographic and baseline characteristics, such as age, sex, race, weight, number of prior 
therapies, and baseline ECOG PS, will be summarized using means, standard deviations, 
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medians, and ranges for continuous variables, and proportions for categorical variables.  All 
summaries will be presented for each combination regimen by the assigned dose cohort, the 
combined MTD dose level, and for all subjects.
13.3
INDEPENDENT REVIEW COMMITTEE
An independent review committee will not be employed for this study.
13.4
DATA MONITORING COMMITTEE 
A formal data monitoring committee will not be employed for this study.  However, a CSRC 
will review safety and tolerability data prior to each dose escalation (see Section 4 for more 
details).
13.5
ANALYSIS OF TREATMENT GROUP COMPARABILITY
No analyses of treatment group in terms of demographic and baseline characteristics will be 
performed. 
13.6
STATISTICAL METHODS
13.6.1
EFFICACY ANALYSES
Response assessment data, PFS, and DOR will be summarized for each combination regimen
by the assigned dose cohort, the combined MTD dose level, and for all subjects.  
Further details on efficacy analysis populations are provided in Section 13.  Definitions of 
study endpoints are provided in Section 13.1.
The lower 1-sided exact Clopper-Pearson 90% confidence intervals will be calculated for 
both the ORR and CRR.  In addition, exact Clopper-Pearson 95% confidence intervals will 
be calculated for estimated ORR and CRR.
Summary statistics for DOR and PFS will be calculated using the Kaplan-Meier method. For 
purposes of calculating PFS, the start date for PD is the date at which progression is first 
observed.  For such subjects, the primary analysis of PFS and DOR will be right-censored 
according to the conventions described in Table 17.
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Table 17
Date of Progression or Censoring for Progression-free Survival 
and Duration of Response
Situation
Date of Progression or Censoring
Outcome
No baseline disease assessments
Date of first study drug
Censored
New anticancer treatment started 
before documentation of PD or deatha
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 visits 
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
Deatha or PD between planned disease 
assessments
Date of death or first disease assessment showing PD, 
whichever occurs first
Progressed
Deatha before first disease assessment
Date of deatha
Progressed
DOR = duration of response; PD = progressive disease; PFS = progression-free survival.
a For DOR, death must be due to disease progression, otherwise, both outcomes will be censored at the date of 
last disease assessment.  For PFS, death due to any cause is counted as an event.
The follow-up time for PFS will be summarized by reverse Kaplan-Meier method 
(Schemper 1996).
13.6.2
SAFETY ANALYSES
All subjects who receive any amount of oprozomib, dexamethasone, lenalidomide, or 
cyclophosphamide will be included in the safety analyses.
Safety and tolerability will be assessed through summaries of study drug administration, 
DLTs (Phase 1b only), AEs, changes in selected laboratory analytes, ECGs, and vital signs, 
by dose cohort, the combined MTD dose level, and for all subjects.  
Study drug administration data will be listed by combination regimen and dose cohort, and 
any dose modifications will be flagged.  Means and standard deviations will be used to 
summarize the total dose for each component of study drug received.  All summaries will be 
presented for each combination regimen by the assigned dose cohort, the combined MTD 
dose level, and for all subjects.  
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All AE data will be listed by study site, treatment regimen, dose cohort, subject number, and 
study day.  All AEs occurring on or after treatment on Cycle 1 Day 1 will be summarized by 
mapped term, appropriate thesaurus levels, and NCI-CTCAE (Version 4.03) toxicity grade.  
In addition, all SAEs, including deaths, will be listed separately and summarized.
Relevant laboratory and vital sign (temperature, heart rate, and blood pressure) data will be 
displayed by visit and time (when available), with NCI-CTCAE (Version 4.03) Grade 3 and 
4 values identified where appropriate.  Additionally, all laboratory data will be summarized 
by NCI-CTCAE grade.
13.6.3
PHARMACOKINETIC ANALYSES
Plasma samples for determination of PK will be collected as outlined in the Laboratory 
Manual.  A population PK software program will be used to fit a nonlinear, mixed effects 
model to estimate PK parameters (clearance and volume of distribution), the inter- and 
intrapatient variability and the population variability in the parameter estimates for 
oprozomib and, if deemed necessary, its metabolite(s).  The sparse sampling approach in this 
study, along with results from 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, reduction in the objective function and posterior predictive checks.  Potential
covariates impacting PK of oprozomib including formulation (Oprozomib Tablet versus
Oprozomib ER Tablet), age, gender and body weight, will be assessed. Potential correlations 
of relevant PK parameters with dose, safety or efficacy outcomes, and other covariates will 
be explored.
13.6.4
EXPLORATORY ANALYSES 
Exploratory analyses of the correlation between PDn, genomic biomarkers, and antitumor 
activity may be conducted.
The extent of inactivation of proteasome activity after oprozomib dosing in RBCs and 
PBMCs will be monitored as a PDn parameter.  Pharmacodynamic inhibition will be listed 
by dose cohort, exposure, and response status.  Additional PK and PDn analyses will be 
conducted as appropriate.
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13.7
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 and DOR and details 
about the handling of missing data are described in Section 13.6.1.
Details on the Response Evaluable population are provided in Section 13.
13.8
DETERMINATION OF SAMPLE SIZE
The estimated sample size for the dose-escalation portion of the study of up to 24 subjects 
per combination regimen is based upon standard 3 + 3 dose-escalation rules (see 
Section 9.1.2) and the expectation that 2 to 6 dosing cohorts of 3 to 6 subjects per cohort will 
be required to establish the MTD.  Enrollment of up to 35 additional subjects per 
combination regimen during the Phase 2 portion of the study is based upon the goal of ruling 
out an ORR < 85% and a CRR < 50% based upon the lower 1-sided 90% confidence interval
for each parameter.  This sample size is based on a simulation of a multinomial outcome of 
CR, PR, or PD for various cohort sizes.  With 35 subjects per combination regimen, and an 
assumed true ORR and CRR of 95% and 75%, respectively, the probability of ruling out an 
ORR < 85% and a CRR < 50% with 90% confidence is approximately 88%, from the 
simulation described above.  The same assumptions for ORR and CRR are used in 
determining the sample size for each combination regimen.  Thus, in total, the study will 
enroll up to a sample size of 118 subjects (up to 48 subjects for the Phase 1b portion of the 
study and 70 subjects for the Phase 2 portion of the study).
13.9
INTERIM ANALYSIS
No formal interim analyses will be conducted for this study.
14
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS
14.1
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 regulatory requirements.  The investigator is responsible for 
ensuring that this protocol, the site’s ICF, and any other information that will be presented to 
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potential subjects are reviewed and approved by the appropriate IRB or IEC prior to the 
enrollment of any study subjects.
14.2
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS 
COMMITTEE
The investigator will submit this protocol, the ICF, 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, as appropriate, prior to 
the implementation of changes in this study.  No protocol violations 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/Onyx 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/Onyx.  
Any deviations from the protocol must be fully explained and documented by the 
investigator.
14.3
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.
Onyx 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 Onyx 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 Onyx or its designated representative prior to initiation of the study.  Before implementing 
any study procedure, informed consent shall be documented in the subject case histories and 
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by the use of a written consent form approved by the IRB/IEC and signed and dated by the 
subject or the subject’s legally authorized representative at the time of consent.  A copy of 
the signed informed consent will be given to the subject or subject’s legally authorized 
representative.  The original signed consent must be maintained by the investigator and 
available for inspection by Onyx, its designated representative, or regulatory authority at 
any time.
14.4
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.
14.5
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.
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. 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.
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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 per 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 
stipulations applying to confidentiality of data.  Study records (e.g., 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 until written 
notification is given by the sponsor or designee for destruction.
14.6
CONFIDENTIALITY
All records identifying the subject will be kept confidential and, to the extent permitted by 
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 eCRF.  If the subject name appears on any other document (e.g., pathologist report) or 
study materials (e.g., biopsy tissue slides), then that information must be deleted 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.  Subjects will be informed in writing 
that representatives of the sponsor, 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.
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.
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15
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Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 Expert consensus 
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Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib,
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cyclophosphamide in combination with bortezomib/dexamethasone for remission induction 
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Kropff M, Bisping G, Schuck E, et al.; Deutsche Studiengruppe Multiples Myelom. 
Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose 
oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007;138(3):330–37
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3777–84.
Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple 
myeloma: updated mayo stratification of myeloma and risk adapted therapy (mSMART) 
consensus guidelines 2013. Mayo Clin Proc. 2013;88(4):360–76.
Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and 
dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for 
autologous transplantation. Blood. 2011;118(5):1231–38. 
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, Inc. Kyprolis (carfilzomib) prescribing information. 7/2012.
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(CCd) for newly diagnosed multiple myeloma (MM) patients. Blood. 2012;120(21). ASH 
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Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed 
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29−37. Erratum in: Lancet Oncol. 2010;11(1):14.
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Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral 
cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin 
Oncol. 2008;26(29):4777–83. 
Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction 
therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115(16):3416–17.
Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone 
induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical 
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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. 2006a;108(11). ASH Annual Meeting 2006. Abstract 405.
Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility 
of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. 
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Sezer O, Vesole DH, Singhal S, et al. Bortezomib-induced tumor lysis syndrome in multiple 
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Simon R, Freidlin B, Rubinstein L, et al. Accelerated titration designs for phase I clinical 
trials in oncology. J Natl Cancer Inst. 1997;89(15):1138–47.
Volpe DA, Warren MK. Myeloid clonogenic assays for comparison of the in vitro toxicity of 
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Weber DM, Chen C, Niesvizky R, et al. Multiple Myeloma (009) Study Investigators. 
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl 
J Med. 2007;357(21):2133–42.
Zangari M, Guerrero J, Cavallo F, et al. Hemostatic effects of bortezomib treatment in 
patients with relapsed or refractory multiple myeloma. Haematologica. 2008;93(6):953–54.
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3028−38.
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APPENDIX A
SCHEDULE OF STUDY ASSESSMENTS FOR 5/14 DOSING SCHEDULE
Visit
Screening
Baseline
Cycle 1
Cycle 2–24
Cycle 25+
End of 
Study 
Treatmentb
Day
-21 to -1
(pre-C1D1 
dose)
Day 1 Day 2
Day 
3, 4
Day 5
Day 
6, 7
Day 
8 ± 1
Day 
9‒14
Day 
15 ± 1
Day 
16–21
Day 
22–28 Day 1
Day 
2–14
Day 
15 ± 1
Day 
22–28
Day
1
Day 
22–28a
Written Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Previous Treatment History
X
Physical Examinationc
X
X
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
Neurological Assessment
(BPNS and CTCAE Grading)d
X
X
X
Vital Signs
X
Xe
Xe
Xe
X
Xe
X
Xf
Xf
X
12–lead ECG (Local) 
X
X
X
Urinalysisg
X
X
Serum Chemistryh
X
Xi
X
X
X
X
Xi
X
Xi
X
CBC with Diff and Plateletsj
X
Xj
X
X
X
X
Xj
X
Xj
X
Coagulation Testsk
X
Xk
Xk
Xk
Pregnancy Testl
X
X
X
X
X
X
X
X
X
SPEP/UPEP/Immunofixationm
X
X
X
X
X
β2 Microglobulin
X
SFLC assay and ration
X
X
X
X
X
Skeletal Surveyo
X
X
X
X
X
Plasmacytoma Evaluationp
X
X
X
X
X
Bone Marrow Aspirate q
X
Biopsy (FISH Analyses)q
X
Optional– Genomic 
Biomarker Assessment:  
Bone Marrow Aspirater
X
X
Optional – Genomic 
Biomarker Assessment:  
Bloodr
X
Optional – Genomic 
Biomarker Assessment:  
Salivar
X
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APPENDIX A
SCHEDULE OF STUDY ASSESSMENTS FOR 5/14 DOSING SCHEDULE (CONT’D)
Visit
Screening
Baseline
Cycle 1
Cycle 2–24
Cycle 25+
End of 
Study 
Treatmentb
Day
-21 to -1
(pre-C1D1 
dose)
Day 1
Day
2
Day 
3, 4
Day
5
Day 
6, 7
Day 
8 ± 1
Day 
9-14
Day 
15 ± 1
Day 
16–21
Day 
22–28
Day 
1a
Day 
2–14
Day 
15 ± 1
Day 
22–28
Day
1
Day 
22–28a
Blood for PKs
X
X
Blood for PDn Assayt
X
X
X
Treatment Regimen 1 (ORd) Dosingu:
Oprozomib
X
X
X
X
X
X
X
X
X
X
Lenalidomide
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
X
X
AEs and Con Medsv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cycle 1 Follow-up Telephone 
Call to Subject
Xw
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; CR = complete response; 
CrCl = creatinine clearance; CRF = case report form; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; eCRF = electronic case 
report form; FCBP = females of child-bearing potential; FISH = fluorescent in-situ hybridization; MRI = magnetic resonance imaging; ORd = oprozomib, lenalidomide, and dexamethasone; 
PD = progressive disease; PDn = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; SFLC = serum free light chain; SPEP = serum protein electrophoresis; UPEP = urine 
protein electrophoresis.
a
Following completion of 24 cycles of ORd or OCyd treatment, disease response assessments will continue every 8 weeks until confirmed PD.  For subjects who discontinue treatment before PD occurs 
(such as for an AE, noncompliance, etc.), disease response assessments will be performed every 4 weeks during the first 24 months of the study and every 8 weeks thereafter, until confirmed PD, or 
the start of alternative, non-protocol antimyeloma therapy.  
b
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.  The same methods of disease assessment must be used throughout the study. If disease assessments show disease progression, assessments do not need to be repeated with End of Study 
Treatment Assessments.
c
Complete physical exams will be performed during Screening and at the End of Study Treatment visit.  All other physical exams will be limited physical exams.  A complete physical examination will 
include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief neurological exam including an assessment for peripheral neuropathy.  Rectal and pelvic 
examinations are optional.  Eastern Cooperative Oncology Group performance status (assessed at the time of the physical exam) will be collected during a complete physical exam.  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.
d
Neurological assessments (BPNS, and if applicable, record adverse events with CTCAE grading; Refer to Appendix G), and if applicable, record adverse events with CTCAE grading) will be 
performed at Screening, on Day 1 for Cycles 2+ until oprozomib is discontinued and at the End of Study Treatment. 
e
Measure on day of dosing, prior to the administration of oprozomib dose and at 30 minutes +/- 10 min, 1 hour +/- 15 min, and 2 hours +/- 15 min after each oprozomib dose (Cycle 1 Days 1 through 5 
and Day 15).  On days when oprozomib is not administered, vital signs will be measured anytime during the clinic visit.  At the investigator’s medical discretion, vital signs monitoring may be 
extended beyond the time periods specified above. Orthostatic BP should be assessed for subjects with evidence of dehydration during site visits.
f
Cycles 2 and higher, vital signs are required on the day of dosing, prior to the administration of oprozomib dose. Orthostatic BP should be assessed for subjects with evidence of dehydration during site 
visits.
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APPENDIX A
SCHEDULE OF STUDY ASSESSMENTS FOR 5/14 DOSING SCHEDULE (CONT’D)
g
Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein.
h
Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, albumin, total 
bilirubin, ALT, AST, phosphorous, and magnesium).  Calculate or measure CrCl. 
i
Day 1 labs can be drawn up to 3 days prior to Day 1.
j
Complete blood count (CBC) with differential includes the following:  hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential (total neutrophils, 
lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell count, and platelet count.
k
Coagulation tests include the following:  prothrombin time, activated partial thromboplastin time, and international normalized ratio.
l
For both treatment regimens (ORd and OCyd):  Screening pregnancy testing for females of childbearing potential (FCBP) must have a sensitivity of at least 25 mIU/mL with 2 medically supervised 
tests performed before lenalidomide or cyclophosphamide dosing starts.  One test must be obtained within 10 through 14 days and 1 test within 24 hours prior to the start of lenalidomide or 
cyclophosphamide on Cycle 1 Day 1 (C1D1).  A medically supervised negative serum pregnancy test will be done within 24 hours prior to each cycle of lenalidomide or cyclophosphamide dosing.
Negative serum pregnancy tests will also be performed on Day 8, Day 15, and between Days 22 through 28 of Cycle 1; on Day 1 for Cycles 2 through 24; and at the End of Study Treatment visit, in 
FCBP only.  Pregnancy tests will be repeated on Day 1 and Day 15 of Cycle 2 through 24 if menses are irregular or not present in FCBP.  A medically supervised serum pregnancy test for FCBP must 
be obtained during Cycle 26 at 4 weeks after the last dose of lenalidomide or cyclophosphamide.
m SPEP and UPEP (24-hour assessment, no substitute method is acceptable) is required for all subjects at Screening before study drug treatment.  Thereafter, SPEP is to be done at each assessment for 
all subjects.  Obtain blood for SPEP, serum immunofixation, serum immunoglobulin levels, and serum FLCs and urine sample for UPEP and immunofixation.  UPEP with 24-hour urine collection is 
required at each assessment only if screening UPEP shows measurable paraprotein in the urine.  If screening UPEP is negative, spot urine is required at each assessment.  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 the absence of paraprotein.  Immunofixation is required at next 
assessment only if SPEP or UPEP results are zero/undetectable.  Subjects with negative serum and urine M-proteins are required to complete FLC at each time point.
n
Serum free light chain:  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.  
o
Baseline skeletal survey does not need to be repeated if previously done within 6 weeks of consent.  Skeletal survey will include 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 screening, bone lesion(s) must be monitored throughout the study per IMWG response criteria and the skeletal 
survey will be only repeated if worsening clinical symptoms suggest PD, or as clinically indicated.
p
Extramedullary plasmacytoma evaluation will be conducted at Screening only if a lesion is suspected clinically.  Baseline plasmacytoma assessment does not need to be repeated if previously done 
within 6 weeks of consent.  Only measurable plasmacytomas will be followed for response and progression.  Measurable lesions must have a longest diameter of at least 1 cm and the product of cross 
diameter is at least 1 cm2.  Plasmacytomas of lessor size are considered non measurable.  If an extramedullary plasmacytoma is detected, evaluation will be repeated during treatment as clinically 
indicated, or to confirm a response of PR or better, or to confirm PD.  The same technique (which may include clinical evaluation by palpation, ultrasound, x-ray, CT scan, MRI, or PET) should be 
employed for each measurement of plasmacytoma dimensions as clinically appropriate (Appendix F).  Bi-dimensional lesion measurements must be performed and recorded in the designated eCRF. 
q
Bone marrow aspiration and/or biopsy are required for all subjects at Screening to confirm diagnosis and eligibility.  Bone marrow aspiration can be collected up to 8weeks prior to C1D1 in Phase 1b 
and can be collected up to 21 days prior to C1D1 in Phase 2.  In Phase 1, the FISH assessment on the Screening bone marrow may be performed locally. Subsequent FISH assessments must be 
performed locally and assessed centrally. In Phase 2 all FISH assessments, including the baseline assessment, performed prior to dosing on C1D1, must be assessed centrally. Please see the lab 
manual for processing information. Central FISH assessment reports will not be provided to sites. Additional bone marrow aspirates will need to be obtained and submitted for local assessment.
r
Optional genomic biomarker samples:  For subjects who consent to participate and who are eligible for the study, bone marrow aspirate (obtained from the bone marrow aspirate for FISH analysis; no 
new bone marrow sample is required at baseline), blood, and saliva samples will be collected at baseline prior to dosing on C1D1.  Bone marrow aspirate will also be collected for isolation of CD138+ 
cells at the end of protocol-defined therapy if end of treatment is due to PD; bone marrow will be collected only from subjects consenting to genomic biomarker analyses. 
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APPENDIX A
SCHEDULE OF STUDY ASSESSMENTS FOR 5/14 DOSING SCHEDULE (CONT’D)
s
Blood for PK for subjects will occur at two postdose time points on C1D1, and one predose and two postdose time points on Cycle 3 Day 1 (C3D1) and Cycle 5 Day 1 (C5D1).  Sampling times and 
volumes are provided in the Laboratory Manual.  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.
t
Blood for measurement of proteasome activity in whole blood and PBMCs will only be collected in Phase 1b.  Samples will be collected predose and at 2 at postdose time points on C1D1 and Cycle 2 
Day 1 (C2D1), and predose on Cycle 1 Day 2 (C1D2).  Sampling times and volumes are provided in the Laboratory Manual.
u
Treatment Regimen 1 (ORd):  Oprozomib treatment will be administered on Days 1 through 5 and 15 through 19 during 28-day cycles until disease progression, unacceptable toxicity, or study 
treatment discontinuation for any reason.  Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle up to Cycle 24.  After Cycle 1, the 
dexamethasone dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the investigator.  On days when both oprozomib and dexamethasone are administered (i.e., on 
Days 1, 2, 15, and 16 of each cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  Lenalidomide will be administered orally at a dose of 25 mg, on Days 1 through 21 of 
each 28 day cycle up to Cycle 24.  Subjects may take lenalidomide following oprozomib administration; however it is recommended that they take lenalidomide at approximately the same time each 
day.  On days when oprozomib is not administered, subjects should take lenalidomide at approximately the same time in the day for consistency.
v
Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 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.
w For subjects in the Ph 1b portion:  The study nurse (or designee) will call the subject on Cycle 1 Days 3 and 4, approximately 6-10 hours after the expected study drug dosing time to follow up on 
dosing compliance and to collect start, stop, and duration times as well as severity of any AEs, if applicable.
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APPENDIX B
SCHEDULE OF STUDY ASSESSMENTS FOR 2/7 DOSING SCHEDULE
Visit
Screening
Baseline
Cycle 1
Cycle 2–24
Cycle 25+
End of 
Study 
Treatmentb
Day
-21 to -1
(pre-C1D1 
dose)
Day 1 Day 2
Day 
3, 4
Day 5
Day 
6, 7
Day 8 Day 9
Day 
15
Day 
16
Day 
22–28 Day 1
Day 
2–14
Day 
15
Day 
22–28
Day
1
Day 
22–28a
Written Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Previous Treatment History
X
Physical Examinationc
X
X
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
Neurological Assessment
(BPNS and CTCAE Grading)d
X
X
X
Vital Signs
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
X
Xf
Xf
X
12–lead ECG (Local) 
X
X
Urinalysisg
X
X
Serum Chemistryh
X
Xi
X
X
X
X
Xi
X
Xi
X
CBC with Diff and Plateletsj
X
Xj
X
X
X
X
Xj
X
Xj
X
Coagulation Testsk
X
Xk
Xk
Xk
Pregnancy Testl
X
X
X
X
X
X
X
X
X
SPEP/UPEP/Immunofixationm
X
X
X
X
X
β2 Microglobulin
X
SFLC assay and ration
X
X
X
X
X
Skeletal Surveyo
X
X
X
X
X
Plasmacytoma Evaluationp
X
X
X
X
X
Bone Marrow Aspirateq
X
Biopsy (FISH Analyses)q
X
Optional– Genomic 
Biomarker Assessment:  
Bone Marrow Aspirater
X
X
Optional – Genomic 
Biomarker Assessment:  
Bloods
X
Optional – Genomic 
Biomarker Assessment:  
Salivar
X
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APPENDIX B
SCHEDULE OF STUDY ASSESSMENTS FOR 2/7 DOSING SCHEDULE (CONT’D)
Visit
Screeninga
Baseline
Cycle 1
Cycle 2–24
Cycle 25+
End of 
Study 
Treatmentb
Day
-21 to -1
(pre-C1D1 
dose)
Day 1
Day
2
Day 
3, 4
Day
5
Day 
6, 7
Day 
8
Day 
9
Day 
15
Day 
16
Day 
22–28
Day 
1a
Day 
2–14
Day 
15
Day 
22–28
Day
1
Day 
22–28b
Blood for PKs
X
X
Blood for PDn Assayt
X
X
X
Blood for Platelet Assessment 
(OCyd arm only) u
X
X
X
X
X
X
Treatment Regimen 1 (ORd) Dosingv:
Oprozomib
X
X
X
X
X
X
X
X
X
X
X
Lenalidomide
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
X
Treatment Regimen 2 (OCyd) Dosingw:
Oprozomib
X
X
X
X
X
X
X
X
X
X
X
Cyclophosphamide
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs and Con Medsx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cycle 1 Follow-up Telephone 
Call to Subject
Xy
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood count; CR = complete response; 
CrCl = creatinine clearance; CRF = case report form; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; eCRF = electronic case 
report form; FCBP = females of child-bearing potential; FISH = fluorescent in-situ hybridization; MRI = magnetic resonance imaging; OCyd = oprozomib, cyclophosphamide, and dexamethasone; 
ORd = oprozomib, lenalidomide, and dexamethasone; PD = progressive disease; PDn = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; SFLC = serum free light 
chain; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis.
a Following completion of 24 cycles of ORd or OCyd treatment, disease response assessments will continue every 8 weeks until confirmed PD.  For subjects who discontinue treatment before PD 
occurs (such as for an AE, noncompliance, etc.), disease response assessments will be performed every 4 weeks during the first 24 months of the study and every 8 weeks thereafter, until confirmed 
PD, or the start of alternative, non-protocol antimyeloma therapy.  
b 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.  The same methods of disease assessment must be used throughout the study. If disease assessments show disease progression, assessments do not need to be repeated with End of Study 
Treatment Assessments.
c Complete physical exams will be performed during Screening and at the End of Study Treatment visit.  All other physical exams will be limited physical exams.  A complete physical examination will 
include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief neurological exam including an assessment for peripheral neuropathy.  Rectal and pelvic 
examinations are optional.  Eastern Cooperative Oncology Group performance status (assessed at the time of the physical exam) will be collected during a complete physical exam.  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.
d Neurological assessments (BPNS, and if applicable, record adverse events with CTCAE grading; [Appendix G]) will be performed at Screening, on Day 1 for Cycles 2+ until oprozomib is 
discontinued and at the End of Study Treatment. 
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APPENDIX B
SCHEDULE OF STUDY ASSESSMENTS FOR 2/7 DOSING SCHEDULE (CONT’D)
e Measure on day of oprozomib dosing prior to the administration of oprozomib dose and at 30 minutes +/- 10 min, 1 hour +/- 15 min, and 2 hours +/- 15 min after each oprozomib dose (Cycle 1 Days 1 
and 2, 7, and 8, 15, and 16).  On days when oprozomib is not administered (Cycle 1 Days 3, 4, and 5), vital signs will be measured anytime during the clinic visit.  At the investigator’s medical 
discretion, vital signs monitoring may be extended beyond the time periods specified above. Orthostatic BP should be assessed for subjects with evidence of dehydration during site visits.
f Cycles 2 and higher, vital signs are required on the day of dosing, prior to the administration of oprozomib dose.  Orthostatic BP should be assessed for subjects with evidence of dehydration during 
site visits.
g Subjects with urine positive for protein (> than trace) will need to collect a 24-hour urine sample for creatinine and protein.
h Full chemistry panel (sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, albumin, total 
bilirubin, ALT, AST, phosphorous, and magnesium).  Calculate or measure CrCl. 
i
Day 1 labs can be drawn up to 3 days prior to Day 1.
j
Complete blood count (CBC) with differential includes the following:  hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential (total neutrophils, 
lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell count, and platelet count.
k Coagulation tests include the following:  prothrombin time, activated partial thromboplastin time, and international normalized ratio.
l
For both treatment regimens (ORd and OCyd):  Screening pregnancy testing for females of childbearing potential (FCBP) must have a sensitivity of at least 25 mIU/mL with 2 medically supervised 
tests performed before lenalidomide or cyclophosphamide dosing starts.  One test must be obtained within 10 through 14 days and one test within 24 hours prior to the start of lenalidomide or 
cyclophosphamide on C1D1.  A medically supervised negative serum pregnancy test will be done within 24 hours prior to each cycle of lenalidomide or cyclophosphamide dosing.  Negative serum 
pregnancy tests will also be performed on Day 8, Day 15, and between Days 22 through 28 of Cycle 1; on Day 1 for Cycles 2 through 24; and at the End of Study Treatment visit, in FCBP only.
Pregnancy tests will be repeated on Day 1 and Day 15 of Cycle 2 through 24 if menses are irregular or not present in FCBP.  A medically supervised serum pregnancy test for FCBP must be obtained 
during Cycle 26 at 4 weeks after the last dose of lenalidomide or cyclophosphamide.
m SPEP and UPEP (24-hour assessment, no substitute method is acceptable) is required for all subjects at Screening before study drug treatment.  Thereafter, SPEP is to be done at each assessment for 
all subjects. Obtain blood for SPEP, serum immunofixation, serum immunoglobulin levels, and serum FLCs and urine sample for UPEP and immunofixation.  UPEP with 24-hour urine collection is 
required at each assessment only if screening UPEP shows measurable paraprotein in the urine.  If screening UPEP is negative, spot urine is required at each assessment.  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 the absence of paraprotein.  Immunofixation is required at next 
assessment only if SPEP or UPEP results are zero/undetectable.  Subjects with negative serum and urine M-proteins are required to complete FLC at each time point.
n Serum free light chain:  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.  
o Baseline skeletal survey does not need to be repeated if previously done within 6 weeks of consent.  Skeletal survey will include 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 screening, bone lesion(s) must be monitored throughout the study per IMWG response criteria and the skeletal 
survey will be only repeated if worsening clinical symptoms suggest PD, or as clinically indicated.
p Extramedullary plasmacytoma evaluation will be conducted at Screening only if a lesion is suspected clinically.  Baseline plasmacytoma assessment does not need to be repeated if previously done 
within 6 weeks of consent.  Only measurable plasmacytomas will be followed for response and progression.  Measurable lesions must have a longest diameter of at least 1 cm and the product of cross 
diameter is at least 1 cm2.  Plasmacytomas of lessor size are considered non measurable.  If an extramedullary plasmacytoma is detected, evaluation will be repeated during treatment as clinically 
indicated, or to confirm a response of PR or better, or to confirm PD.  The same technique (which may include clinical evaluation by palpation, ultrasound, x-ray, CT scan, MRI, or PET) should be 
employed for each measurement of plasmacytoma dimensions as clinically appropriate (refer to Appendix F).  Bi-dimensional lesion measurements must be performed and recorded in the designated 
eCRF. 
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APPENDIX B
SCHEDULE OF STUDY ASSESSMENTS FOR 2/7 DOSING SCHEDULE (CONT’D)
q Bone marrow aspiration and/or biopsy are required for all subjects at Screening to confirm diagnosis and eligibility.  Bone marrow aspiration can be collected up to 8 weeks prior to C1D1 in Phase 1b 
and can be collected up to 21 days prior to C1D1 in Phase 2.  In Phase 1, the FISH assessment on the Screening bone marrow may be performed locally. Subsequent FISH assessments must be 
performed locally and assessed centrally. In Phase 2 all FISH assessments, including the baseline assessment, performed prior to dosing on C1D1, must be assessed centrally. Please see the lab 
manual for processing information. Central FISH assessment reports will not be provided to sites. Additional bone marrow aspirates will need to be obtained and submitted for local assessment.
r Optional genomic biomarker samples:  For subjects who consent to participate and who are eligible for the study, bone marrow aspirate (obtained from the bone marrow aspirate for FISH analysis; no 
new bone marrow sample is required at baseline), blood, and saliva samples will be collected at baseline prior to dosing on C1D1.  Bone marrow aspirate will also be collected for isolation of CD138+ 
cells at the end of protocol-defined therapy if end of treatment is due to PD; bone marrow will be collected only from subjects consenting to genomic biomarker analyses. 
s Blood for PK for subjects will occur at 2 postdose time points on C1D1, and one predose and two postdose time points on C3D1 and C5D1.  Sampling times and volumes are provided in the 
Laboratory Manual. 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.
t
Blood for measurement of proteasome activity in whole blood and PBMCs will only be collected in Phase 1b.  Samples will be collected predose and at 2 postdose time points on C1D1 and C2D1, 
and predose on C1D2.  Sampling times and volumes are provided in the Laboratory Manual.
u For OCyd subjects participating in the assessment of platelet function, samples for the assessment of platelet adherence, activation, aggregation, and interaction with coagulation factors will be 
conducted utilizing the platelet function analyzer (PFA-100 on C1D1 prior to protocol mandated therapy, C1D2, C1D5, C1D8, C4D1 and End of Study Treatment.
v Treatment Regimen 1 (ORd):  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.  Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle up to Cycle 24.  After Cycle 1, the dexamethasone 
dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the investigator.  On days when both oprozomib and dexamethasone are administered (i.e., on Days 1, 2, 8, 9, 15, 
16, 22, and 23 of each cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  Lenalidomide will be administered orally at a dose of 25 mg on Days 1 through 21 of each 28 
day cycle up to Cycle 24.  Subjects may take lenalidomide following oprozomib administration; however it is recommended that they take lenalidomide at approximately the same time each day.  On 
days when oprozomib is not administered, subjects should take lenalidomide at approximately the same time in the day for consistency.
w Treatment Regimen 2 (OCyd): Oprozomib treatment will be administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 during 28-day cycles for up to 8 cycles or until disease progression, unacceptable 
toxicity, or study treatment discontinuation for any reason.  Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day treatment cycle up to Cycle 8.  After 
Cycle 1, the dexamethasone dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the investigator.  On days when both oprozomib and dexamethasone are 
administered (i.e., on Days 1, 2, 8, 9, 15, 16, 22, and 23 during of each cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  Cyclophosphamide will be administered orally 
at 300 mg/m2 (up to a maximum of 600 mg) on Days 1, 8, and 15 of each cycle for a total of 8 cycles.  Subjects may take cyclophosphamide following oprozomib administration; however it is 
recommended that they take cyclophosphamide concurrently with oprozomib at approximately the same time each day.  On days when oprozomib is not administered, subjects should take 
cyclophosphamide at approximately the same time in the day for consistency.
x Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 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.
y For subjects in the Ph 1b portion:  The study nurse (or designee) will call the subject on Cycle 1 Days 3 and 4, approximately 6–10 hours after the expected study drug dosing time to follow up on 
dosing compliance and to collect start, stop, and duration times as well as severity of any AEs, if applicable.
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APPENDIX C
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCALE
Grade
Description
0
Fully active, able to carry on all predisease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, 
office work).
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Death
Source:  Oken 1982.
Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair
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APPENDIX D
NCI-CTCAE VERSION 4.03
Common Terminology Criteria for Adverse Events (CTCAE)
of the National Cancer Institute (NCI) v4.03
Publish Date:  14 June 2010
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
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APPENDIX E
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES WITH 
NARROW THERAPEUTIC RANGE
CYP3A4 substrates with narrow therapeutic range refers to drugs whose exposure-response 
indicates that increases in their exposure levels by the concomitant use of CYP3A4 inhibitors 
may lead to serious concerns.  Investigators should seriously consider switching to an alternative 
agent whenever possible, or exercise caution and be alert for signs requiring dose modification.  
The following list provides examples of CYP3A4 substrates with narrow therapeutic range (note 
that this is not an exhaustive list):
Alfentanil
Diergotamine
Quinidine
Astemizolea
Ergotamine
Sirolimus
Cisapride1
Fentanyl
Tacrolimus
Cyclosporine
Pimozide
Terfenadine1
a Not available in the United States.
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APPENDIX F
RESPONSE CRITERIA FOR MULTIPLE MYELOMA
Summary of International Myeloma Working Group - Uniform Response Criteria 
(IMWG-URC)
Response 
Subcategorya
Response Criteria
sCRb

Negative immunofixation on the serum and urine and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrow and

Normal SFLC ratio and

Absence of clonal cells in bone marrowc
CRb

Negative immunofixation on the serum and urine and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrow
VGPRb, d

Serum and urine M-protein detectable by immunofixation, but not on electrophoresis 
or

≥90% reduction in serum M-component with urine M-component < 100 mg per 
24 hours
PRb, d

≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 
≥90% or to < 200 mg per 24 hours

If the serum and urine M-protein are not measurable, a decrease ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria.

If the serum and urine M-protein are not measurable, a decrease ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria.

If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is 
also requiredd, e
Stable

Not meeting criteria for sCR, CR, VGPR, PR, or PD 
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Summary of International Myeloma Working Group - Uniform Response Criteria 
(IMWG-URC) (cont’d)
Response 
Subcategorya
Response Criteria
PDe
Any one or more of the following:

Increase of ≥ 25% from lowest response value in:
o
Serum M-component (absolute increase must be ≥0.5 g/dL) and/or
o
Urine M-component (absolute increase must be ≥200 mg per 24 hours) and/or
o
Only in subjects without measurable serum and urine M-protein levels:  the 
difference between involved and uninvolved FLC levels (absolute increase must 
be > 10 mg/dL)
o
Only in subjects without measurable serum and urine M-protein levels and 
without measurable disease by FLC levels, bone marrow PC percentage
(absolute percentage must be ≥10%)

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 
2.87 mmol/L) attributed solely to the plasma cell proliferative disorder
Sources:  Durie 2006; Rajkumar 2011.
CR = complete response; sCR = stringent complete response; FLC = serum free light chain; PD = progressive 
disease; PR = partial response; SFLC = serum free light chain; VGPR = very good partial response.
a
Subjects with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to 
meet response criteria in both UPEP and SPEP in order to qualify for a PR or better.  Conversely, it should 
be noted that criteria for PD only need to be met and confirmed in 1 parameter.
b
All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before 
the institution of any new therapy, as well as no known evidence of progressive or new bone lesions if 
radiographic studies were performed.  Radiographic studies are not required to satisfy these response 
requirements.  Bone marrow assessments are not required to be confirmed by repeat testing.
c
Presence/absence of clonal cells is based upon the /ratio.  An abnormal /ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  
An abnormal ratio reflecting presence of an abnormal clone is /of > 4:1 or < 1:2.
d
Response criteria for all categories and subcategories of response except CR and VGPR are applicable only 
to subjects that have “measurable” disease defined by at least one of SPEP ≥0.5 g/dL) or UPEP ≥200 mg 
per 24 hours; except for assessment of sCR, CR, or VGPR, subjects with measurable disease restricted to 
SPEP will need to be followed only by SPEP.  Correspondingly, subjects with measurable disease 
restricted to UPEP will need to be followed only by UPEP.
e
Determination of PD while on study requires 2 consecutive assessments made at any time before 
classification of PD and/or the institution of new therapy.  Serum M-component increases of ≥1 g/dL is
sufficient to define progression if starting M-component is ≥5 g/dL. 
f
Plasmacytomas: A definite increase in the size is defined as a ≥ 50% increase as measured serially by the 
sum of the products of the cross-diameters of the measurable lesion. A plasmacytoma is considered 
measurable if the longest diameter is at least 1 cm and the product of the cross diameters is at least 1 cm2.  
Plasmacytomas of lesser size will be considered nonmeasurable.
g
The requirement for bi-directional measurements will only be applied to plasmacytomas.
h
The plasmacytoma specifications for PD are based on the sponsor’s interpretation of the IMWG-URC and 
practical considerations for study execution.
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APPENDIX G
ACTG BRIEF PERIPHERAL NEUROPATHY
SCREENING TOOL
Source: NIAID Adult AIDS Clinical Trials Group
1. Elicit Subjective Symptoms
Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) to 10 
(most severe) for right and left feet and legs. Enter the score for each symptom in the columns 
marked R (right lower limb) and L (left lower limb). If a symptom has been present in the past, but 
not since the last visit, enter "00 - Currently Absent." If the symptom has never been present, enter 
"11 - Always Been Normal."
Always Been Normal
Currently Absent
Mild ←→Severe
11
00
01
02
03
04
05
06
07
08
09
10
Symptoms
R
L
a. Pain, aching, or burning in feet, legs
b. "Pins and needles" in feet, legs
c. Numbness (lack of feeling) in feet, legs
2. Grade Subjective Symptoms
Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy 
score. If all severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."
Subjective Sensory Neuropathy Score (based on highest severity rating)
01−03 = grade of 1
04−06 = grade of 2
07−10 = grade of 3
11 or 00 = grade of 0
R
L
3. Evaluate Perception of Vibration
Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place the vibrating 
tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she can recognize 
the vibration or "buzzing" quality of the tuning fork. Again, compress the ends of the tuning fork just 
hard enough that the sides touch. Immediately place the vibrating tuning fork gently but firmly on the 
top of the distal interphalangeal (DIP) joint of one great toe and begin counting the seconds. Instruct
the subject to tell you when the "buzzing" stops. Repeat for the other great toe.
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APPENDIX H
REVLIMID PRESCRIBING INFORMATION
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=5fa97bf5-28a2-48f1-8955-
f56012d296be&type=pdf&name=5fa97bf5-28a2-48f1-8955-f56012d296be
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APPENDIX I
CYCLOPHOSPHAMIDE PRESCRIBING INFORMATION
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=367b47d7-c4de-4b39-bd3a-
69c29d80396f&type=pdf&name=367b47d7-c4de-4b39-bd3a-69c29d80396f
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APPENDIX J
DEXAMETHASONE PRESCRIBING INFORMATION
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?id=5672&type=pdf&name=537b424a-3e07-4
c81-978c-1ad99014032a
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APPENDIX K
REVLIMID RISK EVALUATION AND MITIGATION STRATEGY 
(REMS)™PROGRAM
http://www.revlimidrems.com/pdf/REV_Prescriber_Guide.pdf
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APPENDIX K: 
SUMMARY OF CHANGES IN PROTOCOL OPZ003 
AMENDMENT 1 
Study OPZ003 was amended to add a treatment regimen of oprozomib, cyclophosphamide, 
and dexamethasone (OCyd), in addition to the existing treatment regimen of oprozomib, 
lenalidomide, and dexamethasone (ORd).  This and other key changes in Amendment 1 are 
listed below:  
1. Global change:  The study/protocol title was updated to reflect the addition of the
OCyd combination regimen.
2. Global change:  “Cyclophosphamide” was added as appropriate throughout the
protocol to reflect the addition of the cyclophosphamide (in the OCyd treatment
regimen) to the study design.
3. Global change:  References to “each combination regimen”, “each treatment
regimen”, “ORd”, and “OCyd” were added to distinguish and further clarify between
the two treatment regimens.
4. Study Synopsis (Objectives) and Section 3:  Changed “safety and tolerability of
oprozomib” secondary objective to primary objective for both phases of the study.
Revised text to provide clarification on the study objectives.
5. Study Synopsis (Study Design) and Section 4:  Added text to provide details
regarding the OCyd treatment regimen, and added a study schema for additional
clarity on the study design.
6. Study Synopsis (Study Design) and Section 9.1.3:  Updated text to provide additional
clarification on missed doses of study drug and subject replacement, and to reflect the
addition of the OCyd treatment regimen.
7. Study Synopsis (Study Design; Duration of Study/Treatment Periods; Criteria for
evaluation:  Efficacy variables), Section 4.2, Section 4.6, Section 9.1.3, and Section
10.3:  Updated schedule for disease response assessments to reflect the addition of the
OCyd treatment regimen, and for consistency between the two combination regimens.
8. Study Synopsis (Number of Investigational Sites) and Section 4.4:  Updated the
number of investigational sites to reflect the addition of the OCyd treatment regimen.
9. Study Synopsis (Planned Number of Subjects) and Section 4.5:  Updated the sample
sizes to reflect the addition of the OCyd treatment regimen.
10. Study Synopsis (Duration of Study/Treatment Periods) and Section 4.6:  Updated the
estimated study duration and treatment periods to reflect the addition of the OCyd
treatment regimen.
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11. Study Synopsis (Inclusion Criteria) and Section 5.1:  Text was added to clarify that 
the inclusion criteria for females and males of reproductive potential are applicable to 
both treatment regimens.  References were changed to the Revlimid REMS guide 
(added as Appendix J).  Added text to clarify for both treatment regimens, 
contraception is to be used for 3 months following the discontinuation of oprozomib. 
12. Study Synopsis (Exclusion Criteria) and Section 5.2:  Added lenalidomide-specific 
exclusion criteria “A history of deep vein thrombosis or pulmonary embolism, with 
contraindication to anticoagulation and antiplatelet options”, and renumbered 
subsequent exclusion criteria. 
13. Study Synopsis (Statistical Methods and Analyses) and Section 13.1:  Updated text to 
reflect the addition of the OCyd treatment regimen, and to provide clarification on the 
Phase 1b and Phase 2 primary endpoints, and populations for the safety and efficacy 
analyses. 
14. Section 2.1:  Revised text to reflect current treatment options for relapsed/refractory 
multiple myeloma, and updated median OS estimates (based on risk stratification). 
15. Section 2.3.2.1:  Updated text with the current efficacy and safety data from Study 
2009-003. 
16. Section 2.3.2.2:  Updated text to reflect the current status of, and data from, Study 
2011-001. 
17. Section 2.3.4:  Added new subsection to provide background information on 
cyclophosphamide. 
18. Section 2.4:  Revised text to provide updated dose rationale. 
19. Section 2.5:  Updated text for study rationale to reflect the addition of the OCyd 
treatment regimen.  Added text to provide results from a Phase 2 study of the CRd 
treatment regimen in subjects with newly diagnosed multiple myeloma (Korde 2012); 
deleted text as a clarification. 
20. Section 4.2:  Added dose escalation table for the OCyd treatment regimen. 
21. Section 9.1:  Revised text to provide additional clarification regarding oprozomib 
treatment administration in relation to PK sample collection.  Deleted redundant text 
and added a cross-reference to Section 4.1, Study Design. 
22. Section 9.3:  Added table of dose decrements for cyclophosphamide, and revised 
table of dose decrements for dexamethasone to include dose reduction details for 
subjects > 75 years old. 
23. Section 9.3.1:  Updated table of dose modification guidelines for hematologic 
toxicities to include guidance for cyclophosphamide-related hematologic toxicities. 
24. Section 9.3.2:  Updated table of dose modification guidelines for nonhematologic 
toxicities to include guidance for cyclophosphamide-related nonhematologic 
toxicities. 
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25. Section 9.8.1:  Added text to provide specific guidance for the treatment of tumor 
lysis syndrome.  A cross-reference to this section was added in Section 9.7, Safety 
Guidance for Investigators. 
26. Section 9.8.2:  Added text to provide specific guidance for antinausea and 
antiemetics, and antidiarrheals. 
27. Section 10.6:  Revised text to provide clarification regarding disease assessments for 
subjects who discontinue treatment before PD occurs. 
28. Appendix H:  Added cyclophosphamide prescribing information as an appendix, 
reflecting the addition of the OCyd treatment regimen. 
29. Appendix J:  Added Revlimid REMS Guide as an appendix to provide guidance for 
females and males of reproductive potential.  This change was applied to both 
treatment regimens to minimize the risk for confusion around the guidance. 
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes are 
described in the table below.  Changes in sections of the protocol body were also made in the 
protocol synopsis and elsewhere in the document, as applicable.  Deletions of text are 
presented in strikethrough format.  Added text is presented in bold format.  
 
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Section Number 
Changed from 
Changed to 
Rationale 
Cover Page 
Signature Page 
Protocol Acceptance Page 
Phase 1b/2, Multicenter, Open-label Study 
of Oprozomib, Lenalidomide, and 
Dexamethasone in Patients with Newly 
Diagnosed Multiple Myeloma 
Phase 1b/2, Multicenter, Open-label Study 
of Oprozomib and Dexamethasone in 
Combination With Lenalidomide, and 
Dexamethasone  or Oral 
Cyclophosphamide in Patients with Newly 
Diagnosed Multiple Myeloma 
Revised study title to reflect 
the addition of the OCyd 
treatment regimen. 
Cover Page 
, MD, PhD 
Senior Medical Director, Clinical Science 
249 E. Grand Avenue 
South San Francisco, CA 94080 USA 
 
Email:  
 
, MD 
Senior Medical Director, Clinical Science 
249 E. Grand Avenue 
South San Francisco, CA 94080  USA 
 
Email:  
 
Updated. 
Cover Page 
Signature Page 
Protocol Acceptance Page 
 
Amendment 1:  19 September 2013 
Added. 
Signature Page 
, PhD 
Vice President, Global Regulatory Affairs 
, MD 
Vice President, Clinical Science 
, PhD 
Senior Director, Biometrics 
, MD, PhD 
Senior Medical Director, Clinical Science 
 MD 
Executive Vice President, Global 
Research & Development and Technical 
Operations 
MD 
Vice President of Clinical Science and 
Biometrics 
 MD 
Senior Vice President, Clinical 
Development 
PhD 
Vice President, Global Regulatory Affairs 
MD 
Vice President, Clinical Science 
PhD 
Senior Director, Biometrics 
MD, PhD 
Senior Medical Director, Clinical Science 
Updated per Sponsor’s new 
approval process, and to 
reflect proxy approval for 
Barbara Klencke by Natalie 
Sacks. 
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Section Number 
Changed from 
Changed to 
Rationale 
Synopsis – Study Objectives 
3 Study Objectives 
Primary Objectives: 
Phase 1b: 
•To establish the maximum tolerated dose 
(MTD) of oprozomib administered orally in 
combination with lenalidomide and 
dexamethasone 
Phase 2:  
• To estimate the overall response rate 
(ORR) and complete response rate (CRR) 
Secondary Objectives: 
• To evaluate the safety and tolerability of 
oprozomib administered in combination 
with lenalidomide and dexamethasone 
• To evaluate population pharmacokinetic 
(PK) parameter estimates of oprozomib 
and variability in these estimates when 
administered in combination with 
lenalidomide and dexamethasone 
• To estimate the duration of response 
(DOR) 
• To estimate progression-free survival 
(PFS) 
Exploratory Objectives: 
• To evaluate pharmacodynamic (PDn) 
biomarkers that may correlate with 
antitumor activity 
• To evaluate genomic biomarkers that may 
predict response and resistance following 
treatment with proteasome inhibitors 
Primary Objectives: 
Phase 1b: 
• To establish the maximum tolerated dose 
(MTD) of oprozomib given in 
combination with lenalidomide and 
dexamethasone (ORd) or with 
cyclophosphamide and dexamethasone 
(OCyd) administered orally in 
combination with lenalidomide and 
dexamethasone 
• To evaluate the safety and tolerability 
of the ORd and OCyd combination 
regimens, as assessed by the type, 
incidence, severity and seriousness of 
adverse events [AEs], and 
abnormalities in selected laboratory 
analytes) 
Phase 2:  
• 
To estimate the antitumor activity 
of the ORd and OCyd combination 
regimens, as measured by overall 
response rate (ORR) and complete 
response rate (CRR) 
• To evaluate the safety and tolerability 
of the ORd and OCyd combination 
regimens, as assessed by the type, 
incidence, severity and seriousness of 
adverse events [AEs], and 
abnormalities in selected laboratory 
analytes) 
Secondary Objectives: 
• To evaluate the safety and tolerability of 
oprozomib administered in combination 
with lenalidomide and dexamethasone 
• To evaluate population pharmacokinetic 
Updated text to change 
“safety and tolerability of 
oprozomib” from a secondary 
objective to a primary 
objective for both phases of 
the study, to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide clarification on the 
study objectives. 
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(PK) parameter estimates of oprozomib 
and the variability in these estimates 
when administered in combination with 
lenalidomide and dexamethasone 
• To estimate the duration of response 
(DOR) 
• To estimate progression-free survival 
(PFS) 
Exploratory Objectives: 
• To evaluate pharmacodynamic (PDn) 
biomarkers that may correlate with 
antitumor activity 
• To evaluate genomic biomarkers that may 
predict response and resistance following 
treatment with proteasome inhibitors 
Synopsis – Study Design 
4 Study Design 
Appendix A Schedule of 
Assessments 
This is an open-label, Phase 1b/2, single two-combination regimen, non-randomized, 
multicenter study (see study schema below). 
Study Schema for OPZ003 
 
In one combination regimen (ORd), in which subjects will receive Oprozomib Tablets 
(hereafter referred to as oprozomib) administered orally, once daily on Days 1–5 and on  
Added text to provide details 
regarding the OCyd treatment 
regimen. Added a study 
schema for additional clarity 
on the study design. 
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Days 15–19 in combination with lenalidomide at a dose of 25 mg on Days 1–21, and 
dexamethasone at a dose of 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles 
(see dose administration schema below).  Alternative dosing schedules may be evaluated 
during the Phase 1b portion of this study, if deemed necessary due to the observed toxicity 
profile. 
Dose Administration Schema for Oprozomib,  Lenalidomide, and Dexamethasone 
(ORd) 
 
The ORd combination will be administered until progression of disease, unacceptable 
toxicity, or for 24 cycles (approximately 24 months), whichever occurs first.  Subjects who 
complete 24 cycles of treatment and who have stable disease or better will continue on 
oprozomib, with or without dexamethasone premedication (e.g., 4 mg/day) until 
progression of disease or unacceptable toxicity.  Lenalidomide will be administered for a 
maximum of 24 cycles.  Dexamethasone will be administered taken at a dose of 20 
mg/day, as described above, through the first cycle, after which the dose may be decreased 
to 10 mg/day in subjects > 75 years of age, at the discretion of the investigator. 
In the second combination regimen (OCyd), subjects will receive oprozomib 
administered orally, once daily on Days 1–5 and on Days 15–19 in combination with 
oral cyclophosphamide at a dose of 300 mg/m2 on Days 1, 8, and 15, and 
dexamethasone at a dose of 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles 
(See dose administration schema below).  Dexamethasone will be administered at a 
dose of 20 mg/day, as described above, through the first cycle, after which the dose 
may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the 
investigator. 
 
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Dose Administration Schema for Oprozomib, Cyclophosphamide, and 
Dexamethasone (OCyd) 
 
The OCyd combination will be administered until progression of disease, 
unacceptable toxicity, or for 8 cycles (approximately 8 months), whichever occurs 
first.  Subjects who complete 8 cycles of treatment and who have stable disease or 
better will continue on oprozomib, with dexamethasone premedication.  
Dexamethasone dosing, premedication and low-dose (e.g., 20 mg or 10 mg), should 
continue for a total of 24 cycles, or until progression of disease or unacceptable 
toxicity.  Subjects who complete 24 cycles of oprozomib therapy (total) without 
evidence of progression, may continue therapy with or without dexamethasone, 
premedication or low-dose.  A taper of dexamethasone after 24 cycles may be utilized 
as per institutional guidelines.  Cyclophosphamide will be administered for a 
maximum of 8 cycles.   
Note:  Subjects receiving either treatment regimen, who complete at least 4 cycles of 
study treatment and achieve an confirmed objective response (i.e., a partial response [PR], 
very good partial response [VGPR], complete response [CR], or stringent complete 
response [sCR]) may, after discussion with the Onyx study medical monitor, suspend study 
treatment for up to 6 weeks to undergo a hematopoietic stem cell harvest.  Stem cell 
mobilization will be conducted using a noncytotoxic regimen such as granulocyte colony–
stimulating factor (G-CSF).  These subjects may then resume continue study treatment 
until progression of disease, unacceptable toxicity, or for a total of 24 cycles of treatment 
with lenalidomide or a total of 8 cycles of treatment with cyclophosphamide, followed 
by along with continued oprozomib treatment with low-dose dexamethasone (20 mg or  
 
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10 mg) for subjects free from progression, as described above. 
Phase 1b:  The Phase 1b portion of the study will identify any dose-limiting toxicities 
(DLTs) and determine the MTD, evaluate the safety and tolerability, and assess PK/PDn 
of oprozomib when administered as described above in subjects with newly diagnosed 
symptomatic multiple myeloma (see the Study Population section below for details).   
A standard 3 + 3 dose-escalation scheme will be used.  For each combination regimen, 
Ooprozomib doses will be escalated in sequential cohorts of 3 subjects with expansion to 
up to 6 subjects if a DLT is observed in one of the first 3 subjects.  The doses of 
lenalidomide, cyclophosphamide, and dexamethasone will remain fixed in all dose 
cohorts.  The initial cohort for each combination regimen will be entered at a daily dose 
level of 210 mg oprozomib., 25 mg lenalidomide, and 20 mg dexamethasone.  The 
lenalidomide and dexamethasone doses will remain fixed while The dose of oprozomib for 
subsequent cohorts will be escalated in 30- mg increments until the MTD is established.  In 
the Phase 1b portion of the study, dose cohorts will be enrolled sequentially, 
alternating between the ORd and OCyd treatment regimens across sites.   
There will not be a predefined maximum dose to be studied.  Subjects will be evaluated for 
DLTs according to the National Cancer Institute – Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), version 4.03.  In the event that the initial cohorts at the 210 
mg dose is are found to exceed the MTD, dosing will proceed at 180 mg or a lower dose as 
agreed to by the Cohort Safety Review Committee (CSRC), comprised of the Onyx study 
medical monitor, Onyx safety representative, and the active investigators).  Intrasubject 
dose escalation to the MTD or recommended Phase 2 dose may be permitted once that 
dose has been determined and after a discussion has occurred between the treating 
physician and Onyx study medical monitor. 
Maximum Tolerated Dose 
For each dosing schedule, the MTD will be defined as the highest dose at which a DLT 
is observed in fewer than 2 of 6 patients.  At least 6 patients must be treated at the 
MTD for a minimum of 1 cycle to establish this dose as tolerated. 
 
Synopsis – Study Design 
9.1.3 Definition of Dose-limiting 
Toxicity  
Dose-Limiting Toxicities:  During the Phase 
1b portion, assessment of DLTs will occur 
during the first cycle of combination 
therapy (first 4 weeks).   
For the purposes of this study, a DLT is 
defined as any of the following treatment-
related events occurring in the first 28 days 
Dose-Limiting Toxicities:  During the Phase 
1b portion, assessment of DLTs will occur 
during the first cycle of combination 
therapy (first 4 weeks).   
For the purposes of this study, a DLT is 
defined as any of the following treatment-
related events occurring in the first 28 days 
The definition of a DLT for 
use in the Phase 1b 
component of the study was 
modified to accommodate 
FDA’s requested changes to 
another oprozomib protocol; 
text regarding Grade ≥ 3 rash 
and Grade 4 neutropenia was 
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of treatment: 
Nonhematologic DLT: 
• Any ≥ Grade 3 nonhematologic toxicity 
with further clarifications as described 
below: 
o ≥ Grade 3 acute kidney injury 
(creatinine > 3 × baseline or > 4.0 
mg/dL) must last > 72 hours to be a 
DLT 
o Grade 3 nausea, vomiting, diarrhea, or 
constipation will be a DLT only if 
occurring despite optimal supportive 
care, which at a minimum, must 
include a 5–hydroxytryptamine type–3 
(5-HT3) antagonist and aprepitant for 
nausea and vomiting 
o Asymptomatic Grade 3 
hypophosphatemia is not considered a 
DLT 
o Grade 3/4 hyperglycemia or toxicity 
solely due to dexamethasone is not 
considered a DLT (see dose reduction 
guidelines for dexamethasone in 
Section 9.3.2) 
o Grade 3 fatigue lasting < 14 days is 
not considered a DLT 
Hematologic DLT: 
• Grade 4 neutropenia:  Absolute neutrophil 
count (ANC) < 0.5 × 109/L lasting ≥ 7 
days 
of treatment: 
Nonhematologic DLT: 
• Any ≥ Grade 3 nonhematologic toxicity 
with further clarifications as described 
below the following exceptions or 
qualifications: 
o ≥ Grade 3 acute kidney injury 
(creatinine > 3 × baseline or > 4.0 
mg/dL) must last > 72 hours to be a 
DLT 
o ≥ Grade 3 nausea, vomiting, diarrhea, 
or constipation will be considered a 
DLT only if lasting > 7 days 
occurring despite optimal supportive 
care, including which (at a minimum), 
must include a 5-hydroxytryptamine 
type-3 (5-HT3) antagonist and 
aprepitant for nausea and/vomiting 
and (e.g., Imodium), and 
diphenoxylate/atropine (e.g., 
Lomotil) for diarrhea 
o Asymptomatic Grade 3 
hypophosphatemia is not considered a 
DLT 
o ≥ Grade 3 hyperglycemia or toxicity 
solely due to dexamethasone is not 
considered a DLT (see dose reduction 
guidelines for dexamethasone in 
Section 9.3.2) 
o Grade 3 fatigue lasting < 14 days is 
not considered a DLT 
o Grade ≥ 3 rash attributed 
specifically to lenalidomide is not a 
DLT 
Hematologic DLT: 
added for clarification. 
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• Grade 4 neutropenia:  Absolute neutrophil 
count (ANC) < 0.5 × 109/L lasting ≥ 7 
days, despite myeloid growth factor 
support 
Synopsis – Study Design 
4.2 Dose Escalation Plan 
9.1.3 Definition of Dose-limiting 
Toxicity 
Subject Replacement:  In the Phase 1b 
portion of the study, subjects who miss 
more than 1 planned dose of oprozomib, 2 
planned doses of lenalidomide, or 1 planned 
dose of dexamethasone during Cycle 1 for 
reasons other than a DLT, will be 
unevaluable and replaced for the purpose of 
MTD determination.  Subjects who 
discontinue study treatment for any reason 
after Cycle 1 will not be replaced.   
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: 
• A minimum of 8 of 10 planned doses of 
oprozomib must be received 
• A minimum of 6 of 8 planned doses of 
dexamethasone must be received  
• All 3 planned doses of 
cyclophosphamide must be received 
(OCyd combination regimen only) 
• A minimum of 17 of 21 planned doses 
of lenalidomide must be received (ORd 
combination regimen only) 
Subjects not meeting all of the above 
criteria or assessed as unevaluable by the 
CSRC will be replaced.  Subjects who do 
not meet the criteria above because of a 
DLT will be considered DLT-evaluable. 
In the Phase 1b portion of the study, 
subjects who miss more than 1 planned dose 
of oprozomib, 2 planned doses of 
lenalidomide, or 1 planned dose of 
dexamethasone during Cycle 1 for reasons 
other than a DLT, will be unevaluable and 
replaced for the purpose of MTD 
determination.  Subjects who discontinue 
study treatment for any reason after Cycle 1 
will not be replaced.    
Updated text to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide additional 
clarification on missed doses 
of study drug and subject 
replacement. 
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Synopsis – Study Design 
4.1 Type/Design of Study 
The Phase 2 portion of the study will 
include up to 35 additional subjects with the 
same disease characteristics as those in 
Phase 1b.  Phase 2 subjects will be treated 
at the recommended Phase 2 dose and 
schedule of oprozomib identified during the 
Phase 1b portion of the study in order to 
better characterize the safety and 
tolerability, antimyeloma activity, and PK. 
The Phase 2 portion of the study will 
include up to 35 additional subjects in each 
of the two combination regimens, with the 
same eligibility criteria disease 
characteristics as those in Phase 1b.  Phase 
2 subjects will be treated at the 
recommended Phase 2 dose and schedule of 
oprozomib identified during the Phase 1b 
portion of the study in order to better 
characterize the safety and tolerability, 
antimyeloma activity, and PK.  The 
recommended Phase 2 dose may or may 
not be the same as the MTD, and will be 
assessed on the basis of the totality of 
safety and PK/PDn data.  In the Phase 2 
portion of the study, subjects will be 
enrolled alternately between the 
OCyd and ORd treatment regimens at 
each site. 
 
Updated text to reflect the 
addition of the OCyd 
treatment regime, and for 
further clarification on the 
dose of oprozomib and 
method of treatment regimen 
assignment to be used in the 
Phase 2 portion of the study. 
Synopsis – Study Design 
10.4 Pharmacokinetic and 
Pharmacodynamic Measurements 
Pharmacokinetics:  A sparse sampling 
strategy will be employed for PK sample 
collection.   
Pharmacokinetics:  A sparse sampling 
strategy will be employed for PK sample 
collection from all subjects for both 
phases of the study.   
Added text to provide 
clarification regarding PK 
sample collection. 
Synopsis – Study Design 
10.5 Genomic Evaluations 
Genomics:  Analysis of genetic and gene 
expression biomarkers that may predict 
response and resistance following treatment 
with proteasome inhibitors will be 
conducted on all subjects from both phases 
of the study who consent to optional 
genomic biomarker analysis.  These 
analyses will be performed on a baseline 
bone marrow aspirate (a portion of the bone 
marrow aspirate sample obtained at baseline 
will be used; no additional sample is 
required), blood, and saliva.  Additional 
bone marrow samples for biomarkers may 
Genomics:  Analysis of genetic and gene 
expression biomarkers that may predict 
response and resistance following treatment 
with proteasome inhibitors will be 
conducted on all subjects from both phases 
of the study who consent to optional 
genomic biomarker analysis.  These 
analyses will be performed on a baseline 
bone marrow aspirate (a portion of the bone 
marrow aspirate sample obtained at baseline 
will be used; no additional sample is 
required), blood, and saliva.  Additional 
bone marrow samples for biomarkers may 
Revised and added text for 
clarification.  
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be collected at the time of progression from 
all subjects who consent. 
be collected at the End of Study 
Treatment visit time of progression from 
all subjects who consent.  End of Study 
Treatment is defined as the end of 
protocol-defined therapy. 
Synopsis – Study Design 
Synopsis – Criteria for Evaluation 
Activity:  The International Myeloma 
Working Group – Uniform Response 
Criteria (IMWG–URC) will be used to 
evaluate response.  Response assessments 
will be performed at the end of every 4 
week cycle for the first year of study 
treatment, at the end of every other cycle for 
the second year of study treatment, and 
every 12 weeks thereafter.  Overall response 
rate and CRR will be determined based on 
subjects’ best overall response.     
Activity:  The International Myeloma 
Working Group – Uniform Response 
Criteria (IMWG-URC) will be used to 
evaluate response.  Disease response 
assessments will be performed at the end of 
every 4 week cycle for 24 cycles of ORd or 
OCyd treatment, and will continue every 
8 weeks thereafter, until confirmed PD 
(See study schema and dose 
administration schemas for details on the 
duration of cyclophosphamide 
dosing).  the first year of study treatment, at 
the end of every other cycle for the second 
year of study treatment, and every 12 weeks 
thereafter.  Overall response rate and CRR 
will be determined based on subjects’ best 
overall response.     
Updated schedule for disease 
response assessments to 
reflect the addition of the 
OCyd treatment regimen, and 
for consistency between the 
two combination regimens.  
Synopsis –  Number of 
Investigational Sites 
4.4 Number of Centers 
Up to 12 sites in the United States (US) will 
participate in this study. 
Up to 12 20 sites in the United States (US) 
will participate in this study. 
Updated text to reflect the 
addition of the OCyd 
treatment regimen. 
Synopsis – Planned Number of 
Subjects 
4.5 Number of Subjects 
Enrollment of up to 59 subjects is planned 
for this study (up to 24 subjects for the 
Phase 1b portion of the study and 35 
subjects for the Phase 2 portion of the 
study). 
Total enrollment of up to 59 118 subjects is 
planned for this study; (including up to 24 
48 subjects for the Phase 1b portion of the 
study (24 for each combination regimen 
[ORd and OCyd]) and 35 70 subjects for 
the Phase 2 portion of the study (35 
subjects for each combination regimen).  
Updated text to reflect the 
addition of the OCyd 
treatment regimen. 
Synopsis – Sample Size 
Justification 
4.5.1 Phase 1b 
4.5.2 Phase 2 
The estimated sample size for the dose-
escalation portion of the study is based upon 
standard 3 + 3 dose-escalation rules and the 
expectation that 2–6 dosing cohorts of 3–6 
The estimated sample size for the dose-
escalation portion of the study of up to 24 
subjects for each combination regimen is 
based upon standard 3 + 3 dose-escalation 
Added text to provide 
clarification following the 
addition of the OCyd 
treatment regimen. 
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13.8 Determination of Sample 
Size 
subjects per cohort will be required to 
establish the MTD.  Enrollment of 35 
additional subjects during the Phase 2 
portion of the study is based upon the goal 
of ruling out an ORR < 85% and a CRR < 
50% based upon the approximate lower 1-
sided 90% confidence interval.  With 35 
subjects, and an assumed true ORR and true 
CRR of 95% and 75%, respectively, the 
probability of ruling out an ORR < 85% and 
a CRR < 50% with 90% confidence is 
approximately 88%.    
rules and the expectation that 2–6 dosing 
cohorts of 3–6 subjects per cohort will be 
required to establish the MTD for each 
treatment regimen.  Enrollment of 35 
additional subjects in each combination 
regimen during the Phase 2 portion of the 
study is based upon the goal of ruling out an 
ORR < 85% and a CRR < 50% based upon 
the approximate lower 1-sided 90% 
confidence interval for each parameter.  
This sample size is based upon a 
simulation of a multinomial outcome of 
CR, PR, or PD for various cohort sizes.  
With 35 subjects per combination regimen 
and an assumed true ORR and true CRR of 
95% and 75%, respectively, the probability 
of ruling out an ORR < 85% and a CRR 
< 50% with 90% confidence is 
approximately 88%, from the simulation 
described above.  The same assumptions 
for ORR and CRR are used in 
determining the sample size for each 
combination regimen.     
Synopsis – Duration of 
Study/Treatment Periods 
4.6 Estimated Study Duration 
The total study duration is expected to be 
approximately 36 months.  The estimated 
study duration is based upon the assumption 
that approximately 10–12 months may be 
required to enroll all subjects (4–6 months 
to enroll Phase 1b subjects and 6 months to 
enroll Phase 2 subjects) and that the average 
time on study will be approximately 24 
months.  Subjects must complete an End of 
Study visit approximately 4 weeks after the 
last study treatment for safety follow-up.  
Subjects with disease progression will be 
considered to have completed the study 30 
days after the last dose of study drug(s). 
The total study duration is expected to be 
approximately 36 39 months.  The 
estimated study duration is based upon the 
assumption that approximately 10–12 15 
months may be required to enroll all 
subjects (4–6 6–9 months to enroll Phase 1b 
subjects and 6 months to enroll Phase 2 
subjects) and that the average time on study 
will be approximately 24 months.   
Following completion of 24 cycles of ORd 
or OCyd treatment, disease response 
assessments will continue every 8 weeks 
until confirmed progressive disease (PD). 
For subjects who discontinue treatment 
Updated text to reflect the 
addition of the OCyd 
treatment regimen and the 
revised schedule for disease 
response assessments. 
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before PD occurs (such as for an AE, 
noncompliance, etc.), disease response 
assessments will be performed every 4 
weeks during the first 24 months of the 
study and every 8 weeks thereafter, until 
confirmed PD, or the start of alternative, 
non-protocol antimyeloma therapy. 
Subjects must complete an End of Study 
Treatment visit approximately 4 weeks 
after the last study treatment for safety 
follow-up.   
Subjects with disease progression will be 
considered to have completed the study 30 
days after the last dose of study drug(s). 
Synopsis – Test Product, Dose, 
and Mode of Administration 
Oral oprozomib with tablet strengths of 60, 
90, and 120 mg 
Oral lenalidomide with capsule strengths of 
5, 10, 15, and 25 mg 
Oral dexamethasone with tablet strengths of 
4 and 6 mg 
Oral Oprozomib with tablet strengths of 60, 
90, and 120 mg to be given PO  
Oral Lenalidomide with capsule strengths 
of 5, 10, 15, and 25 25 mg to be given PO  
Cyclophosphamide 300 mg/m2 (up to 600 
mg) to be given PO 
Oral Dexamethasone with tablet strengths 
of 4 and 6 mg 20 mg to be given PO 
Added and revised text to 
reflect the addition of the 
cyclophosphamide (in the 
OCyd treatment regimen) to 
the study design. 
Synopsis – Treatment Regimen(s) 
Appendix A, Schedule of 
Assessments 
Oprozomib will be administered in a 28 day cycle at the assigned dose in combination with 
lenalidomide and dexamethasone and either lenalidomide (ORd) or cyclophosphamide 
(OCyd): 
• Oprozomib administered on Days 1–5 and Days 15–19, for all subjects in the study 
• Lenalidomide administered on Days 1–21 for those subjects receiving the ORd 
combination regimen 
• Cyclophosphamide administered on Days 1, 8, and 15, for those subjects receiving 
the OCyd combination regimen 
• Dexamethasone administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 for all subjects in 
the study 
Oprozomib doses may be reduced in 30-mg decrements for up to 2 dose reductions for 
toxicities per the discretion of the investigator.  Interruption of oprozomib dosing for 
> 4 weeks for any reason will result in permanent discontinuation of oprozomib.  No 
dose reductions of oprozomib are allowed in Cycle 1. 
Updated text to reflect the 
addition of the OCyd 
treatment regimen.  
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Note:  Subjects who permanently discontinue lenalidomide or cyclophosphamide during 
the study for reasons other than disease progression may continue treatment with 
oprozomib and dexamethasone, and will be followed until disease progression as 
described above.  After or for a maximum of 24 months the dose of dexamethasone may 
be decreased to premedication doses (4 mg) with allowances for a taper as clinically 
indicated. whichever occurs first.  Subjects who permanently discontinue oprozomib for 
any reason prior to the completion of Cycle 1 will be removed from the study and will not 
be followed for disease progression.  Subjects receiving the ORd treatment regimen who 
permanently discontinue oprozomib for reasons other than disease progression following 
the completion of Cycle 1, may continue treatment with lenalidomide and dexamethasone, 
and will be followed until disease progression or for a maximum of 24 months cycles, 
whichever occurs first.  Subjects who discontinue both lenalidomide and oprozomib may 
not continue treatment with dexamethasone alone.  Subjects receiving the OCyd 
treatment regimen who permanently discontinue oprozomib for reasons other than 
disease progression following the completion of Cycle 1, may continue treatment with 
cyclophosphamide and dexamethasone until disease progression or for a maximum of 
8 cycles, whichever occurs first.  Subjects who discontinue both cyclophosphamide 
and oprozomib may not continue treatment with dexamethasone alone. 
Synopsis – Inclusion Criteria 
5.1 Inclusion Criteria 
Main inclusion criteria are: 
1. Newly diagnosed, symptomatic multiple 
myeloma patients for whom a 
hematopoietic stem cell transplant is not 
planned or scheduled during the study or 
are considered ineligible for 
hematopoietic stem cell transplant, with 
measurable disease as indicated by one 
or more of the following: 
a. Serum M-protein ≥ 500 mg/dL 
b. Urine M-protein ≥ 200 mg/24 hour 
c. Serum free light chain (FLC):  
Involved FLC level ≥ 10 mg/dL 
provided serum FLC ratio is 
abnormal 
Main inclusion criteria are: 
6. Newly diagnosed symptomatic multiple 
myeloma patients multiple myeloma 
patients for whom treatment is 
indicated per the National 
Comprehensive Cancer Network 
(NCCN) guidelines, and for whom a 
hematopoietic stem cell transplant is not 
planned or scheduled during the study or 
are considered ineligible for 
hematopoietic stem cell transplant, with 
measurable disease as indicated by one 
or more of the following: 
a. Serum M-protein ≥ 500 mg/dL 
b. Urine M-protein ≥ 200 mg/24 hour 
c. Serum free light chain (SFLC):  
Involved SFLC level ≥ 10 mg/dL 
provided serum FLC ratio is 
Revised text to provide 
clarification around term 
“symptomatic” 
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abnormal  
Synopsis – Inclusion Criteria 
5.1 Inclusion Criteria  
8. Female patients of childbearing potential 
(FCBP) must agree to ongoing 
pregnancy testing and to practice 
contraception according to, and for the 
timeframe outlined in the Revlimid 
Prescribing Information.  
Postmenopausal females (> 45 years old 
and without menses for > 24 consecutive 
months) and surgically sterilized females 
are exempt from these requirements.  
Two effective contraceptive methods 
must be used by FCBP for at least 4 
weeks prior to start of lenalidomide 
therapy, during therapy, and during dose 
interruptions, and for 4 weeks following 
discontinuation of lenalidomide therapy. 
9.  Male subjects must agree to practice 
contraception according to, and for the 
timeframe outlined in the Revlimid 
Prescribing Information.  Male subjects 
receiving lenalidomide must use an 
effective method of contraception during 
any sexual contact with FCBP, even if 
the subject has undergone a successful 
vasectomy. 
8. For both treatment regimens (ORd 
and OCyd):  Females of childbearing 
potential (FCBP) must agree to ongoing 
pregnancy testing and to practice 
contraception as according to, and for 
the timeframe outlined in the Revlimid 
REMS Guide (Appendix J).  Two 
effective contraceptive methods must be 
used by FCBP for at least 4 weeks prior 
to start of lenalidomide or 
cyclophosphamide therapy, during 
therapy, and during dose interruptions, 
and for 3 months following the 
discontinuation of oprozomib 4 weeks 
following discontinuation of 
lenalidomide or cyclophosphamide 
therapy.  Postmenopausal females 
(> 45 years old and without menses for 
> 24 consecutive months) and surgically 
sterilized females are exempt from these 
requirements. 
9. For both treatment regimens (ORd 
and OCyd):  Male subjects must agree 
to practice contraception as according to, 
and for the timeframe outlined in the 
Revlimid REMS Guide (Appendix J)  
Male subjects receiving lenalidomide or 
cyclophosphamide must use an 
effective method of contraception during 
any sexual contact with FCBP during 
the study, and for 3 months following 
the discontinuation of oprozomib, even 
if the subject has undergone a successful 
vasectomy. 
Text was added to clarify that 
inclusion criteria for females 
and males of reproductive 
potential are applicable to 
both treatment regimens; 
references were changed to 
the Revlimid REMS Guide 
(added as Appendix J); added 
text to clarify for both 
treatment regimens, 
contraception is to be used 
for 3 months following the 
discontinuation of 
oprozomib. 
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Synopsis – Exclusion Criteria 
5.2 Exclusion Criteria 
2. Any prior antimyeloma therapy except 
oral steroids (dexamethasone up to a 
total dose of 160 mg or equivalent within 
14 days prior to the first dose of study 
treatment).  Use of topical or inhaled 
steroids is acceptable.   
2. Any prior systemic antimyeloma 
therapy except oral steroids 
(dexamethasone up to a total dose of 
160 mg or equivalent within 14 days 
prior to the first dose of study 
treatment).  Use of topical or inhaled 
steroids is acceptable.   
Added text for clarification. 
Synopsis – Exclusion Criteria 
5.2 Exclusion Criteria 
 
6.  A history of deep vein thrombosis or 
pulmonary embolism, with 
contraindication to anticoagulation 
and antiplatelet options 
Added lenalidomide-specific 
exclusion criteria, and 
renumbered subsequent 
exclusion criteria.  
Synopsis – Exclusion Criteria 
5.2 Exclusion Criteria 
10. Other malignancy within the past 3 
years with the exception of adequately 
treated basal cell carcinoma of the skin, 
squamous cell skin cancer, thyroid 
cancer, carcinoma in situ of the cervix, 
carcinoma in situ of the breast, prostate 
cancer with Gleason Score 6 or less with 
stable prostate specific antigen levels, or 
cancer considered cured by surgical 
resection 
11. Other malignancy within the past 3 
years except those considered cured 
by surgical resection including some 
cases of: 
• Adequately treated basal or 
squamous cell carcinoma of the 
skin 
• Thyroid cancer 
• Carcinoma in situ of the breast or 
cervix 
• Prostate cancer with Gleason Score 
of 6 or less with stable prostate-
specific antigen levels 
Revised text to provide 
additional clarification. 
Synopsis – Statistical Methods 
and Analyses 
13 Statistics 
The safety evaluable population includes all 
subjects receiving treatment with any 
amount of the treatment regimen 
(oprozomib, lenalidomide, or 
dexamethasone) under study.  Efficacy 
analyses will also be performed using the 
safety evaluable population.  The primary 
endpoints of the Phase 1b portion of the 
study are the safety and assessment of the 
MTD of oprozomib.   
The primary efficacy endpoints for the 
Phase 1b:  The safety evaluable population 
includes all subjects receiving treatment 
with any amount of the treatment regimen 
(oprozomib and dexamethasone with 
either lenalidomide or 
cyclophosphamide) under study.   
Phase 2:  Safety and efficacy analyses will 
be performed using the safety evaluable 
population.  Additional efficacy analyses 
will be performed using the response 
evaluable population, defined as subjects 
Updated text to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide clarification on the 
Phase 1b and Phase 2 primary 
endpoints, and populations 
for the safety and efficacy 
analyses. 
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Phase 2 portion of the study are overall 
response and CR for subjects treated at the 
recommended Phase 2 dose. 
… 
Safety will be assessed through summaries 
of DLTs, AEs, and changes in laboratory 
test results, ECGs, vital signs, and 
oprozomib exposure.  All collected AE data 
will be listed by study site, cohort, patient 
number, and study day. 
who are included in the safety evaluable 
population, and have a baseline disease 
assessment and at least one post-baseline 
disease assessment, or dropped out due to 
AE prior to first post-baseline disease 
assessment.  
The primary safety endpoints for both 
combination regimens (ORd and OCyd) 
in the Phase 1b and Phase 2 portions of 
the study are the incidence, nature, and 
severity of AEs, serious adverse events 
(SAEs), and DLTs (Phase 1b only) of 
oprozomib, given in combination with 
dexamethasone, and either lenalidomide 
or cyclophosphamide, as well as changes 
from baseline in selected laboratory 
analytes, vital signs and ECG findings. 
… 
Safety and tolerability will be assessed 
through summaries of study drug 
administration, DLTs (Phase 1b only), 
AEs, and changes in laboratory test results 
analytes, ECGs, and vital signs, and 
oprozomib exposure by dose cohort, the 
combined MTD dose levels, and for all 
subjects.  All collected AE data will be 
listed by study site, treatment regimen, 
dose cohort, patient subject number, and 
study day. 
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2.1 Multiple Myeloma 
Current treatment options commonly 
include combination chemotherapy with 
regimens using melphalan (Alkeran®), 
bortezomib (Velcade®), thalidomide 
(Thalomid®), and lenalidomide 
(Revlimid®) with and without 
corticosteroids such as dexamethasone or 
prednisone and other agents. 
… 
Median OS from diagnosis was reported at 
42 months (Jawed 2007). 
Current treatment options for multiple 
myeloma commonly include combination 
regimens using alkylators such as 
combination chemotherapy with regimens 
using melphalan (Alkeran®) or 
cyclophosphamide (Cytoxan), bortezomib 
(Velcade®), carflizomib (Kyprolis), an 
immunomodulatory agent including 
thalidomide (Thalomid®), and lenalidomide 
(Revlimid®), or pomalidomide 
(Pomalyst), with and without 
corticosteroids such as dexamethasone or 
prednisone, and other agents.   
… 
Median OS from diagnosis was reported 
3 years for high-risk subjects, 4–5 years 
for intermediate-risk subjects, and 8–20 
years for standard-risk subjects (Mikhael 
2013). Median OS from diagnosis was 
reported at 42 months (Jawed 2007). 
Revised text to reflect current 
treatment options for 
relapsed/refractory multiple 
myeloma, and updated 
median OS estimates based 
on risk stratification. 
2.3.2.1 Study 2009-003 
At least 1 adverse event (AE) was observed 
in all 25 subjects treated on the once daily 
dosing schedule.  The most commonly 
observed study drug-related AEs (≥ 30%) 
were nausea (92.0%), vomiting (92.0%), 
diarrhea (76.0%), fatigue (52.0%), 
abdominal pain (44.0%), and decreased 
appetite (44.0%).  A total of 8 serious 
adverse events (SAEs) were experienced by 
7 of 25 (28.0%) subjects on the once daily 
dosing schedule.  One serious event of 
confusion in a subject treated at the 180 mg 
dose level was assessed as related to study 
drug.   
… 
The most commonly observed study 
At least 1 treatment-related adverse event 
(AE) was observed in 23 (92.0%) of the all 
25 subjects treated on the once daily dosing 
schedule.  The most common treatment-
related AEs were nausea (92.0%), 
vomiting (76.0%), fatigue (52.0%), 
diarrhea (44.0%), and decreased appetite 
(44.0%). The most commonly observed 
study drug-related AEs (≥ 30%) were 
nausea (92.0%), vomiting (92.0%), diarrhea 
(76.0%), fatigue (52.0%), abdominal pain 
(44.0%), and decreased appetite (44.0%).  A 
total of 7 subjects (28.0%) in the once 
daily dosing group experienced at least 1 
treatment-emergent serious adverse 
event (SAE). A total of 8 serious adverse 
Updated text with current 
efficacy and safety data from 
Study 2009-003. 
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drug-related AEs (≥ 30%) were vomiting 
(94.7%), nausea (89.5%), diarrhea (68.4%), 
fatigue (36.8%), and decreased appetite 
(36.8%).  A total of 13 SAEs were 
experienced by 8 of 19 (42.1%) subjects on 
the twice daily dosing schedule.  Of these 
SAEs, nausea and vomiting (observed in a 
subject treated at 90 mg/day total dose), and 
anemia (observed in a subject treated at the 
120 mg/day total dose) were assessed as 
related to study drug. 
events (SAEs) were experienced by 7 of 25 
(28.0%) subjects on the once daily dosing 
schedule.  One serious event of confusion in 
a subject treated at the 180 mg dose level 
was assessed as related to study drug.   
… 
All 19 subjects treated on the twice daily 
dosing schedule experienced at least 1 
treatment-related AE.  The most 
commonly observed study drug 
treatment-related AEs (≥ 30%) were 
vomiting (94.7%), nausea (89.5%), diarrhea 
(68.4%), fatigue (36.8%), and decreased 
appetite (36.8%).  A total of 8 subjects 
(42.1%) in the twice daily dosing group 
experienced at least 1 treatment-
emergent SAE.  A total of 13 SAEs were 
experienced by 8 of 19 (42.1%) subjects on 
the twice daily dosing schedule.  Of these 
SAEs, nausea and vomiting (observed in a 
subject treated at 90 mg/day total dose), and 
anemia (observed in a subject treated at the 
120 mg/day total dose) were assessed as 
related to study drug. 
2.3.2.2 Study 2011-001 
This study has undergone 2 amendments.   
… 
Subjects enrolled under Amendment 2 of 
this study are receiving a new modified-
release tablet formulation of oprozomib. 
… 
In addition to the new tablet formulation 
that is being tested under Amendment 2, a 
second, less-intensive dosing schedule is 
also being evaluated:  treatment on Days 1, 
2, 8, and 9 of the 14–day cycle (2 
consecutive days weekly).  Treatment 
This study has undergone 2 3 amendments.   
… 
Subjects enrolled under and subsequent to 
Amendment 2 of this study are receiving a 
new modified-release tablet formulation of 
oprozomib.   
… 
In addition to the new tablet formulation 
that is being tested under Amendment 2, a 
second, less-intensive dosing schedule is 
also being evaluated was added with 
Updated text to reflect the 
current status of Study 2011-
001. 
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cycles are being repeated until disease 
progression, unacceptable toxicity, or 
discontinuation for any reason occurs.  A 3 
+ 3 dose-escalation scheme using 30 mg 
increments in daily dose is ongoing in order 
to determine the recommended Phase 2 
dose for each treatment schedule.  In Phase 
2, the 2 treatment schedules will assess 
differences in PK, PDn, safety, and efficacy 
between subjects treated on each schedule. 
Amendment 2:  treatment on Days 1, 2, 8, 
and 9 of the 14-–day cycle (2 consecutive 
days weekly).  Treatment cycles are being 
repeated until disease progression, 
unacceptable toxicity, or discontinuation for 
any reason occurs.  A 3 + 3 dose-escalation 
scheme using 30-mg increments in daily 
dose is ongoing in order to determine the 
recommended Phase 2 dose for each 
treatment schedule.  In Phase 2, the 2 
treatment schedules will be assessed for 
differences in PK, PDn, safety, and efficacy 
between subjects treated on each schedule. 
2.3.2.2 Study 2011-001 
2.3.2.2.1 Oprozomib in Capsules (Split Daily Dosing Schedule) 
As of March 2013, thirteen (13) subjects have received Oprozomib in Capsules and 
were evaluable for safety.  Subjects treated with capsules have received between 1–28 
cycles of treatment on the split daily dosing schedule (n = 3 for the 120 mg, 150 mg, 
and 180 mg dose cohorts, and n = 4 for the 210 mg dose cohort).  At least 1 study 
drug-related AE has been observed in all 13 subjects treated with Oprozomib in 
Capsules.  Treatment-related AEs observed in ≥ 25% of subjects include nausea (11 
subjects), vomiting (9 subjects), diarrhea (8 subjects), fatigue (7 subjects), anemia (5 
subjects), and decreased appetite (4 subjects).  Seven subjects have experienced at 
least one Grade 3 AE, which were diarrhea (n = 3), anemia and nausea (n = 2 each), 
and thrombocytopenia, abdominal pain, fatigue, herpes zoster ophthalmic, 
neutropenia, pneumonia, back pain, and vomiting (n = 1 each).  No Grade 5 AEs have 
been reported within 30 days of the last dose of study drug.  One death has occurred 
due to progressive disease (PD), 71 days after the last dose of study drug.   
Three subjects experienced at least 1 treatment-emergent SAE, which were 
pneumonia (n = 1 in the 120 mg cohort), herpes zoster ophthalmic n = 1 in the 120 mg 
cohort), and nausea (n = 1 in the 150-mg cohort).  The event of pneumonia resolved 
after 2 days without any action taken with study drug.  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.   
As of March 2013, no DLTs have been observed at doses up to 210 mg in subjects 
Updated text with current 
data from Study 2011-001 
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treated with Oprozomib in Capsules on a split daily dosing schedule.  
2.3.2.2.2 Oprozomib Tablets (5 Consecutive Days, Bimonthly Schedule) 
As of March 2013, eleven (11) subjects have received 1–8 cycles of Oprozomib Tablets 
on the 5 consecutive days, bimonthly schedule (n = 4 for the 150 mg cohort and n = 7 
for the 180 mg cohort) and were evaluable for safety.  Treatment-related AEs 
observed in ≥ 25% of subjects include diarrhea (n = 7), nausea (n = 5), and vomiting 
(n = 4).  Five subjects have experienced at least 1 treatment-emergent Grade 3 AE, 
including diarrhea (n = 2), and anemia, nausea, vomiting, increased creatinine, acute 
renal failure, confusional state, and headache (n = 1 each).  One subject experienced 
Grade 4 AEs of anemia and sepsis, which which resolved and subject resumed study 
drug.  No Grade 5 AEs have been reported. 
Two subjects treated on the 5 consecutive days, bimonthly schedule experienced at 
least 1 treatment-emergent SAE (renal failure and PD in 1 subject, and sepsis in the 
second subject; both in the 180 mg dose cohort).  Study drug was permanently 
discontinued for the Grade 3 renal failure and PD.  The Grade 4 sepsis event was 
considered unrelated to study drug and resolved when study drug was held. 
2.3.2.2.3 Oprozomib Tablets (2 Consecutive Days, Weekly Schedule) 
As of March 2013, eleven (11) subjects have received 1–7 cycles of Oprozomib Tablets 
on the 2 consecutive days, weekly schedule (n = 3 for each of the 150, 180, and 210 mg 
cohorts, n = 2 for the 240 mg cohort) and were evaluable for safety.  No DLTs have 
been observed for subjects who have received Oprozomib Tablets on the 2 consecutive 
days, weekly schedule.   
At least 1 study drug-related AE has been observed in 10 subjects.  The most common 
treatment-related AEs observed in ≥ 25% of subjects were nausea (n = 9), diarrhea (n 
= 8), vomiting (n = 4), and fatigue (n = 3).  Three subjects experienced at least one 
study treatment-emergent Grade 3 AE, reported individually as diarrhea (n = 2), and 
vomiting, upper respiratory tract infection, and neutropenia (n = 1 each).  The events 
of diarrhea, vomiting, and neutropenia were considered related to study drug.  No 
Grade 4 or 5 AE have been reported.  No SAEs have been reported. 
2.3.2.2.4 Preliminary Pharmacokinetic and Pharmacodynamic Results 
Plasma concentrations of oprozomib reached a time to maximum plasma 
concentration (tmax) at 75.0–90.0 minutes and were cleared with a terminal half-life 
(t½) of 48.9–82.9 minutes following once daily administration of Oprozomib Tablets 
under fasted conditions.  A trend toward a dose-proportional increase in oprozomib 
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area under the plasma concentration-time curve to the last time point (AUClast) and 
Cmax exposure was observed with the QD×5 and QD×2 weekly regimens, though the 
number of subjects evaluated at each dose level and schedule was small (n = 3 to 5).  
The majority (87% to 100%) of the total AUC exposure was observed within 4 hours 
of dosing.  Rapid and potent proteasome inhibition in whole blood was observed after 
administration of Oprozomib Tablets on Cycle 1, Day 1.  Proteasome inhibition was > 
75% at 4 hours postdose for Oprozomib Tablets (150 mg; QD×5 and QD×2 weekly).  
This inhibition was sustained, and surpassed 95% by Cycle 2. 
2.3.2.2.5 
Preliminary Efficacy Results 
A total of 25 subjects have been treated with oprozomib in this study and were 
evaluable for efficacy.  Of the 12 subjects treated with Oprozomib in Capsules, 3 
subjects with multiple myeloma had a partial response (PR) and 2 subjects with 
multiple myeloma had a minimal response (MR).  Of the 6 subjects treated with 
Oprozomib Tablets on the 2 consecutive days, weekly schedule, 2 subjects with 
multiple myeloma had an MR.  Of the 7 subjects treated with Oprozomib Tablets for 
5 consecutive days, bimonthly, 1 subject with multiple myeloma had a very good 
partial response (VGPR), 1 subject with Waldenström’s macroglobulinemia (WM) 
had a PR, and 1 subject with WM had an MR. 
As of January 2013, 13 subjects receiving Oprozomib in Capsules and 11 subjects 
receiving Oprozomib Tablets in Study 2011-001 have been evaluated for safety.  Subjects 
treated with capsules have received between 1–25 cycles of treatment on the twice daily 
dosing schedule (n = 3 for the 120 mg, 150 mg, and 180 mg dose cohorts, and n = 4 for the 
210 mg dose cohort).  
At least 1 AE has been observed in all 13 subjects treated with Oprozomib in Capsules.  
The most common AEs observed in ≥ 4 subjects thus far have been nausea (n = 11), 
diarrhea (n = 10), vomiting (n = 9), fatigue (n = 8), anemia (n = 6), and decreased appetite 
and thrombocytopenia (n = 4 each).  The most common study drug–related AEs observed 
in ≥ 4 subjects have been nausea (n = 11), diarrhea and vomiting (n = 9 each), fatigue (n = 
7), anemia (n = 5), and decreased appetite (n = 4).  Seven subjects experienced at least one 
Grade 3 AE.  Grade 3 AEs were diarrhea (n = 3), anemia and nausea (n = 2 each), and 
neutropenia, thrombocytopenia, vomiting, abdominal pain, fatigue, back pain, ophthalmic 
herpes zoster, and pneumonia (n = 1 each).  Three subjects experienced Grade 4 
thrombocytopenia.  No treatment–related Grade 5 AEs have been observed.  One 
nonrelated Grade 3 pneumonia was observed in one subject.  No DLTs have been observed 
to date at doses up to 210 mg/day in subjects treated with Oprozomib in Capsules after the 
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January 2013 data cutoff.  Four subjects have received 1 4 cycles of Oprozomib Tablets on 
the 5 consecutive days, bimonthly schedule (n = 4 for the 150 mg cohort).  At least 1 AE 
has been observed in 3 of the 4 subjects treated.  The most common AEs observed thus far 
have been nausea and diarrhea (n = 3 each), and vomiting and myalgia (n = 2 each).  
Similarly, the most common study drug–related AEs observed have been diarrhea, nausea, 
and vomiting (n = 2 each).  Two subjects experienced at least one Grade 3 AE of diarrhea 
(n = 2), and nausea and vomiting (n = 1 each).  No Grade 4 or 5 AEs have been observed.  
One DLT (Grade 3 study drug-related acute renal failure) has been observed in a subject 
treated with Oprozomib Tablets as of the January 2013 data cutoff. 
Seven subjects have received 1 5 cycles of Oprozomib Tablets on the 2 consecutive days, 
weekly schedule (n = 3 for the 150 mg dose cohort, n = 3 for the 180 mg dose cohort, and n 
= 1 for the 210 mg cohort).  At least 1 AE has been observed in all subjects.  The most 
common AEs observed thus far have been nausea (n = 6), diarrhea (n = 5), and vomiting (n 
= 3).  Similarly, the most common study drug–related AEs observed thus far have been 
nausea (n = 6), diarrhea (n = 5), and vomiting (n = 3).  One subject has experienced a 
Grade 3 AE of diarrhea.  No Grade 4 or 5 AEs have been observed.  No DLTs have been 
observed to date (up to 210 mg/day total dose) in subjects treated with Oprozomib Tablets 
after the January 2013 data cutoff date. 
The AUC exposures following once daily administration of Oprozomib Tablets appear to 
be similar to the corresponding exposures following twice daily administration of 
Oprozomib in Capsules at the same total daily dose in patients with hematological 
malignancies.  Maximum concentration was reached within 120 minutes and half-life was 
47.4–96.5 minutes after dosing on Cycle 1 Day 1.  There appeared to be no effect of food 
on AUClast or Cmax following Oprozomib Tablet administration.  Whole blood 
proteasome inhibition > 75% was observed in patients receiving Oprozomib Tablets after 
the first day of dosing in Cycle 1.  This inhibition was sustained and reached levels of 
proteasome inhibition greater than 95% by Cycle 2. 
A total of 22 subjects have been treated with oprozomib in this study and were evaluable 
for efficacy.  Of the 13 subjects treated with the powder in capsule formulation on the 5 
consecutive days, bimonthly schedule, 4 had a partial response ([PR], 1 subject with 
chronic lymphocytic leukemia and 3 subjects with multiple myeloma) and 2 subjects with 
multiple myeloma had a minimal response (MR).  None of 5 subjects treated with 
Oprozomib Tablets on the 2 consecutive days, weekly schedule had an objective response 
by International Myeloma Working Group (IMWG) criteria.  Of the 4 subjects treated with 
Oprozomib Tablets on the 5 consecutive days, bimonthly schedule, 1 subject with multiple 
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myeloma had a PR and 1 subject with Waldenström macroglobulinemia had an MR.  
Overall, 8 of 22 subjects treated with oprozomib have achieved either MR or PR. 
2.3.4 Cyclophosphamide 
Background 
The following new subsection was added: 
2.3.4 Cyclophosphamide Background 
Alkylating agents such as melphalan and cyclophosphamide have been the backbone of 
multiple myeloma therapy for over 40 years.  In current practice they are widely used 
during induction therapy in newly diagnosed multiple myeloma subjects in combination 
with steroids and one of the novel agents, particularly a proteasome inhibitor (Dispenzieri 
2007).   
Cyclophosphamide is less stem-cell toxic than other alkylating agents, and has predictable, 
short duration myelosuppression when administered at doses currently in use in multiple 
myeloma (300–500 mg/m2) (Volpe 2003; Morgan 2011).  These properties have 
encouraged the use of oral cyclophosphamide in combination with a steroid and 
proteasome inhibitor in both front-line and relapsed and/or refractory multiple myeloma 
(Kropff 2007, Kropff 2009, Reece 2008, Reeder 2009, Reeder 2010).  The largest 
published experience with cyclophosphamide-based induction regimens was reported by 
Reeder et al. (2010) who combined cyclophosphamide 300 mg/m2 orally (PO) on Days 1, 
8, 15, and 22, with dexamethasone 40 mg PO on Days 1–4, 9–12, and 17–20 or Days 1, 8, 
15, and 22 and bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, and 11 or 1.5 mg/m2 IV on Days 
1, 8, 15, and 22 every 28 days for 4 cycles in transplant-eligible subjects (Reeder 2010).  
The overall response rate (PR or better) for 63 subjects enrolled in this trial was 90%, with 
41% complete response/near complete response (CR/nCR) and 60% VGPR or better.  
Weekly (Days 1, 8, 15, and 22) bortezomib administration led to reduction in Grade 3-4 
toxicity (37% versus 48%), without apparent reduction in efficacy. 
The safety, tolerability, and efficacy of carfilzomib in combination with cyclophosphamide 
and dexamethasone is being evaluated in a Phase 2 study (Palumbo 2012).  Transplant-
ineligible subjects with newly diagnosed multiple myeloma received oral 
cyclophosphamide 300 mg/m2 on Days 1, 8, and 15; oral dexamethasone 40 mg on Days 1, 
8, 15, and 22; and IV carfilzomib 20 mg/m2 on Days 1 and 2 and 36 mg/m2 on Days 8, 9, 
15, and 16 in Cycle 1, Cycle 2, and beyond, every 28 days for 9 cycles.  Median age of the 
34 enrolled subjects was 70years; 46% had International Staging System (ISS) Stage III 
(Appendix F).  Nineteen subjects were evaluable for response and safety after at least 4 
cycles.  All subjects had achieved at least a PR, 74% at least a VGPR, and 42% CR/nCR 
including 10% stringent complete response (sCR).  Responses were rapid with a median 
time to PR of 1 month.  At least one Grade 3-4 nonhematologic AE was reported in 4 
subjects (21%).  No subjects discontinued treatment and 4 subjects (21%) required 
This new subsection was 
added to provide background 
information on 
cyclophosphamide. 
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carfilzomib dose reduction due to AEs (Grade 4 neutropenia, Grade 3 pneumonia, Grade 3 
atrial fibrillation, and Grade 3 renal failure).  These results are consistent with the report of 
the “CYCLONE “Phase 1/2 study in patients with newly diagnosed multiple myeloma 
investigating a combination of carfilzomib with oral cyclophosphamide 300 mg/m2 on 
Days 1, 8, and 15; thalidomide 100 mg Days 1–28, and dexamethasone 40 mg on Days 1, 
8, 15, and 22 in transplant-eligible subjects.  In this report, doses of carfilzomib up to 45 
mg/m2 were safely delivered without DLTs and with a high ORR of 96% (Mikhael 2012). 
These data, along with the emerging data that oprozomib has similar activity as 
carfilzomib, suggest that oprozomib, cyclophosphamide, and dexamethasone may be an 
active regimen for initial treatment of multiple myeloma regardless of transplant eligibility.  
However, the safety, tolerability and MTD of oprozomib in this combination have not been 
evaluated.  This study will investigate the MTD for oprozomib when given in combination 
with cyclophosphamide and dexamethasone. 
2.4 Dose Rationale 
The oprozomib starting dose of 210 mg once daily for 5 consecutive days (QD×5) 
bimonthly for the Phase 1b component of this study is based on preclinical data that 
suggests improved antimyeloma activity with consecutive day dosing of epoxyketone 
proteasome inhibitors (Demo 2007) and clinical data collected for subjects exposed to 
oprozomib on current and completed clinical studies.  In the ongoing, dose-escalation 
phase of Study 2011-001, antimyeloma activity (confirmed MR or better) was 
reported with the QD×2 weekly regimen and the QD×5 bimonthly dosing schedule, 
both beginning at a daily dose of 150 mg (Kaufman 2013).   
Safety results from Study 2011-001 demonstrate similar tolerability profiles for QD×2 
weekly and QD×5 bimonthly dosing schedules.  The most commonly reported adverse 
events (nausea, vomiting, and diarrhea), were generally transient, mild to moderate, 
and manageable with antiemetics and over-the-counter antidiarrheal agents.  
Preliminary data from this trial suggest that dexamethasone premedication (4–8 mg) 
may reduce GI toxicity.  
Given the activity against multiple myeloma and the acceptable safety profile 
demonstrated with QD×5 bimonthly dosing, this schedule was chosen for this study.  
It is further anticipated that oprozomib may have less GI toxicity in combination with 
low-dose, therapeutic dexamethasone. 
The starting dose of 210 mg given once daily on the 5 consecutive days, bimonthly 
schedule is based on the clinical data collected for subjects exposed to Oprozomib Tablets 
on current and completed clinical studies. 
Preliminary safety results from Study 2011-001 (Phase 1b/2, Multicenter, Open-label Study 
of the Safety and Activity of Oprozomib in Patients with Hematologic Malignancies) 
Revised text to provide 
updated dose rationale. 
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demonstrate: 
 Subjects have tolerated 180 mg tablets in the 5 consecutive days, bimonthly schedule. 
 Subjects have tolerated up to 240 mg tablets in the 2 consecutive days, weekly 
schedule without the occurrence of 2 DLTs in 3 treated patients and with no other 
significant safety concerns. 
 Subjects were able to tolerate up to 210 mg total daily dose with Oprozomib in 
Capsules administered on the 5 consecutive days, bimonthly schedule without 
occurrence of DLTs or the occurrence of other significant safety concerns. 
In a previous study, the addition of steroids to bortezomib has demonstrated a reduction in 
GI toxicity when compared to bortezomib alone (Jagannath 2006).  Preliminary review of 
safety data from Study 2011-001 suggests that the addition of low doses of therapeutic 
dexamethasone may reduce GI toxicity.  Given that GI AEs have been the most frequent 
events observed in subjects treated with oprozomib, it is anticipated that Oprozomib 
Tablets will have less GI toxicity in combination with dexamethasone and therefore, may 
be safely dosed at the same level as oprozomib monotherapy. 
2.5 Study Rationale 
An ongoing, Phase 1/2 study of carfilzomib 
in combination with lenalidomide and low-
dose dexamethasone in patients with newly 
diagnosed multiple myeloma has 
demonstrated excellent activity and 
tolerability with 62% of 53 patients 
achieving near complete response or better 
and with only Grade 1/2 peripheral 
neuropathy in 23% of the patients 
(Jakubowiak 2012).  Based on these results, 
Onyx is conducting an ongoing pivotal 
study of carfilzomib in combination with 
lenalidomide and low-dose therapeutic 
dexamethasone in patients with relapsed 
multiple myeloma.   
An ongoing, Phase 1/2 study of carfilzomib 
in combination with lenalidomide and low-
dose dexamethasone in patients subjects 
with newly diagnosed multiple myeloma 
has demonstrated excellent activity and 
tolerability with 62% of 53 patients 
subjects achieving nCR or better and with 
only Grade 1/2 peripheral neuropathy 
reported in 23% of the patients subjects 
(Jakubowiak 2012).  Preliminary results 
from an ongoing Phase 2 study of CRd in 
untreated newly diagnosed nontransplant 
and transplant candidates with multiple 
myeloma have also been reported.  After 
a median of 4 cycles of CRd completed 
(range 1–8) in 15 evaluable subjects, 40% 
of subjects achieved nCR or better (4 
sCR and 2 nCR), 33% of subjects had 
VGPR (n = 5), 20% of subjects had PR (n 
= 3), and 1 subject had SD (6%).  No 
subjects reported grade ≥ 3 neuropathy 
Added text to provide results 
from a Phase 2 study of the 
CRd treatment regimen in 
subjects with newly 
diagnosed multiple myeloma 
(Korde 2012); deleted text as 
a clarification. 
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(Korde 2012).  Based on these results, 
Onyx is conducting an ongoing pivotal 
study of carfilzomib in combination with 
lenalidomide and low-dose therapeutic 
dexamethasone in patients with relapsed 
multiple myeloma. 
2.5 Study Rationale 
Oprozomib appears to have clinically 
meaningful, single-agent activity in an 
ongoing study in patients with hematologic 
malignancies, including multiple myeloma.  
These properties make oprozomib a 
promising proteasome inhibitor to combine 
with lenalidomide and low dose therapeutic 
dexamethasone to provide an all oral 
treatment regimen for the frontline 
treatment of multiple myeloma.  The current 
study is designed to establish the MTD of 
oprozomib when combined with standard 
doses of lenalidomide and low-dose 
therapeutic dexamethasone and to provide a 
preliminary assessment of the antimyeloma 
activity of this combination. 
Likewise, and as described above in 
Section 2.3.4, the combination of 
carfilzomib and cyclophosphamide also 
appears to have good anti-myeloma 
activity and an acceptable safety profile. 
Oprozomib appears to have clinically 
meaningful, single-agent activity in an 
ongoing study in of patients with 
hematologic malignancies, including 
multiple myeloma.  Combining oprozomib 
promising proteasome inhibitor to combine 
with low-dose therapeutic dexamethasone, 
plus either cyclophosphamide or 
lenalidomide, to provide an all oral 
treatment regimen for the frontline 
treatment of multiple myeloma has obvious 
appeal. The current study is designed to 
establish the MTD of oprozomib when 
combined with standard doses of 
lenalidomide and low-dose therapeutic 
dexamethasone and standard doses of 
either cyclophosphamide or 
lenalidomide, and to provide a preliminary 
assessment of the antimyeloma activity of 
this these combinations. 
Updated text to reflect the 
addition of the OCyd 
treatment regimen. 
4.2 Dose Escalation Plan 
In the Phase 1b portion of the study, oprozomib doses in combination lenalidomide and 
dexamethasone will be escalated in sequential groups of 3 subjects for each combination 
regimen, with expansion to up to 6 subjects if a DLT is observed in one of the first 3 
subjects.  The doses of lenalidomide, cyclophosphamide, and dexamethasone will 
remain fixed in all dose cohorts.  The initial cohort (Table 1 and Table 2) for each 
Updated text to reflect the 
addition of the OCyd 
treatment arm, and added 
dose escalation table for 
OCyd. 
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combination regimen will be entered at a daily dose level of 210 mg oprozomib, 25 mg 
lenalidomide, and 20 mg dexamethasone.  The lenalidomide and dexamethasone doses will 
remain fixed while The dose of oprozomib for subsequent cohorts will be escalated by 
30- mg increments of oprozomib until the MTD is reached established.  There will not be 
a predefined maximum dose to be studied.  Additional details regarding dose escalation can 
be found in the Cohort Management Plan.  Details on subject replacement are provided 
in Section 9.1.3.  The MTD will be defined as the highest dose in which a DLT is 
observed in fewer than 2 of 6 patients (Kummar 2006).  At least 6 patients must be 
treated at the MTD for a minimum of 1 cycle to establish this dose as tolerated. 
Table 1: Dose Escalation Scheme: Using Oprozomib in Combination With Lenalidomide 
and Dexamethasone (ORd) Tablets 
Cohorts 
Oprozomib Daily 
Dose (mg) 
Lenalidomide Doses 
(mg) 
Dexamethasone Doses 
(mg) 
−101a 
180 
25 
20 
101 
210 
25 
20 
102 
240 
25 
20 
103 
270 
25 
20 
104b 
300 
25 
20 
Note: This table is for illustrative purposes. 
a  If DLTs are observed in 2 or more subjects at the first dose level of 210 mg, dosing of Cohort -
101 will proceed at 180 mg, or a lower dose as agreed with the Cohort Safety Review Committee 
(CSRC) and may be expanded to include up to 6 evaluable subjects. 
b  Additionally, subsequent cohorts of 3–6 subjects will continue to be enrolled with doses 
escalated by 30 mg until the MTD (the highest dose at which a DLT is observed in less than 2 of 6 
evaluable subjects) is defined. 
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Table 2: Dose Escalation Scheme: Oprozomib in Combination With 
Cyclophosphamide and Dexamethasone (OCyd) 
Cohorts 
Oprozomib Daily 
Dose (mg) 
Cyclophosphamide 
Doses (mg/m2) 
Dexamethasone Doses 
(mg) 
−201a 
180 
300 
20 
201 
210 
300 
20 
202 
240 
300 
20 
203 
270 
300 
20 
204b 
300 
300 
20 
Note: This table is for illustrative purposes. 
a If DLTs are observed in 2 or more subjects at the first dose level of 210 mg, dosing of 
Cohort -201 will proceed at 180 mg, or a lower dose as agreed with the Cohort Safety Review 
Committee (CSRC) and may be expanded to include up to 6 evaluable subjects. 
b Additionally, subsequent cohorts of 3–6 subjects will continue to be enrolled with doses 
escalated by 30 mg until the MTD (the highest dose at which a DLT is observed in less than 2 
of 6 evaluable subjects) is defined. 
 
8 Study Drug 
The following new subsection was added: 
8.3 
CYCLOPHOSPHAMIDE 
8.3.1 
PHYSICAL DESCRIPTION AND FORMULATION 
Cyclophosphamide is an alkylating agent (Cyclophosphamide Prescribing 
Information 2011; Appendix H). 
8.3.2 
PACKAGING AND LABELING 
Cyclophosphamide is a commercially available drug, available both as tablets for PO 
administration and as various sterile formulations for parenteral administration 
(Cyclophosphamide Prescribing Information 2011).  Only the tablet formulation will 
be used in this protocol. 
8.3.3 
STORAGE 
Cyclophosphamide is to be stored at controlled room temperature. Do not store above 
25°C.  Consult the package insert for additional storage and usage instructions 
(Cyclophosphamide Prescribing Information 2011). 
8.3.4     ACCOUNTABILITY 
Sites will be required to record and document patient compliance regarding 
This new subsection was 
added to provide information 
on cyclophosphamide. 
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cyclophosphamide dosing.  Please refer to the Pharmacy Manual for additional 
details. 
9.1 Oprozomib 
9.1.1 
TREATMENT ADMINISTRATION 
Oprozomib Tablets will be administered in single daily doses (Table 1 and Table 2) in 
the following manner:   
Dosing instructions for days on which PK samples will not be collected (non-PK 
days):  Subjects should take oprozomib with approximately 8 ounces of water at 
approximately the same time of day, with or without food at their discretion.  When 
oprozomib is given on the same day with other treatments, dexamethasone should be 
administered 30 minutes before oprozomib, lenalidomide and cyclophosphamide.  
Subjects may take lenalidomide or cyclophosphamide following oprozomib 
administration at investigator’s discretion, however it is recommended that they take 
their study drugs at approximately the same time each day.  
Dosing instructions for days on which PK samples will be collected (PK days):  
Dexamethasone should be administered at least 30 minutes before the other 
medications.  Oprozomib and either lenalidomide or cyclophosphamide will be 
administered in the clinic.  Oprozomib should be administered concurrently 
(i.e., within 5 minutes of each other) with lenalidomide or cyclophosphamide, with 
approximately 8 ounces of water, to subjects on an empty stomach (at least 2 hours 
after and 1 hour before a meal). 
Oprozomib Tablets will be administered in single daily doses (Table 1).  Subjects should 
take oprozomib at approximately the same time of day, in the morning , with or without 
food at their discretion, except on PK sample collection days.  On the days on which PK 
samples are to be collected, the oprozomib, dexamethasone, and either lenalidomide or 
cyclophosphamide will be administered in the clinic.  The dexamethasone should be 
administered approximately 30 minutes before the other medications.  The oprozomib and 
lenalidomide or oprozomib and cyclophosphamide should be administered to subjects 
within 5 minutes of each other.  Theis should be done with subjects having and on an 
empty stomach (at least 2 hours after or and 1 hour before a meal) with 8 ounces of water.  
Oprozomib will be administered orally, once daily for 5 consecutive days every other week 
(i.e., on Days 1, 2, 3, 4, through 5, and 15, 16, 17, 18, and through 19) of each 28-day 
treatment cycle (Figure 1). and Treatment with oprozomib will continue until disease 
progression, unacceptable toxicity, or study treatment discontinuation for any reason (see 
Section 11).   Lenalidomide will be administered at 25 mg, orally, on Days 1 21, and 
dexamethasone at 20 mg, orally, on Days 1, 2, 8, 9, 15, 16, 22, and 23.   On days when 
oprozomib and dexamethasone are administered concurrently (i.e., on Days 1, 2, 15, and 16 
Updated text to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide additional 
clarification regarding 
oprozomib treatment 
administration in relation to 
PK sample collection.  
Deleted redundant text and 
added a cross-reference to 
Section 4.1, Study Design. 
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of each cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  
Oprozomib and lenalidomide should be taken concurrently, i.e., within 5 minutes of each 
other.   
Note:  Subjects who permanently discontinue lenalidomide or cyclophosphamide during 
the study for reasons other than disease progression may continue treatment with 
oprozomib and dexamethasone and will be followed until disease progression or for a 
maximum of 24 months, whichever occurs first as described above.  After 24 months, 
the dose of dexamethasone may be decreased to premedication doses (4 mg), with 
allowances for a taper as clinically indicated.   
Subjects who permanently discontinue oprozomib for any reason prior to the completion of 
Cycle 1 will be removed from the study and will not be followed for disease progression.  
Subjects receiving the ORd treatment regimen, who permanently discontinue oprozomib 
for reasons other than disease progression following the completion of Cycle 1, may 
continue treatment with lenalidomide and dexamethasone and will be followed until 
disease progression or for a maximum of 24 months, whichever occurs first.  Subjects who 
permanently discontinue both lenalidomide and oprozomib may not continue treatment 
with dexamethasone alone.  Subjects receiving the OCyd treatment regimen, who 
permanently discontinue oprozomib for reasons other than disease progression 
following the completion of Cycle 1, may continue treatment with cyclophosphamide 
and dexamethasone until disease progression or for a maximum of 8 months, 
whichever occurs first.  Subjects who discontinue both cyclophosphamide and 
oprozomib may not continue treatment with dexamethasone alone.   
Guidelines Procedures for dose modification are provided summarized in Section 9.3.  
Details on the study design are provided in Section 4.1. 
All subjects will continue on combination therapy until disease progression, unacceptable 
toxicity, or 24 cycles (approximately 24 months), whichever occurs first.  Subjects who 
complete 24 cycles of treatment and who have stable disease or better will continue on 
oprozomib, with or without dexamethasone premedication (e.g., 4 mg/day) until 
progression of disease or unacceptable toxicity.  Dexamethasone will be taken at a dose of 
20 mg/day, as described above, through the first cycle, after which the dose may be 
decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the investigator. 
In the Phase 1b portion, subjects will be enrolled in treatment dose-cohorts in escalating 
order (see Section 4.2 and Table 1 for doses/cohorts, and see Section 9.1.2 for methods of 
dose escalation to the MTD).  Dose escalation will proceed only after the safety and 
tolerability of the previous dose level have been assessed as acceptable as determined by 
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the CSRC (comprised of Onyx’s study medical monitor, Onyx’s drug safety representative, 
and the investigators) or until a MTD has been determined.   
In the Phase 2 portion, oprozomib will be administered in combination with lenalidomide, 
and dexamethasone at the recommended Phase 2 dose and schedule of oprozomib, as 
defined in the Phase 1b portion of the study (see Section 4.2 and Table 1 for doses/cohorts, 
and see Section 9.1.2 for methods of dose escalation to the MTD). 
9.2 Lenalidomide, 
Cyclophosphamide, and 
Dexamethasone Administration 
9.2.1 
LENALIDOMIDE 
ADMINISTRATION 
Lenalidomide will be administered at 25 
mg, orally, daily on Days 1–21 of each 28 
day cycle for a maximum of 24 cycles of 
therapy (approximately 24 months).  
Lenalidomide and oprozomib should be 
administered concurrently, i.e., within 5 
minutes of each other.  On days on which 
oprozomib is not administered, it is 
suggested that subjects take lenalidomide at 
approximately the same time in the morning 
for consistency. 
9.2.2 
DEXAMETHASONE 
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 (i.e., on Days 1, 2, 15, and 
16), dexamethasone should be taken at least 
30 minutes prior to oprozomib.   
Note:  Dexamethasone will be taken at a 
dose of 20 mg/day through the first cycle, 
after which the dose may be decreased to 10 
mg/day in subjects > 75 years of age, at the 
discretion of the investigator.  In addition, 
treatment with dexamethasone 
premedication (e.g., 4 mg/day) in 
9.2.1 
LENALIDOMIDE 
ADMINISTRATION 
Except for PK collection days, 
lenalidomide will be administered orally at 
a dose of 25 mg with or without food at 
investigator and subject discretion, orally, 
daily on Days 1–21 of each 28 day cycle for 
a maximum of 24 cycles of therapy 
(approximately 24 months).   Subjects may 
take lenalidomide following oprozomib 
administration, however it is 
recommended that they take 
lenalidomide at approximately the same 
time each day (Refer to Section 9.1.1 for 
details on oprozomib treatment 
administration).  Lenalidomide and 
oprozomib should be administered 
concurrently, i.e., within 5 minutes of each 
other.   On days on which when oprozomib 
is not administered, it is suggested that 
subjects should take lenalidomide at 
approximately the same time of the morning 
day for consistency. 
9.2.2 
CYCLOPHOSPHAMIDE 
ADMINISTRATION 
Except for PK collection days, 
cyclophosphamide will be administered 
orally at 300 mg/m2 (up to a maximum of 
600 mg), with or without food at 
Revised text on lenalidomide 
and dexamethasone 
administration to provide 
clarity; a section on 
cyclophosphamide 
administration was added to 
(to reflect the addition of the  
OCyd treatment regimen). 
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combination with oprozomib may continue 
after if a subject demonstrates stable disease 
or better after 24 cycles of combination 
therapy.   
investigator and subject discretion, on 
Days 1, 8 and 15 of each 28 day cycle for 
a maximum of 8 cycles of therapy 
(approximately 8 months).  Subjects may 
take cyclophosphamide following 
oprozomib administration, however it is 
recommended that they take 
cyclophosphamide at approximately the 
same time each day (Refer to Section 
9.1.1 for details on oprozomib treatment 
administration). On days when 
oprozomib is not administered, subjects 
should take cyclophosphamide at 
approximately the same time of the day 
for consistency. 
9.2.2 
DEXAMETHASONE 
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 when 
both oprozomib and dexamethasone are 
administered (i.e., on Days 1, 2, 15, and 16), 
dexamethasone should be taken at least 30 
minutes prior to oprozomib.   
Note:  Dexamethasone will be taken at a 
dose of 20 mg/day through the first cycle, 
after which the dose may be decreased to 10 
mg/day in subjects > 75 years of age, at the 
discretion of the investigator.  In addition, 
treatment with Dexamethasone dosing 
(premedication and low-dose) as per the 
schedule above (e.g., 4 mg/day)  in 
combination with oprozomib may should 
be continued after if a for subjects who 
demonstrates a response of stable disease 
or better after for 24 cycles of for both the 
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ORd or 8 cycles of and OCyd treatment 
regimens.  After 24 cycles, this treatment 
may be continued or tapered at the 
discretion of the investigator and per 
institutional guidelines.   
9.3 Dose Modification Guidelines 
The following sections and tables 
summarize dose modifications for 
oprozomib, lenalidomide, and 
dexamethasone to manage possible toxicity.  
Administration of oprozomib or 
lenalidomide will be discontinued in the 
event of a treatment-related toxicity that, in 
the opinion of the investigator, warrants 
permanent discontinuation.  The subject 
will remain on protocol treatment as long as 
either oprozomib or lenalidomide is being 
administered (either alone or in combination 
with dexamethasone).  Monotherapy with 
dexamethasone is not allowed.  Exceptions 
to the dose modification guidelines are 
permitted with written approval from the 
Onyx study medical monitor. 
Dose reduction levels for oprozomib and 
lenalidomide are provided in Table 3 and 
Table 4, respectively. 
The following sections and tables 
summarize dose modifications for 
oprozomib, lenalidomide, 
cyclophosphamide, and dexamethasone to 
manage possible toxicity.  Administration 
of oprozomib, or lenalidomide, or 
cyclophosphamide will be discontinued in 
the event of a treatment-related toxicity that, 
in the opinion of the investigator, warrants 
permanent discontinuation.  Interruption 
of oprozomib dosing for > 4 weeks for 
any reason will result in permanent 
discontinuation of oprozomib.  No dose 
reductions of oprozomib are allowed in 
Cycle 1.  The subject will remain on 
protocol treatment as long as either 
oprozomib, or lenalidomide, or 
cyclophosphamide is being administered 
(either alone or in combination with 
dexamethasone).  Monotherapy with 
dexamethasone is not allowed.  Exceptions 
to the dose modification guidelines are 
permitted with written approval from the 
Onyx study medical monitor. 
Dose modifications made during the first 
cycle of treatment for either combination 
regimen in the Phase 1b portion of this 
study should be discussed with the Onyx 
medical monitor.   
Dose reduction levels for oprozomib and , 
lenalidomide, and cyclophosphamide are 
provided in Table 3 Table 4 and , Table 4 
Revised text to reflect the 
addition of the dose reduction 
table for cyclophosphamide 
and to provide clarification 
on dose modifications or 
interruptions. 
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Table 5, and Table 6, respectively. 
9.3 Dose Modification Guidelines 
The following table was revised: 
Table 3 4: 
Dose Decrements for Oprozomib 
Nominal Dose 
Reduced Oprozomib Doses 
Dose –1 
Dose –2 
Dose –3 
210 mg 
Nominal dose -30 mg 
Nominal dose -60 mg 
— 
 
The table was revised with 
the Dose –3 column removed 
to clarify that there is no third 
dose decrement of oprozomib 
9.3 Dose Modification Guidelines 
The following table was added: 
Table 6:  Dose Decrements for Cyclophosphamide 
Nominal Dose 
Reduced Cyclophosphamide Doses 
Dose –1 
Dose –2 
300 mg/m2  
200 mg/m2 
100 mg/m2 
Note:  Dose adjustments should, in general, follow the Cyclophosphamide Prescribing 
Information 201 (Appendix H). 
This table was added to 
provide dose reduction levels 
for cyclophosphamide (for 
the OCyd treatment regimen). 
9.3 Dose Modification Guidelines 
Table 7:  Dose Decrements for Dexamethasone 
Nominal Dose 
Reduced Dexamethasone Doses 
Dose –1 
Dose –2 
20 mg 
12 mg 
8 mg 
Cycle 2:  Age > 75  and nominal 
dose is 10 mg post-Cycle 1 
8 mg 
4 mg 
 
This table was revised to 
include dexamethasone dose 
reduction details for subjects 
> 75 years old. 
9.3.1 Dose Modification 
Guidelines for Hematologic 
Toxicities 
Dose modification guidelines for hematologic toxicities are outlined below in Table 8.   
Guidelines for the management of thrombocytopenia for lenalidomide and oprozomib are 
summarized in Table 6 and Table 7, respectively.  Guidelines for the management of 
neutropenia are summarized in Table 8. 
Updated text and table to 
include dose modification 
guidelines for 
cyclophosphamide-related 
hematologic toxicities 
(reflecting the addition of the 
OCyd treatment regimen). 
Table 8: Dose Modification Guidelines for Oprozomib-, Lenalidomide-, and 
Cyclophosphamide-Related Hematologic Toxicities Post-Cycle 1 
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Toxicity 
Recommended Actiona 
Oprozomib 
Lenalidomide 
Cyclophosphamide 
Toxicity on Day 1 of Cycle 
Platelets < 25 × 
109/L (oprozomib 
and 
cyclophosphamide) 
Hold dose until 
recovery ≥ 25 × 109/L 
restart at previous 
dose 
Hold dose, follow 
CBC 3 times per 
week; Hold 
prophylactic 
anticoagulation until 
platelets return to 
≥ 30 × 109/La, then 
resume at 1 dose 
decrement 
Hold dose until 
recovery to 
≥ 25 × 109/L restart 
at 1 dose decrement  
ANC < 1.0 × 109/L 
Hold dose 
Add myeloid growth 
factorb 
With resolution to 
≥ 1.0 × 109/L, restart 
at previous dose 
Hold dose 
Add myeloid growth 
factorb 
With resolution to 
≥ 1.0 × 109/L, restart 
at previous dose 
Hold dose 
Add myeloid 
growth factorb 
With resolution to 
≥ 1.0 × 109/L, 
restart at 1 dose 
decrement  
Toxicity on Subsequent Days of Cycle 
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 dose; follow CBC 3 times per week 
Add myeloid growth factorb 
With resolution of fever and ANC ≥ 1.0 × 109/L, restart at 1 dose 
decrement 
ANC < 0.75 × 109/L 
(Grade 3) 
Hold dose 
Add myeloid growth 
factorb 
With resolution to 
≥ 1.0 × 109/L, restart 
at previous dose 
Hold dose; follow 
CBC 3 times per week 
Administer myeloid 
growth factorb 
Resume at full dose 
when ANC 
≥ 1.0 × 109/L 
(Resume at 1 dose 
decrement for each 
subsequent decrease 
to < 0.75 × 109/L) 
 
Hold dose 
Add myeloid 
growth factorb 
With resolution to 
≥ 1.0 × 109/L, 
restart at 1 dose 
decrement 
ANC < 0.5 × 109/L 
(Grade 4) 
Hold dose; follow 
CBC 3 times per 
week; add myeloid 
growth factorb.  
Resume at full dose if 
Hold dose; follow 
CBC 3 times per 
week; add myeloid 
growth factorb.   
When ANC 
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ANC rises to 
≥ 0.5 × 109/L within 
7 days; Resume at 1 
dose decrement if 
ANC returns to 
≥ 0.5 × 109/L after 7 
days. 
≥ 1.0 × 109/L, 
resume at 1 dose 
decrement  
Platelets 25 to < 50 
× 109/L without 
≥ Grade 2 bleeding/ 
hemorrhage  
Full dose 
Hold dose, follow 
CBC weekly 
Hold prophylactic 
anticoagulation until 
platelets return to 
≥ 30 × 109/L.  When 
platelets reach 50 × 
109/L, then resume at 
1 dose decrement. 
Hold dose until 
platelets return to 
≥ 50 × 109/L, and 
then resume at 1 
dose decrement 
Platelets 25 to < 50 
× 109/L with 
≥ Grade 2 bleeding/ 
hemorrhage  
Hold dose until 
platelets return to 
≥ 50 × 109/L and/or 
bleeding is 
controlled, then 
resume at 1 dose 
decrement 
Hold dose, follow 
CBC weekly 
Hold prophylactic 
anticoagulation until 
platelets return to 
≥ 30 × 109/L.  When 
platelets reach 
50 × 109/L, then 
resume at 1 dose 
decrement. 
Hold dose until 
platelets return to 
≥ 50 × 109/L and/or 
bleeding is 
controlled, then 
resume at 1 dose 
decrement 
Platelets < 25 × 
109/L or any degree 
of  
thrombocytopenia 
with ≥ Grade 2 
bleeding/ 
hemorrhage  
 
Hold dose until 
platelets return to 
≥ 50 × 109/L and/or 
bleeding is 
controlled, then 
resume at 1 dose 
decrement 
Hold dose, follow 
CBC weekly 
Hold prophylactic 
anticoagulation until 
platelets return to 
≥ 30  × 109/L.  When 
platelets reach 
50 x 109/L, then 
resume at 1 dose 
decrement 
Hold dose until 
platelets return to 
≥ 50 × 109/L and/or 
bleeding is 
controlled, then 
resume at 1 dose 
decrement 
ANC = absolute neutrophil count; CBC = complete blood count. 
a  The maximum allowed dose interruption is 4 weeks. 
b  Myeloid growth factors include filgrastim or sargramostim. 
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9.3.2 Dose Modification 
Guidelines for Nonhematologic 
Toxicities 
Dose modification guidelines for nonhematologic toxicities are outlined below in 
Table 11.    
Table 11:  Dose Modification Guidelines for Oprozomib-, Lenalidomide-, and 
Cyclophosphamide-Related Nonhematologic Toxicities 
Nonhematologic Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Actiona 
 
 
Oprozomib 
Lenalidomide 
Cyclophosphamide 
Tumor Lysis 
Syndrome 
(TLS)  
Generally 
recognized as 
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 lenalidomide/cyclophosphamide 
until all abnormalities in serum chemistries have resolved to 
baseline; resume at full doses.  See Section 9.8.1.1 for specific 
prophylaxis and treatment guidelines for TLS. 
Neuropathy 
Grade 2 
neuropathy 
with pain or 
> Grade 3 
neuropathy 
Hold dose until 
toxicity resolve to 
≤ Grade 1 or has 
returned to 
baseline.  Resume 
study drug at 1 dose 
decrement. 
Hold dose until 
toxicity resolve to 
≤ Grade 1 or has 
returned to 
baseline.  Resume 
study drug at 1 dose 
decrement. 
Full dose. 
Infection  
Grade 3 or 4 
Hold both oprozomib and lenalidomide/cyclophosphamide 
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. 
Updated text and table to 
include dose modification 
guidelines for 
cyclophosphamide-related 
nonhematologic toxicities 
(reflecting the addition of the 
OCyd treatment regimen). 
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Nausea, 
vomiting, 
diarrhea, or 
constipation 
> Grade 3 
without 
optimal 
supportive 
care as 
defined by 
use of both a 
5HT3 
antagonist 
and 
antiemetic 
(aprepitant) 
Continue full-dose therapy. Institute optimal supportive care. 
> Grade 3 
with optimal 
supportive 
care as 
defined by 
use of both a 
5HT3 
antagonist 
and 
antiemetic 
(aprepitant) 
Oprozomib 
related:  Hold dose 
until toxicity 
resolve to 
< Grade 1 or has 
returned to 
baseline.  Resume 
study drug at 1 
dose decrement 
Hold dose until toxicity resolve to < 
Grade 1 or has returned to baseline.  
Resume study drug at full dose. 
If recurs after oprozomib dose reduction, 
hold dose until toxicity resolve to < Grade 
1 or has returned to baseline.  Resume 
study drug at 1 dose decrement. 
Fatigue 
Grade 3 
fatigue 
lasting < 14 
days 
Full dose. 
If recurs after 
oprozomib dose 
reduction, hold dose 
until toxicity 
resolves to < Grade 
1 or has returned to 
baseline.  Resume 
study drug at 1 dose 
decrement. 
Full 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. 
Renal 
Dysfunction 
CrCL 30 to 
<50 mL/min 
(Grade 2) 
Full dose 
Reduce dose to 
10 mg once daily. 
Full dose 
CrCl 15 to < 
30 mL/min 
(Grade 3) 
Hold dose.  When 
CrCl recovers to 
≤ Grade 2, resume 
at 1 dose 
Hold dose.  When 
CrCl recovers to 
≤ Grade 2, resume 
dose at 1 dose 
Hold dose until 
resolution to 
≤ Grade 2 or 
baseline, then 
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decrement.  
decrement.  If Grade 
3 reduction in CrCl 
reappears, then hold 
dose until CrCl 
recovers to ≤ Grade 
2 and reduce dose to 
15 mg every 48 
hours.   
resume at full dose 
CrCl 0 to 
<15 mL/min 
(Grade 4) 
Discontinue  
Discontinue 
Discontinue 
Elevation in 
Liver 
Function Tests 
(LFTs)  
≥ Grade 3 
(AST, ALT, 
or total 
bilirubin)b 
Hold dose until 
resolves to 
baseline.  Resume 
at one dose 
decrement.   
Hold dose until 
resolution, then 
resume at full dose 
Hold dose until 
resolution to 
≤ Grade 1 or 
baseline, then 
resume at full dose 
Hemorrhagic 
cystitis 
Grade 1 or 2 Continue full dose Continue full dose 
Hold dose until 
resolution, then 
resume at 1 dose 
decrement 
Grade 3 or 4 Continue full dose Continue full dose 
Discontinue; do not 
resume. 
Other Non-
Hematologic 
Toxicity 
Assessed as 
cyclophosph
amide-
related and 
≥ Grade 3 
Full dose 
Not Applicable 
Hold 
cyclophosphamide 
dose 
Follow at least 
weekly 
If the toxicity 
resolves to 
≤ Grade 1 or 
baseline, restart at 
1 dose decrement 
Other Non-
Hematologic 
Toxicity 
Assessed as 
oprozomib-
related and ≥ 
Grade 3 
Hold oprozomib 
dose until toxicity 
resolves to 
≤ Grade 1 or 
baseline; restart at 
1 dose decrement 
Full dose 
Full dose 
Other Non-
Hematologic 
Toxicity 
Assessed as 
lenalidomide
-related and 
Full dose 
Hold lenalidomide 
dose until toxicity 
resolves to ≤ Grade 
No Applicable 
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Abbreviations:  5-HT3 = 5-hydroxytryptamine type-3; ALT = alanine aminotransferase; ANC = 
absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine clearance; 
eCRF = electronic case report form; LDH = lactate dehydrogenase; LFTs = liver function tests; 
TLS = tumor lysis syndrome 
a  The maximum allowed dose interruption is 4 weeks. 
b  If AST, or ALT is ≥ 3 × ULN, the “evaluation of treatment emergent liver abnormalities” 
eCRF should be completed. 
≥ Grade 3 
1 or baseline; restart 
at 1 dose decrement 
9.4 Dose Delays 
Dosing delays are not permitted in Cycle 1.  
If the initiation of Cycle 2 or later must be 
adjusted for reasons unrelated to toxicity 
(e.g., holidays or subject requests), the cycle 
should be started no later than 7 days after 
the originally scheduled next cycle.  If a 
dose delay for toxicity is > 28 days, then the 
subject will be permanently discontinued 
from study treatment.  Schedule 
adjustments can only be made at the 
beginning of each cycle and cannot be made 
mid-cycle. 
Dosing delays are not permitted in Cycle 1.  
If the initiation of Cycle 2 or later must be 
adjusted for reasons unrelated to toxicity 
(e.g., holidays or subject requests), the cycle 
should be started no later than 7 days after 
the originally scheduled next cycle.  If a 
dose delay for toxicity is > 28 days, then the 
subject will be permanently discontinued 
from study treatment.  Schedule 
adjustments can only be made at the 
beginning of each cycle and cannot be made 
mid-cycle. 
Deleted text for clarity and 
consistency around patient 
discontinuations. 
9.6 Missed Doses 
Subjects in the Phase 1b portion of the 
study may not miss more than 1 planned 
dose of oprozomib, 2 planned doses of 
lenalidomide, or 1 planned dose of 
dexamethasone in Cycle 1.  A missed dose 
occurs when the subject does not take the 
dose on the planned calendar day, and the 
dose will not be made up.  If a subject 
misses more than 28 consecutive days after 
completing Cycle 1 for reasons other than a 
hematopoietic stem cell harvest, the subject 
will be permanently discontinued from 
study treatment.   
Subjects in the Phase 1b portion of the 
study may not miss more than 1 any of the 
planned doses of oprozomib or 
cyclophosphamide, or more than  2 4 
planned doses of lenalidomide, or 1 2 
planned doses of oprozomib or 
dexamethasone in Cycle 1 (See Section 4.2 
for details of replacing subjects who miss 
more doses than allowed).  A missed dose 
occurs when the subject does not take the 
dose on the planned calendar day, and the 
dose will not be made up.  If a subject 
misses more than 28 consecutive days after 
completing Cycle 1 for reasons other than a 
hematopoietic stem cell harvest, the subject 
will be permanently discontinued from 
Updated text to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide additional 
clarification on missed doses 
of study drug.  
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study treatment (See Section 9.3 for 
interrupted oprozomib dosing > 4 weeks).   
9.7 Safety Guidance for 
Investigators 
See Section 9.3 for information and 
recommendations for dose adjustments 
required for specific hematologic and 
nonhematologic toxicities. 
See Section 9.3 for information and 
recommendations for dose adjustments 
guidelines required for specific hematologic 
and nonhematologic toxicities.  
Cases of tumor lysis syndrome have been 
observed with proteasome inhibitors.  It 
is recommended that all subjects orally 
hydrate the day before, and days of 
oprozomib dosing.  Additionally, 
allopurinol prophylaxis is recommended 
for renally impaired subjects and those 
with a high tumor burden.  For specific 
recommendations, see Section 9.8.1. 
Added text regarding TLS in 
this section and a cross-
reference to Section 9.8.1, 
Required Concomitant 
Medications. 
9.7.2 Cyclophosphamide 
 
9.7.2  CYCLOPHOSPHAMIDE 
See cyclophosphamide prescribing 
information for additional details 
(Cyclophosphamide Prescribing 
Information 2011; Appendix H) 
Added text to reflect the 
addition of 
cyclophosphamide (in the 
OCyd treatment regimen). 
9.8.1 Required Conconmitant 
Medications 
The following subsection was added: 
9.8.1 
REQUIRED CONCOMITANT MEDICATIONS 
Outside of antimyeloma regimens and the TLS measures noted below, there are no 
required concomitant medications.   However, supportive medications for nausea, 
vomiting and diarrhea are strongly recommended; details are provided in Section 
9.8.2. 
9.8.1.1  Tumor Lysis Syndrom 
For subjects at risk for TLS (Sezer 2006), the following are required: 
Monitoring and Prophylaxis Guidelines:  Oral hydration of 1.5–2 liters per 24 hours 
should be instituted in all subjects 24–48 hours prior to initiation of therapy in every 
cycle, and continued throughout days of 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 ISS Stage II/III or 
rapidly increasing M protein or light chains) or compromised renal function (CrCl < 
Added text to provide 
specific guidance for 
prophylaxis and treatment of 
tumor lysis syndrome. 
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50 cc/min).  These subjects may be at elevated risk for TLS and should be closely 
monitored.  Uric acid levels should be normalized prior to initiation of treatment, if 
appropriate.  
Subjects with laboratory abnormalities prior to dosing that are consistent with lysis of 
tumor cells should not receive the scheduled dose prior to institution of the 
aforementioned preventative measures. 
TLS Laboratory Abnormalities:  Subjects with laboratory abnormalities prior to 
dosing that are consistent with lysis of tumor cells (e.g., as defined by increases of 3 of 
the four categories ) [1] a 2 fold increase of lactate dehydrogenase (LDH) above the 
ULN] [2] increases in serum creatinine, uric acid, or phosphorus > 50% over baseline, 
[3] potassium > 30% above the ULN; or [4] decreases from baseline of calcium > 20% 
in the absence of concomitant bisphosphonate therapy) (Sezer 2006) should not 
receive the scheduled dose prior to institution of the aforementioned preventative 
measures. 
Treatment Guidelines:  If TLS occurs, cardiac rhythm, fluid and serial laboratory 
monitoring should be instituted.  Correction of electrolyte abnormalities, monitoring 
of renal function and fluid balance, 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, subject can resume 
treatment at the initial dose level.       
All cases of TLS must be reported to Onyx Therapeutics, Inc. as an SAE as outlined 
in the protocol. 
9.8.2 Optional and Allowed 
Concomitant Medications 
At least 24 hours prior to Cycle 1 Day 1 and 
for the duration of the study, the following 
medications are strongly recommended per 
published guidelines and institutional 
standards of care (Palumbo 2011): 
• A proton pump inhibitor, such as 
omeprazole or lansoprazole while taking 
dexamethasone 
• Herpes zoster prophylaxis, with acyclovir, 
valacyclovir, or equivalent antiviral while 
taking oprozomib 
• Thrombo-prophylaxis with aspirin (or 
other anticoagulant or antiplatelet 
At least 24 hours prior to Cycle 1 Day 1 and 
for the duration of the study, the following 
medications are strongly recommended per 
published guidelines and institutional 
standards of care (Palumbo 2011): 
• A proton pump inhibitor, such as 
omeprazole or lansoprazole while taking 
dexamethasone 
• Herpes zoster prophylaxis, with acyclovir, 
valacyclovir, or equivalent antiviral while 
taking oprozomib 
• Thrombo-prophylaxis with aspirin (or 
Added text to provide 
specific guidance for 
antinausea and antiemetics, 
and antidiarrheals. 
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medication such as clopidogrel bisulfate, 
low-molecular-weight heparin, or 
warfarin) while taking lenalidomide is 
also strongly recommended (refer to the 
Revlimid Prescribing Information 2012 
for more information). 
Subjects may be premedicated with a 5-HT3 
inhibitor, such as ondansetron or 
granisetron, before administration of the 
first dose of oprozomib each day. 
other anticoagulant or antiplatelet 
medication such as clopidogrel bisulfate, 
low-molecular-weight heparin, or 
warfarin) while taking lenalidomide is 
also strongly recommended (refer to the 
Revlimid Prescribing Information 2012, 
Appendix G for more information). 
9.8.2.1 Antinausea and Antiemetics 
It is strongly recommended that subjects 
be premedicated with a 5 HT3 inhibitor, 
such as ondansetron or granisetron, at 
the first onset of nausea and/or vomiting 
prior to oprozomib dosing 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 be used if needed. 
9.8.2.2 Antidiarrheals 
Grade 1 diarrheas is defined as an 
increase over baseline of < 4 stools per 
day or mild increase in ostomy output 
compared with baseline.  For subjects 
developing any grade of diarrhea, 
Imodium is strongly recommended at the 
first onset of symptoms.  For subjects 
with persistent diarrhea despite the use 
of Imodium, the addition of 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. 
Subjects may be premedicated with a 5-HT3 
inhibitor, such as ondansetron or 
granisetron, before administration of the 
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first dose of oprozomib each day. 
9.8.3 Excluded Concomitant 
Medications 
Concurrent therapy with an approved or 
investigative anticancer therapeutic is not 
allowed. 
During the study, glucocorticoid therapy (in 
addition to dexamethasone) is only 
permitted at the discretion of the treating 
physician after consultation with the Onyx 
study medical monitor to treat a concurrent 
medical condition (e.g., asthma, 
inflammatory bowel disease, or as an 
antiemetic, etc.). 
Concurrent therapy with an approved or 
investigative anticancer therapeutic is not 
allowed. 
During the study, concurrent 
glucocorticoid therapy (in addition to 
dexamethasone) is only permitted to treat a 
concurrent medical condition (e.g., 
asthma, inflammatory bowel disease, or 
as an antiemetic, etc.) at the discretion of 
the treating physician after consultation 
with the Onyx study medical monitor to 
treat a concurrent medical condition (e.g., 
asthma, inflammatory bowel disease, or as 
an antiemetic, etc.). 
Revised text to provide 
clarification regarding 
concurrent glucocorticoid 
therapy. 
10.3 Disease Response 
Assessments 
The schedule of disease assessments for 
subjects treated is provided in Appendix A.  
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 year of 
study participation, at the end of every other 
cycle for the second year of study treatment, 
and every 12 weeks thereafter.  Response 
assessment will be according to the 
International Myeloma Working Group – 
Uniform Response Criteria (IMWG-URC) 
(Appendix E).  All subjects will be followed 
until confirmed disease progression, 
unacceptable toxicity, withdrawal of 
consent, whichever occurs first. 
The schedule of disease assessments for 
subjects treated is provided in Appendix A.  
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 year of 
study participation, at the end of every other 
cycle for the second year of study treatment, 
and every 12 weeks thereafter.  Disease 
response assessments will be performed 
at the end of every 4-week cycle for 24 
cycles of ORd or OCyd treatment,  and 
will continue every 8 weeks thereafter, 
until confirmed PD (See Figure 1, Figure 
2, and Figure 3, for details on the 
duration of cyclophosphamide 
dosing).  Response assessment will be 
according to the International Myeloma 
Working Group – Uniform Response 
Criteria (IMWG-URC) (Appendix E). 
Revised and added text to 
provide clarification 
regarding disease assessments 
and to reflect the addition of 
the OCyd treatment regimen. 
10.6 Assessments at End of Study 
Early discontinuation and End of Study 
For subjects who discontinue treatment 
Revised text to provide 
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Treatment or Early 
Discontinutation 
Assessments must be performed within 30 
days following the subject’s last 
administration of study drug and prior to 
initiation of any other treatment. 
For subjects who discontinue treatment for 
reasons other than progression in either 
study phase, disease assessments will be 
performed at the end of every 4 weeks for 
the first year of study treatment, at the end 
of every other cycle for the second year of 
treatment, and every 12 weeks thereafter.  
The same methods of disease assessment 
must be used throughout the study.  If 
disease assessments show disease 
progression, assessments do not need to be 
repeated with End of Study Assessments. 
before PD occurs (such as for an AE, 
noncompliance, etc.), disease response 
assessments will be performed every 4 
weeks during the first 24 months of the 
study and every 8 weeks thereafter, until 
confirmed PD. 
Early discontinuation and End of Study 
Assessments must be performed within 30 
days following the subject’s last 
administration of study drug and prior to 
initiation of any other treatment. 
For subjects who discontinue treatment for 
reasons other than progression in either 
study phase, disease assessments will be 
performed at the end of every 4 weeks for 
the first year of study treatment, at the end 
of every other cycle for the second year of 
treatment, and every 12 weeks thereafter.  
The same methods of disease assessment 
must be used throughout the study.  If 
disease assessments show disease 
progression, assessments do not need to be 
repeated with End of Study Assessments. 
clarification regarding disease 
assessments for subjects who 
discontinue treatment before 
PD occurs. 
11.1 Study Treatment 
Discontinuation 
Subjects who discontinue from all study 
treatments (i.e., oprozomib, lenalidomide, 
and dexamethasone) will be monitored for 
AEs for 30 days after the last dose of study 
treatment.    
Patients may discontinue study treatment 
for the following reasons: 
• Disease progression  
• Unacceptable toxicity 
• Noncompliance with study procedures 
• Treatment with prohibited concomitant 
medications 
• Intercurrent illness that interferes with 
Subjects who discontinue from all study 
treatments (i.e., oprozomib, lenalidomide, 
and dexamethasone) will be monitored for 
AEs for 30 days after the last dose of study 
treatment (i.e., oprozomib, 
lenalidomide/cyclophosphamide or 
dexamethasone). 
Subjects may discontinue study treatment 
for the following reasons: 
• Disease progression  
• Unacceptable toxicity 
• Noncompliance with study procedures 
Revised text to reflect the 
addition of the OCyd 
treatment regimen and for 
clarification. 
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study assessments 
• Female subject who becomes pregnant, in 
which case treatment must be 
immediately discontinued 
Onyx Therapeutics, Inc., or designee must 
be notified within 24 hours if a subject is 
discontinued from study treatment.  
If the reason for discontinuation is the 
occurrence of an AE, the subject will be 
followed by the investigator until such 
event(s) resolve, stabilize, and according to 
the investigator’s judgment, there is no need 
for further follow-up.  Subjects who 
discontinue study treatment for reasons 
other than disease progression or death may 
continue on study until disease progression 
or death.  The reason for discontinuation 
from study treatment will be documented on 
the eCRF. 
Additional subjects may be enrolled to 
account for subjects who have not had 
adequate safety or efficacy evaluations. 
• Treatment with prohibited concomitant 
medications; details provided in Section 
9.8.3 
• Intercurrent illness that interferes with 
study assessments 
• Female subject who becomes pregnant, in 
which case treatment must be 
immediately discontinued 
Onyx Therapeutics, Inc., or designee must 
be notified within 24 hours if a subject is 
discontinued discontinues from all study 
treatment.  
If the reason for discontinuation is the 
occurrence of an AE, the subject will be 
followed by the investigator until such 
event(s) resolve, stabilize, and according to 
the investigator’s judgment, there is no need 
for further follow-up.  Subjects who 
discontinue study treatment for reasons 
other than disease progression or death may 
continue on study until disease progression 
or death.  The reason for discontinuation 
from study treatment will be documented on 
the eCRF. 
In the Phase 1b portion of the study, 
additional subjects may be enrolled to 
account for subjects who have not had 
adequate safety or efficacy evaluations. 
13.1 Study Endpoints 
13.1.1  Primary Endpoints 
The primary endpoints for the Phase 1b 
portion of this study are: 
• Incidence, nature, and severity of AEs and 
SAEs graded according to NCI-CTCAE, 
version 4.03  
• The MTD of oprozomib given orally on a 
13.1.1  Primary Endpoints 
The primary safety endpoints for the Phase 
1b and Phase 2 portions of this study are: 
• Incidence, nature, and severity of AEs,  
and SAEs, and DLTs (Phase 1b only) of 
oprozomib, given in combination with 
dexamethasone, and either 
Updated text to reflect the 
addition of the OCyd 
treatment regimen, and to 
provide clarification on the 
study endpoints. 
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5 consecutive days, bimonthly schedule in 
combination with lenalidomide and 
dexamethasone 
The primary endpoints for the Phase 2 
portion of this study are: 
• Overall response, defined as a best overall 
response of sCR, CR, VGPR, or PR 
according to the IMWG-URC (see 
Appendix E).  
• Complete response, defined as a best 
overall response of either sCR or CR 
13.1.2  Secondary Endpoints 
The secondary endpoints of this study are: 
• Incidence, nature, and severity of AEs and 
SAEs graded according to NCI-CTCAE 
(version 4.03), changes in laboratory 
parameters, ECGs, and vital signs.   
• Population-based PK parameters 
including, but not limited to, clearance 
and volume of distribution will be 
determined  
• Duration of response, defined as the time 
from evidence of PR or better to 
confirmation of disease progression or 
death due to any cause 
• PFS, defined as duration from the start of 
treatment to disease progression or death 
(due to any cause), whichever comes first  
13.1.3  Exploratory Endpoints 
The exploratory endpoints of this study are: 
• Pharmacodynamic analyses of 
proteasome inhibition will be determined  
• Analyses to potentially identify genetic 
and gene expression biomarkers will be 
lenalidomide or cyclophosphamide, as 
well as changes from baseline in 
selected laboratory analytes, vital signs, 
and ECG findings graded according to 
NCI-CTCAE, version 4.03  
The primary efficacy endpoints for the 
Phase 2 portion of this study are: 
• Overall response, defined as a best overall 
response of sCR, CR, VGPR, or PR 
according to the IMWG-URC (see 
Appendix E).  
• Complete response, defined as a best 
overall response of either sCR or CR 
13.1.2  Secondary Endpoints 
The secondary endpoints of this study are: 
• Incidence, nature, and severity of AEs and 
SAEs graded according to NCI-CTCAE 
(version 4.03), changes in laboratory 
parameters, ECGs, and vital signs.   
• Population-based PK parameters 
including, but not limited to, clearance 
and volume of distribution will be 
determined  
• Duration of response, defined as the time 
from first evidence of PR or better to 
confirmation of disease progression or 
death due to any cause 
• PFS, defined as duration the time from 
the start of treatment to disease 
progression or death (due to any cause), 
whichever comes first  
13.1.3  Exploratory Endpoints 
The exploratory endpoints of this study are: 
• Pharmacodynamic analyses of 
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conducted 
proteasome inhibition will be determined  
• Analyses to potentially identify genetic 
and gene expression biomarkers will be 
conducted 
13.2 Analysis of Study Conduct 
Enrollment, major protocol violations, and 
discontinuations from the study will be 
summarized by the assigned dose cohort 
and for all subjects. 
Demographic and baseline characteristics, 
such as age, sex, race, weight, number of 
prior therapies, and baseline ECOG 
performance status, will be summarized 
using means, standard deviations, medians, 
and ranges for continuous variables, and 
proportions for categorical variables.  All 
summaries will be presented by the 
assigned dose cohort and for all subjects.   
Study drug administration data will be listed 
by dose cohort, and any dose modifications 
will be flagged.  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 cohort and for all 
subjects.   
Enrollment, major protocol violations, and 
discontinuations from the study will be 
summarized for each combination 
regimen by the assigned dose cohort, the 
combined MTD dose level, and for all 
subjects. 
Demographic and baseline characteristics, 
such as age, sex, race, weight, number of 
prior therapies, and baseline ECOG 
performance status, will be summarized 
using means, standard deviations, medians, 
and ranges for continuous variables, and 
proportions for categorical variables.  All 
summaries will be presented for each 
combination regimen by the assigned dose 
cohort, the combined MTD dose level, and 
for all subjects.   
Study drug administration data will be listed 
by arm and dose cohort, and any dose 
modifications will be flagged.  Means and 
standard deviations will be used to 
summarize the total dose for each 
component of study drug received.  All 
summaries will be presented for each arm 
by the assigned dose cohort and for all 
subjects.   
Added text to reflect the 
addition of the OCyd 
treatment regimen, and for 
clarification of summaries to 
be presented.  Text describing 
study drug administration 
data listings was moved to 
Section 13.6.2, Safety 
Analyses.  
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13.5.1 Efficacy Analyses 
All subjects who receive any amount of oprozomib, lenalidomide, or dexamethasone will 
be included in the efficacy analyses. 
Response assessment data, PFS, and DOR will be summarized and listed for all subjects 
by combination regimen, the combined MTD dose level, and dose cohort level. 
Further details on efficacy analysis populations are provided in Section 13.  
Definitions of study endpoints are provided in Section 13.1. 
Overall response rate will be estimated as the proportion of subjects achieving a best 
overall response of sCR, CR, VGPR, or PR according to the IMWG-URC (see Appendix 
E).   
Complete response rate will be estimated as the proportion of subjects achieving a best 
overall response of sCR or CR. 
The approximate lower 1-sided exact Clopper-Pearson 90% confidence intervals based 
upon the normal approximation will be calculated for both the ORR and CRR.  In addition, 
exact Clopper Pearson 95% confidence intervals will be calculated for estimated ORR and 
CRR. 
Among subjects who respond, DOR will be defined as the time from the first evidence of 
confirmed PR or better to confirmation of disease progression or death due to any cause 
(see Table 13 for more information).   
Progression-free survival is defined as the time from the first day of study treatment (Cycle 
1 Day 1) to the earlier of disease progression or deaths due to any cause.   
Summary statistics for DOR and PFS will be calculated using the Kaplan-Meier method.  
For purposes of calculating PFS, the start date for PD is the date at which progression 
is first observed.   For such subjects, the primary analysis of PFS and DOR will be 
right-censored according to the conventions described in Table 13. 
Added text to define the 
response evaluable 
population.  Redundant text 
was deleted and cross-
references were added to 
Sections 13 and 13.1.  Text 
describing censoring for 
primary analysis of PFS and 
DOR was moved to this 
section from Section 13.7, 
Handling of Missing Data. 
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Table 13:  Date of Progression or Censoring for Progression-free Survival and 
Duration of Response 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first study drug 
Censored 
New anticancer treatment started 
before documentation of PD or deatha 
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 visits  
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 
Deatha or PD between planned disease 
assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first 
Progressed 
Deatha before first disease assessment 
Date of deatha 
Progressed 
DOR = duration of response; PD = progressive disease; PFS = progression-free survival. 
a For DOR, death must be due to disease progression, otherwise, both outcomes will be 
censored at the date of last disease assessment.  For PFS, death due to any cause is counted 
as an event. 
The follow-up time for PFS will be summarized by reverse Kaplan-Meier method 
(Schemper 1996). 
 
13.5.2 Safety Analyses 
All subjects who receive any amount of 
oprozomib, lenalidomide, or dexamethasone 
will be included in the safety analyses. 
Safety will be assessed through summaries 
of DLTs, AEs, and changes in laboratory 
test results, ECGs, vital signs, and 
oprozomib exposure by dose cohort and for 
all subjects.   
All collected AE data will be listed by study 
site, dose cohort, subject number, and study 
day.   
All subjects who receive any amount of 
oprozomib, and dexamethasone, 
lenalidomide, or cyclophosphamide will be 
included in the safety analyses. 
Safety and tolerability will be assessed 
through summaries of study drug 
administration, DLTs (Phase 1b only), 
AEs, and changes in selected laboratory test 
results analytes, ECGs, and vital signs, and 
oprozomib exposure by dose cohort, the 
combined MTD dose level, and for all 
Revised text to reflect the 
addition of the OCyd 
treatment regimen and for 
clarification of summaries to 
be presented.  Text describing 
study drug administration 
data listings was moved here 
from Section 13.2, Analysis 
of Study Conduct. 
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subjects.   
Study drug administration data will be 
listed by combination regimen and dose 
cohort, and any dose modifications will 
be flagged.  Means and standard 
deviations will be used to summarize the 
total dose for each component of study 
drug received.  All summaries will be 
presented for each combination regimen 
by the assigned dose cohort, the 
combined MTD dose level, and for all 
subjects.   
All collected AE data will be listed by study 
site, treatment regimen, dose cohort, 
subject number, and study day.   
13.5.3 Pharmacokinetic Analyses 
The NONMEM statistical software program 
(Pharsight, Sunnyvale, CA) will be used to 
fit a nonlinear, mixed effects model to 
estimate PK parameters (clearance and 
volume of distribution), the inter- and intra-
patient variability and the population 
variability in the parameter estimates.   
A population PK software program The 
NONMEM statistical software program 
(Pharsight, Sunnyvale, CA) will be used to 
fit a nonlinear, mixed effects model to 
estimate PK parameters (clearance and 
volume of distribution), the inter- and intra-
patient variability and the population 
variability in the parameter estimates. 
Text was revised as the PK 
software and vendor are to be 
determined. 
13.6 Handling of Missing Data 
Subjects with no post baseline response assessments will be classified as nonresponders in 
the estimation of ORR or CRR. 
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 for subjects who meet any one 
of the following conditions:  1) no baseline disease assessments; 2) begin a new anticancer 
therapy prior to documentation of disease progression or death due to any cause; 3) disease 
progression or death immediately after more than 1 consecutively missed disease 
assessment visit; or 4) are alive without documentation of disease progression prior to the 
data cutoff date.  The same conventions hold for DOR.  For such subjects, the primary 
analysis of PFS and DOR will be right-censored according to the conventions described in 
Table 13. 
Table 13:  Date of Progression or Censoring for Progression-free Survival and Duration of 
Deleted redundant text 
describing nonresponders; 
cross-reference to definition 
of response evaluable 
population in Section 13 was 
added.  
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Section Number 
Changed from 
Changed to 
Rationale 
Response 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first study drug 
Censored 
New anticancer treatment started before 
documentation of PD or deatha 
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 
visits  
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 
Deatha or PD between planned disease 
assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Progressed 
Deatha before first disease assessment 
Date of deatha 
Progressed 
DOR = duration of response; PD = progressive disease; PFS = progression-free survival. 
a For DOR, death must be due to disease progression, otherwise, both outcomes will be censored 
at the date of last disease assessment.  For PFS, death due to any cause is counted as an event. 
Missing data for partial dates on AEs or concomitant medication may be imputed 
according to prespecified, conservative imputation rules.  Censoring rules for PFS 
and DOR and details about the handling of missing data are described in Section 
13.5.1. 
Details on the response evaluable population are provided in Section 13. 
14 References 
Cyclophosphamide [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 
April 2011. 
Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR-171, a novel 
irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383-6391. 
Dispenzieri A, Rajkumar SV, Gertz MA, et al.  Treatment of newly diagnosed 
multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted 
Therapy (mSMART): consensus statement.  Mayo Clin Proc. 2007 Mar;82(3):323-41. 
Kaufman JL, Siegel 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. Presented at the European Hematological Association (EHA) Meeting; June 13–
16, 2013; Stockholm, Sweden. Abstract P233. 
Added references to provide 
background on 
cyclophosphamide (reflecting 
the addition of the OCyd 
treatment regimen).  Updated 
reference for median OS 
estimates for patients with 
multiple myeloma (Mikhael 
2013).  Added reference for 
guidance on TLS laboratory 
abnormalities (Sezer 2006).  
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Section Number 
Changed from 
Changed to 
Rationale 
Kropff M, Bisping G, Schuck E, et al.; Deutsche Studiengruppe Multiples Myelom. 
Bortezomib in combination with intermediate-dose dexamethasone and continuous 
low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 
Aug;138(3): 330–7. 
Korde N, Zingone A, Kwok M, et al. Phase II Clinical and Correlative Study of 
Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple 
Myeloma (MM) Patients.  Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 
732. 
Kropff M, Liebisch P, Knop S, et al.; Deutsche Studiengruppe Multiples Myelom, 
DSMM. DSMM XI study: dose definition for intravenous cyclophosphamide in 
combination with bortezomib/dexamethasone for remission induction in patients with 
newly diagnosed myeloma. Ann Hematol. 2009;88(11):1125–30. 
Kummar S, Gutierrez M, Doroshow JH, Murgo, AJ. Drug development in oncology: 
classical cytotoxics and molecularly targeted agents. Br J Clin Pharm. 2006;62:15–26. 
Mikhael JR, Reeder CB, Libby EN III, et al. Results from the phase II dose expansion 
of cyclophosphamide, carfilzomib, thalidomide and dexamethasone (CYCLONE) in 
patients with newly diagnosed multiple myeloma. ASH 2012, abstr 445. 
Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic 
multiple myeloma: updated mayo stratification of myeloma and risk adapted therapy 
(msmart) consensus guidelines 2013. Mayo Clin Proc. n April 2013;88(4):360 376. 
Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and 
dexamethasone (CTD) as initial therapy for patients with multiple myeloma 
unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. 
Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and 
dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. ASH 
2012; abstr 730 
Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral 
cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J 
Clin Oncol. 2008 Oct 10;26(29):4777–83.  
Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and 
dexamethasone induction for newly diagnosed multiple myeloma: high response rates 
in a phase II clinical trial. Leukemia. 2009;23(7):1337–41. 
Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib 
induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 
2010;115(16):3416–7. 
Sezer O, Vesole DH, Singhal S, et al.  Bortezomib-Induced Tumor Lysis Syndrome in 
Multiple Myeloma. Clinical Lymphoma and Myeloma. Vol. 7, No. 3, 233-235, 2006. 
Added reference for the 
definition of MTD (Kummar 
2006). 
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Section Number 
Changed from 
Changed to 
Rationale 
Volpe DA, Warren MK. Myeloid clonogenic assays for comparison of the in vitro 
toxicity of alkylating agents. Toxicol In Vitro. 2003 Jun;17(3):271-7. 
14 References 
Jagannath S, Richardson RG, Barlogie B, et 
al. Bortezomib in combination with 
dexamethasone for the treatment of patients 
with relapsed and/or refractory multiple 
myeloma with less than optimal response to 
bortezomib alone. Haematologica. 
2006;91(7): 929–34. 
Jagannath S, Richardson RG, Barlogie B, et 
al. Bortezomib in combination with 
dexamethasone for the treatment of patients 
with relapsed and/or refractory multiple 
myeloma with less than optimal response to 
bortezomib alone. Haematologica. 
2006;91(7): 929–34. 
Removed reference as it is no 
longer relevant in the revised 
section. 
14 References 
Jawed I, Lee CM, Tward JD, et al. Survival 
outcomes for multiple myeloma over three 
decades: A Surveillance, Epidemiology, and 
End Results (SEER) analysis. J Clin Oncol. 
2007;25 (No. 18S June 20 Supplement): 
Abstract 8019. 
Jawed I, Lee CM, Tward JD, et al. Survival 
outcomes for multiple myeloma over three 
decades: A Surveillance, Epidemiology, and 
End Results (SEER) analysis. J Clin Oncol. 
2007;25 (No. 18S June 20 Supplement): 
Abstract 8019. 
Removed reference as an 
updated reference was added 
(Mikhael 2013). 
Appendix B 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 
Added the ECOG source 
information in the table 
footnote; revised text to 
match the source information. 
Appendix H Cyclophosphamide 
Prescribing Information 2011 
 
Cyclophosphamide Prescribing 
Information 2011 
Added cyclophosphamide 
prescribing information as an 
appendix, reflecting the 
addition of the OCyd 
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Section Number 
Changed from 
Changed to 
Rationale 
treatment regimen. 
Appendix J Revlimid REMS 
Guide 
 
http://www.revlimidrems.com/pdf/REV_
Prescriber_Guide.pdf 
Added Revlimid REMS 
Guide as an appendix to 
provide guidance for females 
and males of reproductive 
potential.  This change was 
applied to both treatment 
regimens to minimize the risk 
for confusion around the 
guidance. 
Other 
Administrative updates, editorial changes, 
and style and formatting revisions have 
been made to improve clarity and 
consistency throughout the document.   
 
 
 
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Changes in Appendix A of Amendment 1:  Strikethrough indicates text that was deleted and bold indicates text that was added. The 
changes in Appendix A were made to reflect the addition of the OCyd treatment regimen, and to provide additional clarification 
regarding the study assessments. 
APPENDIX A:  SCHEDULE OF STUDY ASSESSMENTS 
Visit 
Screening 
Cycle 1 
Cycle 2–24 
Cycle 25+ 
EOS/ 
Early 
Discon. 
End of 
Study 
Treatmentb 
Day 
-14 to -1 
Day 
1 
Day 
2 
Day  
3, 4 
Day 
5 
Day 
6, 7 
Day 
8 ± 1 
Day 
9‒14 
Day 
15 ± 1 
Day 
16–21 
Day 
22–28 Day 1 
Day 
2–14 
Day 
15 ± 1 
Day 
22–28 
Day  
1 
Day 
22–28a 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Neurological Assessment 
(BPNS and CTCAE Grading)d  
X 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
 
X 
Vital Signs 
X 
Xe 
Xe 
 
Xe 
 
X 
 
Xe 
 
X 
Xf 
 
Xf 
 
 
 
X 
12–lead ECG (Local)  
X 
Xg 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
X 
Urinalysish 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum Chemistryi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Xj 
 
X 
 
Xj 
 
X 
CBC with Diff and Plateletsk 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Xj 
 
X 
 
Xj 
 
X 
Coagulation Testsl 
X 
X 
 
 
 
 
 
 
 
 
 
Xj 
 
 
 
Xj 
 
 
Pregnancy Testm 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
SPEP/UPEP/Immunofixationn 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
β2 Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SFLC assay and ratioo 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Skeletal Surveyp 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Plasmacytoma Evaluationq 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Bone Marrow Aspirate and 
FISH Analysesr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xs 
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APPENDIX A:  SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Visit 
Cycle 1 
Cycle 2–24 
Cycle 25+ 
End of 
Study 
Treatmentb 
Day 
-14 to -1 
Day 
1 
Day 
2 
Day  
3, 4 
Day 5 
Day 
6, 7 
Day 
8 ± 1 
Day 9-
14 
Day 
15 ± 1 
Day 
16–21 
Day 
22–28 
Day 
1a 
Day 
2–14 
Day 
15 ± 1 
Day 
22-28 
Day  
1 
Day 
22–28a 
Optional – Genomic Biomarker 
Assessment:  Bloods 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Optional – Genomic Biomarker 
Assessment:  Salivas 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PKt 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Blood for PDn Assayu 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Oprozomib Dosing 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
Dexamethasone Dosing 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Lenalidomide Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Treatment Regimen 1 (ORd) 
Dosingv: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oprozomib 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
Lenalidomide 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Dexamethasone 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Treatment Regimen 2  
(OCyd) Dosingw: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oprozomib 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
Cyclophosphamide 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
 
 
Dexamethasone 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AEs and Con Medsx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cycle 1 Follow-up Telephone  
Call to Subject 
 
 
 
Xy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE, = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPNS = Brief Peripheral Neuropathy Screen; CBC = complete blood 
count; CR = complete response; CrCl = creatinine clearance; CRF = case report form; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End of Study;  FCBP = females of child-bearing potential; 
FISH = fluorescent in-situ hybridization; MRI = magnetic resonance imaging; OCyd = oprozomib, cyclophosphamide, and dexamethasone; ORd = oprozomib, 
lenalidomide, and dexamethasone; PD = progressive disease; PDn = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; 
SFLC = serum free light chain; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis. 
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a Disease response assessments will occur every cycle for the first year (Cycles 1–12), every other cycle for the second year (Cycles 13–24) and every 12 weeks 
(3 cycles) starting with Cycle 27 (e.g., Cycle 27, Cycle 30, Cycle 33, etc.).  Test results must be available before starting the next 28–day cycle of oprozomib. 
Following completion of 8 cycles of ORd or OCyd treatment, disease response assessments will continue every 8 weeks until confirmed PD. For subjects 
who discontinue treatment before PD occurs (such as for an AE, noncompliance, etc.), disease response assessments will be performed every4 weeks 
during the first 24 months of the study and every 8 weeks thereafter, until confirmed PD or the start of alternative, non-protocol antimyeloma therapy.   
b 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.  The same methods of disease assessment must be used throughout the study.  For subjects who 
discontinue treatment for reasons other than progression, disease assessments must be performed every 8 weeks (or 12 weeks if patient at cycle > 24) or until a new 
multiple myeloma therapy is started or disease progresses.  If disease assessments show disease progression, assessments do not need to be repeated with End 
of Study Treatment Assessments. 
c Complete physical exams will be performed during Screening and at the End of Study Treatment visit.  All other physical exams will be limited physical exams.  A 
complete physical examination will include examination of the skin, head and neck, chest (heart and lungs), abdomen, extremities, and a brief neurological exam 
including an assessment for peripheral neuropathy.  Rectal and pelvic examinations are optional.  Eastern Cooperative Oncology Group performance status 
(assessed at the time of the physical exam) will be conducted collected during a complete physical exam.  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. 
d Neurological assessments (BPNS, and if applicable, record adverse events with CTCAE grading) will be performed at Screening and on Day 1 for Cycles 2–24.  
e Measure within 1 hour prior to on day of dosing, prior to the administration of oprozomib dose and at 30 minutes, 1 hour, and 2 hours after each oprozomib dose 
(Cycle 1 Days 1, 2, 5, 8, and 15).  At the investigator’s medical discretion, vital signs monitoring may be extended beyond the time periods specified above 
f 
Cycles 2 and higher, vital signs are required within 1 hour on the day of dosing, prior to the administration of oprozomib dose. 
g Perform ECG within 1 hour predose and 2 hours postdose of oprozomib (see Laboratory Manual) for Cycles 1, 2, 3, 4, 6, 8, 12, 18, 24 and then every 6 months 
(Cycle 30, 36, etc.).   
h Subjects with urine positive for protein (> than trace) will need to collect a 24–hour urine sample for creatinine and protein. 
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) to be done within 4 hours prior to dosing.  Calculate or measure CrCl. 
Screening results may be used for Cycle 1 Day 1 if obtained within 72 hours of Cycle 1 Day 1. 
j 
Day 1 labs can be drawn up to 3 days prior to Day 1. 
k Complete blood count (CBC) with differential includes the following:  hemoglobin, hematocrit, white blood cell count with complete manual or automated 
differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell count, and platelet count. 
l 
Coagulation tests include the following:  prothrombin time, activated partial thromboplastin time, and international normalized ratio. 
m For both treatment regimens (ORd and OCyd):  Screening pregnancy testing for females of childbearing potential (FCBP) must have a sensitivity of at least 25 
mIU/mL with TWO medically supervised tests performed before lenalidomide or cyclophosphamide dosing starts.  One test must be obtained within 10–14 days 
and one test within 24 hours prior to the start of lenalidomide or cyclophosphamide on Cycle 1 Day 1.  A medically supervised negative serum pregnancy test will 
be done within 1 day prior to each cycle of lenalidomide or cyclophosphamide dosing, on Day 8, Day 15, and between Days 22–28 of Cycle 1; on Day 15 for 
Cycles 2 and higher; and at the End of Study Treatment visit, in FCBP potential only.  Pregnancy tests will be repeated on Day 15 of each Cycle 2 and beyond 
if menses are irregular or not present in FCBP. 
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n Results for both SPEP and UPEP done 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 for the first year (Cycles 1–12),  every other cycle for year 2 (Cycle 13–24) and every 3 cycles for 
year 3 (Cycle 27, Cycle 30, Cycle 33, etc.).  If the subject comes off study then disease response assessments will be performed every 4 weeks during the first year 
of treatment, every 8 weeks during the second year and every 12 weeks thereafter.  Obtain blood for serum electrophoresis (SPEP), serum immunofixation, serum 
immunoglobulin levels, and serum FLCs and 24–hour urine sample for urine protein electrophoresis (UPEP) and urine immunofixation.  NOTE: UPEP (on a 24–
hour collection) is required; no substitute method is acceptable.  Subjects with negative serum and urine M–proteins are required to complete FLC at each time 
point.   
SPEP and UPEP (24-hour assessment, no substitute method is acceptable) is required for all subjects at Screening.  Thereafter, SPEP is to be done at each 
assessment for all subjects.  UPEP with 24-hour urine collection is required at each assessment only if screening UPEP shows measurable paraprotein in 
the urine.  If screening UPEP is negative, spot urine is required at each assessment.  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 the absence of paraprotein.  Immunofixation is required 
at next assessment only if SPEP or UPEP results are zero/undetectable. 
o Serum free light chain:  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.   
p Skeletal survey does not need to be repeated if previously done within 30 days of consent.  If a skeletal survey was previously done greater than 30 days before 
consent, it may be acceptable with study medical monitor approval.  If present at Baseline, bone lesion (s) must be monitored throughout the study per IMWG 
response criteria.   
Skeletal survey will include lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and 
humeri.  The skeletal survey will be conducted at Screening and will be repeated if worsening clinical symptoms suggest PD, or as clinically indicated. 
q Subjects are required to have a plasmacytoma evaluation at Screening and End of Study.  If present at Baseline, the plasmacytoma(s) must be monitored throughout 
the study per IMWG response criteria. 
Extramedullary plasmacytoma evaluation will be conducted at Screening only if a lesion is suspected clinically.  Only measurable plasmacytomas will be 
followed for response and progression.  Measurable lesions must have a longest diameter of at least 1 cm and the product of cross diameter is at least 1 
cm2.  Plasmacytomas of lessor size are considered non measurable.  If an extramedullary plasmacytoma is detected, evaluation will be repeated during 
treatment as clinically indicated, or to confirm a response of PR or better, or to confirm PD.  The same technique (which may include clinical evaluation 
by palpation, ultrasound, x-ray, CT scan, MRI, or PET) should be employed for each measurement of plasmacytoma dimensions as clinically appropriate 
(refer to Appendix D).  Bi-dimensional lesion measurements must be performed and recorded in the designated eCRF. 
r 
Bone marrow aspirate or biopsy – quantitate percent myeloma cell involvement.  Obtain bone marrow sample for fluorescent in situ hybridization (FISH) studies. 
Repeat bone marrow aspirate when appropriate to confirm achievement of sCR or CR.   
Bone marrow aspiration and biopsy are required for all subjects at Screening to quantify percent plasma cell involvement and for FISH.  FISH will be 
performed at a central laboratory.  Thereafter, an additional bone marrow aspiration is required to confirm a CR; a biopsy is required if bone marrow 
aspiration cannot be performed.  
s 
Optional genomic biomarker samples:  For subjects who consent to participate, bone marrow aspirate (obtained from the bone marrow aspirate for FISH analysis; 
no new sample is required), blood, and saliva samples will be collected at baseline.  Bone marrow aspirate will also be collected at the time of progression End of 
Study Treatment visit (may be at time of treatment discontinuation or during long term follow-up) for isolation of CD138+ cells; bone marrow will be collected 
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only from subjects consenting to genomic biomarker analyses and who achieve less than a CR; bone marrow will be collected at the time of PD or End of 
Treatment.  
t 
Blood for PK for subjects will occur at two postdose time points on Cycle 1 Day 1, one predose and 2 postdose time points on Cycle 3 Day 1 and Cycle 5 Day 1.  
Sampling times and volumes are provided in the Laboratory Manual. 
u Blood for PDn analyses  measurement of proteasome activity in whole blood and PBMCs will only be collected in Phase 1b.  Samples will be collected 
predose, and at 2 postdose time points on Day 1 of Cycles 1 and 2, and predose on Cycle 1 Day 2.  Sampling times and volumes are provided in the Laboratory 
Manual. 
v Treatment Regimen 1 (ORd):  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.  Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day 
treatment cycle up to Cycle 24.  After Cycle 1, the dexamethasone dose may be decreased to 10 mg/day in subjects > 75 years of age, at the discretion of the 
investigator.  On days when both 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.  Except for PK collection days, lenalidomide will be administered orally at a dose of 25 mg, with or without 
food at investigator and subject discretion, on Days 1–21 of each 28 day cycle up to Cycle 24.  Subjects may take lenalidomide following oprozomib 
administration, however it is recommended that they take lenalidomide at approximately the same time each dayOprozomib and lenalidomide should be 
taken concurrently, i.e., within 5 minutes of each other.  On days when oprozomib is not administered, subjects should take lenalidomide at approximately 
the same time of the day for consistency. 
w Treatment Regimen 2 (OCyd): Oprozomib treatment will be administered on Days 1–5 and 15–19 during 28-day cycles for up to 8 cycles or until disease 
progression, unacceptable toxicity, or study treatment discontinuation for any reason.  Subjects will receive 20 mg of dexamethasone on Days 1, 2, 8, 9, 15, 
16, 22 and 23 of each 28-day treatment cycle up to Cycle 8.  After Cycle 1, the dexamethasone dose may be decreased to 10 mg/day in subjects > 75 years 
of age, at the discretion of the investigator.  On days when both oprozomib and dexamethasone are administered (i.e., on Days 1, 2, 15, and 16 of each 
cycle), dexamethasone should be taken at least 30 minutes prior to oprozomib.  Except for PK collection days, cyclophosphamide will be administered 
orally at 300 mg/m2 (up to a maximum of 600 mg), with or without food at investigator and subject discretion, on Days 1, 8, and 15 of each cycle for a total 
of 8 cycles.  Subjects may take cyclophosphamide following oprozomib administration at, however it is recommended that they take cyclophosphamide 
concurrently with oprozomib at approximately the same time each day.  On days when oprozomib is not administered, subjects should or must take 
cyclophosphamide at approximately the same time of the day for consistency. 
x Record all AEs from time of consent through 30 days after the last dose of study drug.  Start to record concomitant medications from 30 days prior to Day 1 until 
30 days after the last dose of study drug.  If there is any change in the subject’s concomitant medications during the study, it must be recorded on the CRF. 
y For subjects in the Phase 1b portion:  The study nurse (or designee) will call the subject on Cycle 1 Days 3 and 4, approximately 6–10 hours after the expected 
study drug dosing time to follow up on dosing compliance and to collect start, stop, and duration times as well as severity of any AEs, if applicable. 
 
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UserName: 
 
Title:  Vice President, Global Regulatory Affairs 
Date: Wednesday, 18 September 2013, 03:09 PM   Pacific Daylight Time 
Meaning: I have reviewed and approved this document. 
================================================
UserName: 
 
Title:  Executive Vice President, Global R&D and Technical Operations 
Date: Wednesday, 18 September 2013, 07:42 PM   Pacific Daylight Time 
Meaning: I have reviewed and approved this document. 
================================================
UserName: 
 
Title:  Vice President of Clinical Science and Biometrics 
Date: Thursday, 19 September 2013, 12:20 PM   Pacific Daylight Time 
Meaning: I have reviewed and approved this document. 
================================================
Document Title:
protocol-opz003-a1
Workflow Number:
10158950
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130410
14 January 2020
Page 183

Superseded 
 
 
Onyx Therapeutics
Clinical Study Protocol No. OPZ003
Oprozomib
Page 119 of 142
CONFIDENTIAL
APPENDIX L
SUMMARY OF CHANGES IN PROTOCOL OPZ003 
AMENDMENT 2
The main changes in Clinical Study OPZ003 Amendment 2 are listed below:
Study Design
1. The current dose of oprozomib on the 5/14 schedule is 150 mg.  The study was initiated 
at 210 mg and the dose was reduced to 150 mg after DLTs were reported in the 210 and 
180 mg cohorts.  The protocol has been updated through out to reflect these events.  The 
150 mg dose is 3 full dose levels below the single-agent MTD.
2. The dosing schedule was changed from 5/14 to 2/7 for subsequent cohorts in the ORd 
arm and for all subjects in the OCyd arm to provide an increased margin of safety for 
subjects participating in this study.  The initial dose of oprozomib for the OCyd and ORd 
arms on the 2/7 schedule is 210 mg.  It is 3 full dose levels below the single agent MTD 
on the 2/7 schedule.
3. Introduced the new Oprozomib Extended Release (ER) Tablet and the strengths to be 
used in this study.
Exclusion Criteria
4. Added language excluding patients undergoing or expected to require plasmapheresis 
during the screening process or any time during the study.
5. Added exclusion criterion for patients with prior clinically significant bleed in the 
6 months prior to first dose of study treatment.
Dose Modification Guidelines/Safety Guidance for the Investigator
6. Additional safety guidance regarding Grade 3 or 4 GI hemorrhages.
7. Added guidance for subjects receiving anti-hypertensive therapy about the risk for 
hypotension.
Laboratory Evaluations for Safety
8. Platelet function assessment to understand impact of oprozomib, if any, on platelet 
adherence, activation, aggregation and interaction with clotting factors.
Administrative updates, editorial changes, and style and formatting revisions have been made to 
improve clarity and consistency throughout the document.  Significant changes are described in 
the table below.  Detailed, changed text is displayed for first major occurrence only.  Changes 
in sections of the protocol body were also made in the protocol synopsis and elsewhere in the 
document, as applicable.  Deletions of text are presented in strikethrough format.  Added text is 
presented in bold format.
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Date: 
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14 January 2020
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Clinical Study Protocol No. OPZ003
Oprozomib Tablets
Page 120 of 142
CONFIDENTIAL
Section Number
Changed from
Changed to
Rationale
Cover Page
Signature Page
Protocol Acceptance Page
New text added
Amendment 2 and 15 October 2014 
Updated for new amendment
Compliance, confidentiality, 
and approval statements
This document is signed with electronic 
signatures at Onyx Therapeutics, Inc. (a wholly 
owned subsidiary of Onyx Pharmaceuticals, Inc.).  
Electronic signatures made by our employees, 
agents, or representatives, located anywhere in 
the world, are the legally binding equivalent of 
traditional handwritten signatures.
This document is signed with electronic 
signatures at Onyx Therapeutics) a wholly 
owned subsidiary of Onyx Pharmaceuticals) 
an Amgen subsidiary.  Electronic signatures 
made by our employees, agents, or 
representatives, located anywhere in the 
world, are the legally binding equivalent of 
traditional handwritten signatures.
Updated compliance 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
Cover Page
Added text
Amendment 2 or “2”
Updated for new amendment
Signature Page
Superseded: List of approvers
Updated: List of approvers
Updated list of approvers
Synopsis
  Study Objectives
    Secondary Objective
Section 3.2 Study Objectives
Synopsis
  Study Design
    Pharmacokinetics
Section 13.6.3 Pharmacokinetic
Analysis
Secondary Objectives

To evaluate population pharmacokinetic (PK) 
parameter estimates of oprozomib and the 
variability in these estimates. 
Secondary Objectives

To evaluate population pharmacokinetic 
(PK) parameter estimates of oprozomib
and, may include its metabolite(s), and 
the variability in these estimates. 
Added option to perform these 
analyses if necessary
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Oprozomib Tablets
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CONFIDENTIAL
Section Number
Changed from
Changed to
Rationale
Synopsis
  Study Design
  Treatment regimen
Section 4 Study Design
Updated the study schema to 
add the 2/7 schedule and added 
an additional study scheme for 
2/7 schedule
Added a dose administration 
figure for the  2/7 schedule
Section 9 Dosage and 
Treatment Administration
Added Appendix B Schedule of 
Assessments for the 2/7 
Schedule
In one combination regimen, ORd, subjects will 
receive Oprozomib Tablets (hereafter referred to 
as oprozomib) administered orally, once daily on 
Days 1-5 and on Days 15-19 in combination with 
lenalidomide at a dose of 25 mg on Days 1 
through 21, and dexamethasone at a dose of 20 
mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 of 
28-day cycles (see dose administration schema 
below).  
In the second combination regimen (OCyd), 
subjects will receive oprozomib administered 
orally, once daily on Days 1–5 and on Days 15–
19 in combination with oral cyclophosphamide at 
a dose of 300 mg/m2 on Days 1, 8, and 15, and 
dexamethasone at a dose of 20 mg on Days 1, 2, 
8, 9, 15, 16, 22, and 23 of 28-day cycles (See 
dose administration schema below).   
Dexamethasone will be administered at a dose of 
20 mg/day, as described above, through the first 
cycle, after which the dose may be decreased to 
10 mg/day in subjects > 75 years of age, at the 
discretion of the investigator.
The ORd combination regimen treatment 
cycles are 28 days in duration.  Subjects 
enrolled under the original protocol and 
Amendment 1 will receive oprozomib once 
daily on Days 1 through 5 and Days 15 
through 19 (referred to as the 
5/14 schedule).  Subjects enrolled under 
Amendment 2 will receive oprozomib once 
daily on 2 consecutive days every 7 days; 
specifically on Days 1, 2, 8, 9, 15, 16, 22, and 
23 (referred to as the 2/7 schedule).  All 
subjects on the ORd arm will receive 
lenalidomide at a dose of 25 mg will be given 
on Days 1 through 21 and dexamethasone at a 
dose of 20 mg will be given on Days 1, 2, 8, 9, 
15, 16, 22, and 23 of every 28-day cycle (see 
dose administration schemas below).
The OCyd regimen treatment cycles are 
28 days in duration.  One (1) oprozomib 
dosing schedule (2/7) will be assessed 
during dose escalation.  All study subjects 
will receive oprozomib administered orally, 
once daily on 2 consecutive days every 
7 days; specifically on Days 1, 2, 8, 9, 15, 16, 
23, and 22 (referred to as the 2/7 schedule)
in combination with oral cyclophosphamide at 
a dose of 300 mg/m2 on Days 1, 8, and 15, and 
dexamethasone at a dose of 20 mg on Days 1, 
2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. 
(See dose administration schema below.)  
Dexamethasone will be administered at a dose 
of 20 mg/day, as described above, through the 
first cycle, after which the dose may be 
decreased to 10 mg/day in subjects > 75 years 
of age, at the discretion of the investigator.
The dosing schedule was 
changed from 5/14 to 2/7 for 
subsequent cohorts in the ORd 
arm and for all subjects in the 
OCyd arm to provide an 
increased margin of safety for 
subjects participating in this 
study.  
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Oprozomib Tablets
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Section Number
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Changed to
Rationale
Synopsis
  Study Design
    Phase 1b
Section 2.5 Dose Rationale
Section 4 Study Design
Section 4.2 Dose Escalation 
Plan
Modified Tables 3 and 4 and 
added Table 5
Added Appendix B Schedule of 
Assessments for the 2/7 
Schedule
Phase 1b
The initial cohort for each combination regimen 
will be entered at a dose level of 210  mg/day 
oprozomib.  
The dose of oprozomib for subsequent cohorts 
will be escalated in 30-mg increments until the 
MTD is established.  
In the Phase 1b portion of the study, dose cohorts 
will be enrolled sequentially, alternating between 
the ORd and OCyd treatment regimens across 
sites.
There will not be a predefined maximum dose to 
be studied.  Subjects will be evaluated for DLTs 
according to the National Cancer Institute –
Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), version 4.03.  In the event 
that the initial cohorts at the 210 mg dose are
found to exceed the MTD, dosing will proceed at 
180 mg or a lower dose as agreed to by the 
Cohort Safety Review Committee (CSRC), 
comprised of the Onyx study medical monitor, 
Onyx safety representative, and the active 
investigators.  Intrasubject dose escalation to the 
MTD or recommended Phase 2 dose may be 
permitted once that dose has been determined and 
after a discussion has occurred between the 
treating physician and Onyx study medical 
monitor.
Phase 1b
The initial cohort dose levels for each 
combination regimen is as follows:

Original Protocol and Amenment 1 -
ORd (5/14 schedule):  210 mg/day of 
oprozomib (current 5/14 cohort dose 
level is 150 mg/day of oprozomib)  
There have been 2 dose de-escalations 
in the ORd 5/14 arm in response to 
dose limiting toxicities (DLTs) 
occurring at the 210 mg and the 180 
mg cohort level.

Amendment 2 - ORd (2/7 schedule):  
210 mg/day of oprozomib

Amendment 2 - OCyd (2/7 schedule):  
210 mg/day of oprozomib
The dose of oprozomib for cohorts will be 
escalated or de-escalated in 30-mg 
increments until the MTD is established. 
Subjects on the 5/14 schedule will not have 
their oprozomib dose escalated above 
150 mg/day.
There will not be a predefined maximum dose 
to be studied.  Subjects will be evaluated for 
DLTs according to the National Cancer 
Institute - Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 4.03.
In the event that the ORd cohort at the 
210 mg dose (2/7 schedule) is found to 
exceed the MTD, dosing will proceed at 
180 mg or a lower dose as agreed to by the 
Cohort Safety Review Committee (CSRC), 
comprised of the Onyx study medical monitor, 
Onyx safety representative, and the active 
investigators. 
In the event that the initial OCyd cohorts at 
the 210 mg dose (2/7 schedule) are found to 
The dosing schedule was 
changed from 5/14 to 2/7 for 
subsequent cohorts in the ORd 
arm and for all subjects in the 
OCyd arm to provide an 
increased margin of safety for 
subjects participating in this 
study
Dose de-escalation language 
has been added.
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exceed the MTD, dosing will proceed at 
180 mg or a lower dose as agreed to by the 
CSRC. Intrasubject dose escalation to the 
MTD or recommended Phase 2 dose (RP2D) 
may be permitted once that dose has been 
determined and after a discussion has occurred 
between the treating physician and Onyx 
study medical monitor.
Synopsis
    Study Design
      Dose-Limiting Toxicities
Section 9.1.3 Definition of 
Dose-Limiting Toxicity
Table 13: Dose Modification 
Guidelines for Oprozomib-, 
Lenalidomide-, and 
Cyclophosphamide-Related 
Nonhematologic Toxicities 
Post-Cycle 1 (added last row 
and related footnote)
Hematologic DLT:

Grade 4 neutropenia:  Absolute neutrophil 
count (ANC) < 0.5 × 109/L lasting ≥7 days, 
despite myeloid growth factor support

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)

Grade 4 thrombocytopenia lasting ≥ 7 days  
or Grade 3 thrombocytopenia with bleeding 
or requiring platelet transfusion

Note:  Grade 4 anemia will not be considered 
a DLT.
Hematologic DLT:

Grade 4 neutropenia:  Absolute neutrophil 
count (ANC) < 0.5 × 109/L lasting ≥7 
days, despite myeloid growth factor 
support

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)

Grade 4 thrombocytopenia lasting ≥ 7 
days or

Grade 4 thrombocytopenia lasting 
< 7 days with > Grade 2 clinically 
significant bleeding 
or < 10,000 platelets requiring platelet 
transfusion, or 

Grade ≥3 thrombocytopenia with 
clinically significant bleeding or 
requiring platelet transfusion.
Note:  Grade 4 anemia will not be considered 
a DLT, but should be treated with 
supportive measures in accordance with 
institutional guidelines.
Additional guidance to 
investigators to mitigate Grade 
3 or 4 GI hemorrhage
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Section Number
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Rationale
Synopsis
    Study Design
      Subject Replacement
Subject Replacement
Phase 1b: 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:
A minimum of 8 of 10 planned doses of 
oprozomib must be received
A minimum of 6 of 8 planned doses of 
dexamethasone must be received 
All 3 planned doses of cyclophosphamide 
must be received (OCyd combination 
regimen only)
A minimum of 17 of 21 planned doses of 
lenalidomide must be received (ORd 
combination regimen only)
Subjects not meeting all of the above criteria 
or assessed as unevaluable will be replaced.  
Subjects who do not meet the criteria above 
because of a DLT will be considered DLT-
evaluable.  
Subject Replacement
Phase 1b: 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:
A minimum of 8 of 10 planned doses of 
oprozomib must be received for the 
5/14 dosing schedule
A minimum of 7 of 8 planned doses of 
oprozomib must be received for the 
2/7 dosing schedule
A minimum of 6 of 8 planned doses of 
dexamethasone must be received 
All 3 planned doses of 
cyclophosphamide must be received 
(OCyd combination regimen only)
A minimum of 17 of 21 planned doses of 
lenalidomide must be received (ORd 
combination regimen only)
Subjects not meeting all of the above 
criteria or assessed as unevaluable will 
be replaced.  Subjects who do not meet 
the criteria above because of a DLT will 
be considered DLT-evaluable.  
Updated to include subject 
replacement information for 
both dosing schedules
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Oprozomib Tablets
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Section Number
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Rationale
Synopsis
    Study Design
      Phase 2
Section 4 Study Design
Section 4.2 Dose-Escalation 
Plan
Modified Tables 3 and 4, and 
added Table 5
Phase 2
The Phase 2 portion of the study will include up 
to 35 additional subjects in each of the two
combination regimens, with the same eligibility 
criteria as those in Phase 1b.  Phase 2 subjects 
will be treated at the recommended Phase 2 dose
and schedule of oprozomib identified during the 
Phase 1b portion of the study in order to better 
characterize the safety and tolerability, 
antimyeloma activity, and PK.  The 
recommended Phase 2 dose may or may not be 
the same as the MTD, and will be assessed on the 
basis of the totality of safety and PK/PDn data.  In 
the Phase 2 portion of the study, subjects will be 
enrolled alternately between OCyd and ORd 
treatment regimens at each study site.
Phase 2
The Phase 2 portion of the study will include 
up to 35 additional subjects in each of the 2 
combination regimens, with the same 
eligibility criteria as those in Phase 1b.  Phase 
2 subjects will be treated at the RP2D dose 
and schedule of oprozomib identified during 
the Phase 1b portion of the study in order to 
better characterize the safety and tolerability, 
antimyeloma activity, and PK.  The RP2D
may or may not be the same as the MTD, and 
will be assessed on the basis of the totality of 
safety and PK/PDn data.  Subjects enrolled 
under Amendment 2 will receive 
Oprozomib Extended Release (ER) Tablets
Introduce the new Oprozomib 
Extended Release (ER) Tablet.
Removed last sentence to 
allow flexibility for enrollment
and avoid possible protocol 
deviations. 
Synopsis
  Study Design
   Genomics
  Criteria for evaluation
    Other
     Genomics
Section 10.5 Genomic 
Evaluations
Appendix A and B:  Schedule 
of Study Assessments and 
related footnotes
Genomics:  Analysis of genetic and gene 
expression, biomarkers that may predict for 
response and resistance following treatment with 
proteasome inhibitors will be performed on all 
subjects who consent to optional genomic 
biomarker analysis.  These analysis will be 
performed on a baseline bone marrow aspirate 
(the remaining portion of the bone marrow 
aspirate sample obtained at baseline will be used, 
no additional samples are required) of blood, and 
saliva.  Additional bone marrow samples for 
biomarkers may be collected at the End of Study 
Treatment visit from all subjects who consent.  
End of Study Treatment is defined as the end of 
protocol-defined therapy.
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 baseline and disease progression.  In addition, 
WGS or WES will be performed on a normal 
tissue sample (e.g., saliva or CD3+ T–cells 
Genomics:  Analysis of genetic, gene 
expression and cell surface biomarkers that 
may predict for response and resistance 
following treatment with proteasome 
inhibitors will be performed on all subjects 
who consent to optional genomic biomarker 
analysis.  These analyses will be performed on 
a bone marrow aspirate collected at Baseline, 
prior to Cycle 1 Day 1 (C1D1), and a 
sample of blood and/or saliva will be 
collected at Baseline, prior to dosing on 
C1D1. The bone marrow aspirate used for 
genomics is the remaining portion of bone 
marrow sample left after the amount 
required for disease assessment using FISH 
is performed.  No additional bone marrow 
sample is required at Baseline.  Additional 
bone marrow samples for biomarkers may be 
collected at the End of Study Treatment visit 
from all subjects who consent.  End of Study 
Treatment is defined as at disease 
progression or at the end of protocol-defined 
Updated text to what is 
currently planned for genomic 
biomarker analysis.
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isolated from PBMCs) to determine the presence 
of somatic mutations in tumor cell samples.  Data 
will be analyzed to characterize whether drug 
response is related to alterations in genes 
regulated by or involved in activation of 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 hypotheses about 
mechanisms of drug response, resistance, and 
safety.
therapy if end of treatment is due to 
progressive disease (PD). 
Whole genome sequencing (WGS), whole 
exome sequencing (WES), whole 
transcriptome sequencing (RNA-Seq), and/or 
other forms of nucleic acid and protein 
quantification will be conducted on isolated 
tumor (CD138+) cells from bone marrow 
samples taken at Baseline and disease 
progression.  In addition, WGS or WES will 
be performed on a normal tissue sample (e.g., 
saliva or CD3+ T-cells isolated from PBMCs) 
to distinguish germline mutations from 
somatic mutations in tumor cell samples.  
Data will be analyzed to characterize whether 
drug response is related to alterations in genes 
regulated by or involved in immunoglobulin 
production and protein homeostasis, i.e., 
IGH, as well as in genes regulated by or 
involved in the activation of nuclear factor 
kappa light chain enhancer of activated B cell 
(NF-Kappa B) transcription factors.  
Immunoglobulin levels in tumor cells will be 
quantified by qPCR, or 
immunocytochemistry and/or other protein 
or gene expression quantification methods.  
These data will also be used to derive 
hypotheses about mechanisms of drug 
response, resistance, and safety.
Synopsis
  Planned number of subjects
Section 5 Number of Subjects
Total enrollment of up to 118 evaluable subjects 
is planned for this study, including up to 
approximately 48 evaluable subjects for the Phase 
1b portion of the study (24 for each combination 
regimen and schedule for ORd and OCyd
respectively) and 70 subjects for the Phase 2 
portion of the study (35 subjects for each 
combination regimen).
Total enrollment of up to approximately 134
evaluable subjects is planned for this study, 
including up to approximately 64
evaluable subjects for the Phase 1b portion of 
the study (40 and 24 for ORd and OCyd, 
respectively) and approximately 70 subjects 
for the Phase 2 portion of the study (35 
subjects for each combination regimen).
Added additional subjects due 
to added dose schedule (2/7)
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Synopsis
  Sample size justification
Section 4.5.1 Phase 1b
The estimated sample size for the dose-escalation 
portion of the study of up to 24 subjects for each 
combination regimen is based upon standard 
3 + 3 dose-escalation rules and the expectation 
that 2–6 dosing cohorts of 3–6 subjects per cohort 
will be required to establish the MTD for each 
treatment regimen.  Enrollment of 35 additional 
subjects in each combination regimen during the 
Phase 2 portion of the study is based upon the 
goal of ruling out an ORR < 85% and a CRR < 
50% based upon the approximate lower 1-sided 
90% confidence interval for each parameter.  This 
sample size is based upon a simulation of a 
multinomial outcome of CR, PR, or PD for 
various cohort sizes.  With 35 subjects per 
combination regimen, and an assumed true ORR 
and true CRR of 95% and 75%, respectively, the 
probability of ruling out an ORR < 85% and a 
CRR < 50% with 90% confidence is 
approximately 88%, from the simulation 
described above.  The same assumptions for ORR 
and CRR are used in determining the sample size 
for each combination regimen.   
The estimated sample size for the dose-
escalation portion of the study of up to 40 
subjects for the ORd combination regimen 
and up to 24 subjects for the OCyd 
combination regimen is based upon standard 
3 + 3 dose-escalation rules and the expectation 
that 2–6 dosing cohorts of 3–6 subjects per 
cohort will be required to establish the MTD 
for each treatment regimen.  Enrollment of 35 
additional subjects in each combination 
regimen during the Phase 2 portion of the 
study is based upon the goal of ruling out an 
ORR < 85% and a CRR < 50% based upon the 
approximate lower 1-sided 90% confidence 
interval for each parameter.  This sample size 
is based upon a simulation of a multinomial 
outcome of CR, PR, or PD for various cohort 
sizes.  With 35 subjects per combination 
regimen, and an assumed true ORR and true 
CRR of 95% and 75%, respectively, the 
probability of ruling out an ORR < 85% and a 
CRR < 50% with 90% confidence is 
approximately 88%, from the simulation 
described above.  The same assumptions for 
ORR and CRR are used in determining the 
sample size for each combination regimen.   
Added additional subjects due 
to added dose schedule (2/7)
Synopsis
  Duration of study/treatment 
period
Section 4.6 Estimated Study 
Duration
The total study duration is expected to be 
approximately 39 months based upon the 
assumption that approximately 15 months may be 
required to enroll all subjects (approximately 9
months to enroll Phase 1b subjects and up to 
approximately 6 months to enroll Phase 2 
subjects) and that the average time on study will 
be approximately 24 months. 
The total study duration is expected to be 
approximately 59 months based upon the 
assumption that approximately 35 months may 
be required to enroll all subjects
(approximately 23 months to enroll Phase 1b 
subjects and up to approximately 12 months 
to enroll Phase 2 subjects) and that the 
average time on study will be approximately 
24 months.  
Updated to reflect new 
timetable for study
Synopsis
  Test product, dose, and mode 
of administration
Oprozomib with tablet strengths of 60, 90, and 
120 mg to be given orally (PO).
Oprozomib Tablets containing 60, 90, or 120 
mg of oprozomib or Oprozomib ER Tablet 
with strengths of 120, 150, 180, 210, 240, 
Introduce the new Oprozomib 
Extended Release (ER) Tablet 
and the strengths to be used in 
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  Study Design
Section 4 Study Design
8.1.2 Packaging and Labeling
Section 8.1.3 Oprozomib ER 
Tablet Drug Properties
Lenalidomide 25 mg to be given PO 
Cyclophosphamide 300 mg/m2 (up to 600 mg) to 
be given PO
Dexamethasone 20 mg to be given PO
and 270 mg to be given orally (PO). 
Lenalidomide 25 mg to be given PO 
Cyclophosphamide 300 mg/m2 (up to 600 mg) 
to be given PO
Dexamethasone 20 mg to be given PO
New Formulation: A new oprozomib tablet, 
Oprozomib Extended Release (ER) Tablet, 
will be introduced in the trial with 
Amendment 2.  There are minimal changes 
in the tablet coating and ratio of current 
excipients, and no change in the ratio of 
active pharmaceutical ingredient to 
excipients.  Given these minimal changes, 
the new Oprozomib ER Tablet is not 
expected to result in altered exposure or 
additional adverse events related to 
formulation.  
Subjects enrolled in the original protocol or 
Amendment 1 will receive Oprozomib 
Tablets and may receive Oprozomib 
Extended Release (ER) Tablets when 
available.  Subjects enrolled under 
Amendment 2 will receive Oprozomib ER 
Tablets only.
this study.
Synopsis
  Exclusion Criteria
Section 5.2 Exclusion Criteria
Added Text
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.
6. Clinically significant GI bleed in the 
6 months prior to Cycle 1 Day 1 (C1D1) 
Added plasmapheresis to 
excluded concomitant 
medications to indicate that 
plasmapheresis is not 
permitted at any time during 
the study.
Added GI exclusion criteria 
because of the toxicities 
observed.
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first dose  
Added Section
Section 2.1 Introduction
2.1 INTRODUCTION
New section, too long to include here
Section added to briefly 
summarize the purpose of the 
amendments
Section 2.4.2 Oprozomib 
Clinical Background
Replaced section, too long to include here
Section 2.4.2 was replaced 
with updated information from 
the current IB. 
Section 2.4.4 
Cyclophosphamide Background
Section 2.4.4.1 Section heading 
added to second paragraph
2.4.4.1
Cyclophosphamide and 
Dexamethasone with Epoxyketone 
Proteosome Inhibitors
Content of paragraph is the same, only 
heading added
Section heading added to 
second paragraph for clarity
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Section 2.5 Dose Rationale
Section heading added
2.5.1 Amendment 1
Section added
2.5.2 Amendment 2
Two of the 3 subjects enrolled in the 210 mg 
cohort of the OPZ003 ORd arm 
experienced syncope, a DLT (see Section 
2.4.2.4).  These DLTs prompted a dose de-
escalation to the 180 mg cohort.  Seven 
subjects were enrolled at the 180 mg dose 
level.  Two DLTs, abdominal pain with 
distension and hypotension were observed 
prompting dose de-escalation to 150 mg on 
the 5/14 schedule.
The dose of oprozomib for subjects enrolled 
in the ORd arm will continue at 150 mg on 
the 5/14 schedule unless 2 or more DLTs 
are reported.
Given the increased clinical experience with 
the 2/7 schedule in 2011-001, and the 
experience in Amendment 1 of this trial, the 
starting dose for subjects enrolling in the 
ORd arm under Amendment 2 will be 210 
mg on the 2/7 schedule.  
The starting dose for subjects enrolled in 
the OCyd arm under Amendment 2 will 
also be 210 mg on the 2/7 schedule.  No 
subjects were enrolled in the OCyd arm 
prior to Amendment 2.
Starting with Amendment 2, an ER tablet 
will be administered.  There are minimal 
changes between the ER formulation and 
the modified release formulation used in 
Amendment 1.  As such, dosing with the ER 
formulation will occur at the same level as 
the modified formulation.
Subjects enrolled in the original protocol or 
Section headings added for 
clarity
Amendment 2 dose rationale 
added
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Amendment 1 will receive Oprozomib 
Tablets and may receive Oprozomib 
Extended Release (ER) Tablets when 
available.  Subjects enrolled under 
Amendment 2 will receive Oprozomib ER 
Tablets only.
Added Section
Section 4.1.1 Patients Electing 
To Have Stem Cells Collected
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
Subjects enrolling in the OPZ 003 study must be newly diagnosed and require treatment as 
per the NCCN guidelines.  Subjects scheduled for or planning to proceed with transplant in 
the front-line setting should not be enrolled.  However, subjects may have their stem cells 
collected for future salvage transplant.  The schema below (Figure 5) depicts the schedule 
for subjects electing to bank their stem cells.
In the event that a subject who had not previously intended to proceed to front-line 
transplant elects to proceed, that subject will be discontinued from study (see Section 11.0).
Figure 5 Schedule for Stem Cell Collection 
ASCT = autologous stem cell transplantation; Cyd= cyclophosphamide and dexamethasone; OPZ = oprozomib; 
PD progressive disease; PR = partial response; Rd = lenalidomide and dexamethasone
Added guidance for 
investigators if patient 
achieves a good objective 
response and investigator 
decides to proceed to stem cell 
collection.
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Section 4.2 Dose-Escalation 
Plan
Modified Tables 3 and 4, and 
added Table 5
In the Phase 1b portion of the study, oprozomib 
doses will be escalated in sequential groups of 3 
subjects for each combination regimen, with 
expansion to up to 6 subjects if a DLT is observed 
in 1 of the first 3 subjects.  The doses of 
lenalidomide, cyclophosphamide, and 
dexamethasone will remain fixed in all dose 
cohorts.  
Enrollment in the initial cohort (Table 3) for the 
ORd arm was entered at a daily dose level of 210 
mg on the 5/14 schedule.  Two DLTs (syncope) 
were observed in the first 3 subjects and the 
cohort dose was decreased by 1 dose level to 180 
mg of oprozomib.  The dosing cohort was de-
escalated to 150 mg after 2 DLTs (abdominal 
pain and hypotension) in 6 DLT evaluable 
subjects were reported at the 180 mg dosing level.  
In the Phase 1b portion of the study, 
oprozomib doses will be escalated in 
sequential groups of 3 subjects for each 
combination regimen, with expansion to up to 
6 subjects if a DLT is observed in 1 of the first 
3 subjects.  The doses of lenalidomide, 
cyclophosphamide, and dexamethasone will 
remain fixed in all dose cohorts.  
Enrollment in the initial cohort (Table 3) for 
the ORd arm was entered at a daily dose level 
of 210 mg on the 5/14 schedule.  Two DLTs 
(syncope) were observed in the first 3 subjects 
and the cohort dose was decreased by 1 dose 
level to 180 mg of oprozomib.  The dosing 
cohort was de-escalated to 150 mg after 2 
DLTs (abdominal pain and hypotension) in 6 
DLT evaluable subjects were reported at the 
180 mg dosing level.  With the introduction 
of the ER Tablet with Amendment 2, there
will be no further attempt at dose escalation 
in the 5/14 schedule with the tablet 
formulation.   The starting dose for subjects 
enrolled in the ORd and OCyd arms under 
Amendment 2 will be 210 mg on the 2/7 
schedule (Table 4 and Table 5).
New ER Tablet formulation 
dose-escaltion language added
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Section 6 Subject Screening
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
A signed and dated ICF will be obtained before 
any screening procedures are performed.  
Evaluations obtained as part of routine medical 
care and performed prior to obtaining informed 
consent may be used in place of the study-specific 
evaluations, provided they meet the time windows 
described in the Schedule of Assessments 
(Appendix A).  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 when the subject undergoes the first 
study-specific screening assessment, and must be 
completed within 14 days.  
A signed and dated ICF will be obtained 
before any screening procedures are 
performed.  Evaluations obtained as part of 
routine medical care and performed prior to 
obtaining informed consent may be used in 
place of the study-specific evaluations, 
provided they meet the time windows 
described in the Schedule of Assessments 
(Appendix A and Appendix B).  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 when the 
subject undergoes the first study-specific 
screening assessment, and must be completed 
within 14 days.  The window of assessment 
for bone marrow aspirate and biopsy in the 
Phase 1b is 8 weeks and is the only 
exception to the 21-day screening 
assessment window.  In the Phase 2, the 
bone marrow assessments must be 
performed within 21 days prior to Cycle 1 
Day 1 (C1D1).
Revised for consistency and 
clarity
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Section 7 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 Onyx 
study medical monitor will review the subject’s 
information before enrollment.  Only subjects 
who are approved by the Onyx study medical 
monitor will be allowed to enroll into the study.  
A minimum of 24 hours during weekdays 
(Monday through Friday) will be required for the 
Onyx study medical monitor 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 Onyx study medical monitor 
approves the patient for 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 
Onyx study medical monitor will review the 
subject’s information before enrollment.  Only 
subjects who are approved by the Onyx study 
medical monitor or designee will be allowed 
to enroll into the study.  A minimum of 24 
hours during weekdays (Monday through 
Friday) will be required for the Onyx study 
medical monitor 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 Onyx study 
medical monitor approves the patient for
enrollment.  The logistics of cohort 
assignment are detailed in the Cohort 
Management Plan.
Added language to clarify 
where the cohort assignment 
plan is located
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Section 9.1.1 Treatment 
Administration
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
Dosing instructions for days on which PK 
samples will not be collected (non-PK days):  
Subjects should take oprozomib with 
approximately 8 ounces of water at approximately 
the same time of day, with foodor without food at 
their descretion.  When oprozomib is given on the 
same day with other treatments, dexamethasone 
should be administered 30 minutes before 
oprozomib, lenalidomide and cyclophosphamide.  
Subjects may take lenalidomide or 
cyclophosphamide following oprozomib 
administration at investigator’s discretion, 
however it is recommended that they take their 
study drugs at approximately the same time each 
day.  
Dosing instructions for days on which PK 
samples will be collected (PK days):  
Dexamethasone should be administered at least 
30 minutes before the other medications.  
Oprozomib and either lenalidomide or 
cyclophosphamide will be administered in the 
clinic.  Oprozomib should be administered 
concurrently (i.e., within 5 minutes of each other) 
with lenalidomide or cyclophosphamide, with 
approximately 8 ounces of water, to subjects on 
an empty stomach (at least 2 hours after and 1 
hour before a meal). 
Oprozomib ER Tablets will be administered 
in single daily doses (Table 3, Table 4, and 
Table 5) in the following manner:  
It is recommended that subjects should take 
oprozomib with approximately 8 ounces of 
water at approximately the same time of day, 
with food.  When oprozomib is given on the 
same day with other treatments, 
dexamethasone should be administered 
30 minutes before oprozomib, lenalidomide 
and cyclophosphamide.  Subjects may take 
lenalidomide or cyclophosphamide following 
oprozomib administration at investigator’s 
discretion; however it is recommended that 
they take their study drugs at approximately 
the same time each day.  
Revised for clarity and 
consistency
Section 9 Dosage and 
Treatment Administration
Added section heading 
9.1.4 Subject Replacement
Added section heading for 
clarity
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Section 9.6 Missed Doses
Subjects in the Phase 1b portion of the study may 
not miss any of the planned doses of 
cyclophosphamide, or more than 4 planned doses 
of lenalidomide, or 2 planned doses of oprozomib 
or dexamethasone in Cycle 1.  (See Section 4.2 
for details of replacing subjects who miss more 
doses than allowed.)  A missed dose occurs when 
the subject does not take the dose on the planned 
calendar day, and the dose will not be made up.  
If a subject misses more than 28 consecutive days 
after completing Cycle 1 for reasons other than a 
hematopoietic stem cell harvest, the subject will 
permanently discontinue study treatment (See 
Section 9.3 for interrupted oprozomib dosing > 4 
weeks).
Subjects in the Phase 1b portion of the study 
may not miss any of the planned doses of 
cyclophosphamide, or more than 4 planned 
doses of lenalidomide, or 2 planned doses of 
oprozomib for the 5/15 schedule or 1 
planned dose of oprozomib for the 2/7 
schedule , or 2 planned doses of 
dexamethasone in Cycle 1.  Subjects who 
miss more doses than allowed during Cycle 
1 will not be evaluable and will be replaced.  
A missed dose occurs when the subject does 
not take the dose on the planned calendar day.  
The missed dose will not be made up.  If a 
subject misses more than 28 consecutive days 
after completing Cycle 1 for reasons other 
than a hematopoietic stem cell harvest, the 
subject will permanently discontinue study 
treatment (see Section 9.3 for interrupted 
oprozomib dosing > 4 weeks).
Revised for clarity and 
consistency
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Section 9.7 Safety Guidance for 
Investigators
See Section 9.3 for dose adjustments guidelines 
required for specific hematologic and 
nonhematologic toxicities. 
Cases of tumor lysis syndrome have been 
observed with proteasome inhibitors.  It is 
recommended that all subjects orally hydrate the 
day before, and days of oprozomib dosing.  
Additionally, allopurinol prophylaxis is 
recommended for renally impaired subjects and 
those with a high tumor burden.  For specific 
recommendations, see Section 9.8.1.
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.

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.

Syncope, hypotension (including 
orthostatic hypotension), and 
dehydration have been reported for 
subjects treated with oprozomib.  Blood 
pressure monitoring as detailed in 
Appendix A and Appendix B is 
required.

Tumor lysis syndrome has been reported 
for subjects treated with oprozomib.  
Hydration and allopurinol prophylaxis is 
recommended for renally impaired 
subjects and those with a high tumor 
burden. For specific recommendations, 
see Section 9.8.1.
See Section 9.3 for additional dose adjustment 
guidelines required for specific hematologic 
and nonhematologic toxicities.
Additional safety guidance 
added regarding Grade 3 or 4 
GI hemorrhages and other 
toxicities
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9.8.1 Required Concomitant 
Medications
Outside of antimyeloma regimens and the TLS 
measures noted below, there are no required 
concomitant medications.  However, supportive 
medications for nausea, vomiting and diarrhea are 
strongly recommended; details are provided in 
Section 9.8.2
Required medications are: TLS prophylaxis, 
proton pump inhibitors such as omeprazole 
or lansoprazole, anti-thrombotic agents for 
those on the ORd arem, such as asprin (or 
other anticoagulant or antiplatelet 
medication such as clopidogrel bisulfate, 
low-molecular-weight heparin, or warfarin) 
while taking lenalidomide. Supportive 
medications for nausea, vomiting and diarrhea 
are strongly recommended; details are 
provided in Section 9.8.2.
9.8.1.1
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.
9.8.1.3 Anti-thrombotic Agents
Antithrombitic agents are required for 
those on the ORd arm such as aspirin (or 
other anticoagulant or antiplatelet 
medication such as clopidogrel bisulfate, 
low-molecular-weight heparin, or warfarin) 
while taking lenalidomide is required (refer 
to the Revlimid Prescribing Information, 
Appendix H for more information).
Added as proton pump 
inhibitors are now required for 
subjects on oprozomib
Added antithrombotic agents 
as required to conform with 
Revlimid PI
Section 9.8.2 Optional and 
Allowed Concomitant 
Medications
•
A proton pump inhibitor, such as 
omeprazole or lansoprazole while taking 
dexamethasone
Anti-thrombotic Agents
Antithrombitic agents are required for those on 
the ORd arm such as aspirin (or other 
anticoagulant or antiplatelet medication such as 
clopidogrel bisulfate, low-molecular-weight 
heparin, or warfarin) while taking lenalidomide is 
required (refer to the Revlimid Prescribing 
Added references
Added text:

Bisphosphonate therapy such as 
pamidronate or zoledronic acid for 
skeletal prophylaxis
Section 9.8.2.3 Antihypertensives
Dehydration, hypotension and syncope 
have been reported in subjects treated with 
oprozomib monotherapy and combination 
therapy.  It is strongly recommended that 
Added additional concomitant 
information to prevent peptic 
disease that occurs with use of 
dexamethasone.
Move anti-thrombotic agents 
to 9.8.1
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Information 2012, Appendix H for more 
information).
subjects utilizing anti-hypertensives have 
their volume status, blood pressure, and 
antihypertensive therapy dosing monitored 
closely while on protocol directed therapy.  
See Appendix A and Appendix B.
Section 10.1.1 Vital Signs
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
Vital signs measurements include blood pressure, 
pulse rate, respiration rate, and temperature.  At 
the investigator’s discretion, vital signs 
monitoring may be extended beyond the time 
periods specified in the Schedules of Assessments 
(Appendix A). 
Vital signs measurements include blood 
pressure, pulse rate, and temperature. 
Orthostatic BP should be assessed for 
subjects with evidence of dehydration.  At 
the investigator’s discretion, vital signs 
monitoring may be extended beyond the time 
periods specified in the Schedules of 
Assessments (Appendix A and Appendix B). 
Added additional guidance for 
subjects who may experience 
orthostatic hypotension.
Section 10.3 Disease Response 
Assessments
The schedule of disease assessments is provided 
in Appendix A.  Disease response will 
be assessed by the investigator.  Disease response 
assessments will be performed at the end of every 
4-week cycle for 24 cycles of ORd or OCyd 
treatment, and will continue every 8 weeks 
thereafter, until confirmed PD (See Figure 1, 
Figure 2, and Figure 3 for details on the duration 
of cyclophosphamide dosing).   Response 
assessment will be according to the International 
Myeloma Working Group – Uniform Response 
Criteria (IMWG-URC) (Appendix E). 
The schedule of disease assessments is 
provided in Appendix A and Appendix B.  
Disease response will be assessed by the 
investigator.  Disease response assessments 
will be performed at the end of every 4-week 
cycle for 24 cycles of ORd or OCyd treatment, 
and will continue every 8 weeks thereafter, 
until confirmed PD (see Figure 1, Figure 2, 
and Figure 3 for details on the duration of 
cyclophosphamide dosing) or the start of 
alternative, nonprotocol antimyeloma 
therapy.   Response assessment will be 
according to the IMWG-URC (Appendix E). 
Revised for clarity and 
consistency.
Added Section
Section 10.3.1 Tumor 
Response Assessments
Appendix A and Appendix B:  
Schedule of Study Assessments
and related footnotes
The following confirmation assessments are 
required for all response categories (sCR, 
CR, VGPR, and PR; refer to definitions in 
Appendix E):
All response categories require 2 
consecutive assessments made at any 
time before initiation of any new 
therapy
All response categories require no 
evidence of progression including new 
bone lesions if radiographic studies 
Added for clarity and 
consistency across protocols.
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were performed  
Confirmation of CR or sCR requires 
bone marrow biopsy or aspirate slides 
(a confirmatory bone marrow sample is 
not required)  
Extramedullary plasmacytoma 
evaluation (if present at Screening)
Added Section
Section 10.6 Platelet 
Functional Assessment
10.2 Laboratory Evaluations for 
Safety (added related sentence)
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
Platelet function assessments will be 
conducted in the 10 to 20 subjects enrolled 
in the OCyd arm for which the platelet 
function tests below may be performed.  
Assessments of platelet adherence, 
activation, aggregation, and interaction 
with coagulation factors will be conducted 
utilizing the PFA-100 (N=10).
Subjects participating in this study 
component:

May not be treated with antiplatelet 
agents, aspirin or nonsteroidal anti-
inflammatory drugs in the 2 weeks 
prior to assessment.  

Must have a screening and pretest 
value for platelets of ≥ 100,000/mm3.

Must have hematocrit of 28%
The PFA-100 test will be conducted 
according to site SOPs on C1D1 (prior to 
protocol mandated dosing), Cycle 1 Day 2 
(C1D2), Cycle 4 Day 1 (C4D1) and 30 days 
after the completion of oprozomib therapy.
Revised the limit for platelets 
to increase patient safety.
Moved Section from 10.7 to
11.1.1 Assessments at End of 
Study Treatment or Early 
Discontinuation
10.7 Assessments at End of Study Treatment or 
Early Discontinuation
For subjects who discontinue treatment before PD 
occurs (such as for an AE, noncompliance, etc.), 
disease response assessments will be performed 
every 4 weeks during the first 24 months of the 
11.1.1 Assessments at End of Study Treatment 
or Early Discontinuation
For subjects who discontinue treatment before 
PD occurs (such as for an AE, noncompliance, 
etc.), disease response assessments will be 
performed every 4 weeks during the first 
Moved for clarity and 
consistency.
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study and every 8 weeks thereafter, until 
confirmed PD, or the start of alternative, 
nonprotocol antimyeloma therapy.
24 months of the study and every 8 weeks 
thereafter, until confirmed PD, or the start of 
alternative, nonprotocol antimyeloma therapy.
Added Section
11.1.2 Follow-up for Subjects 
Who End Study Treatment 
Without Documented 
Progressive Disease
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
Subjects who have ended study therapy 
without evidence of progression enter active 
follow up after completing their end of 
study treatment visit.  They will be followed 
for progression free survival.  
Disease response assessments will be 
performed every 4 weeks through 
24 months post C1D1, and then every 
8 weeks thereafter, until progression or 
initiation of new anti-myeloma therapy 
whichever occurs first  
Subjects who have consented to evaluate 
their genomic biomarkers and end study 
treatment prior to progression will have 
a bone marrow aspirate collected for 
genomic analysis at the time of 
progression or the start of new anti-
myeloma therapy, whichever comes first
Active 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.  
Added for clarity and 
consistency across protocols.
Section 12.3.2 Disease 
Progression
Disease progression will be documented in an 
eCRF intended to capture PD information and 
will be analyzed as a study endpoint. Signs and 
symptoms related to disease progression (e.g., 
pathologic fracture in a subject with progressive 
multiple myeloma) should be reported in the 
appropriate case report form as an AE or as an 
SAE (if the event in question meets the criteria 
for seriousness).  Verbatim terms such as “disease 
progression”, “progressive disease”, etc., should 
not be reported as AEs or SAEs unless the 
Signs and symptoms related to disease 
progression (e.g., pathologic fracture in a 
subject with progressive multiple myeloma) 
should be reported in the appropriate case 
report form as an AE or as an SAE (if the 
event in question meets the criteria for 
seriousness).  Verbatim terms such as “disease 
progression”, “progressive disease”, etc., 
should not be reported as AEs or SAEs unless 
the investigator considers the progression to 
be atypical and/or accelerated. 
Revised for clarity and 
consistency across protocols.
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investigator considers the progression to be 
atypical accelerated. or caused by the study 
drug.  
Added Section
Section 12.4 Long-term 
Follow-up
Appendix A and Appendix B:  
Schedule of Study Assessments 
and related footnotes
After completion of the End of Study 
Treatment visit, subjects who have ended 
study therapy due to an AE enter long term 
follow up.  They will be followed for 
progression free survival.  
Disease response assessments will be 
performed every 4 weeks through
24 months post C1D1, and then every 
8 weeks thereafter, until progression or 
initiation of next therapy, whichever occurs 
first.  
Subjects who have consented to evaluate 
their genomic biomarkers and end study 
treatment prior to progression will have a 
bone marrow aspirate collected for genomic 
analysis at the time of progression or the 
start of new anti-myeloma therapy, 
whichever comes first.
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.  
Added to clarify procedures 
for the post-treatment follow-
up for subjects who 
discontinue treatment for a 
reason other than PD.
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130410
14 January 2020
Page 207
Superseded 

Superseded 
 
 
UserName: 
 
Title:  Vice President, Clinical Development and Biometrics 
Date: Friday, 17 October 2014, 07:30 AM   Pacific Daylight Time 
Meaning: I have reviewed and approved this document. 
================================================
Document Title:
15OCT2014_APPROVAL_protocol-opz003-a2.docx
Workflow Number:
15123760
Product: 
Date: 
Oprozomib
Supplemental Clinical Study Report:  20130410
14 January 2020
Page 208