Clinical trial NCT01246063
Conditions: Multiple Myeloma
Sponsor: Washington University School of Medicine
Start date: 2012-05-14; Completion date: 2018-03-23
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The aim of this phase I/II trial is to determine the maximal tolerated dose (MTD) of carfilzomib together with pegylated liposomal doxorubicin hydrochloride (PLD) with or without dexamethasone, and then to establish the efficacy and safety of this novel combination in patients with relapsed or refractory multiple myeloma

Detailed description:

Arms: arm 1: Dose Level 0: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (27 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (27 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (27 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6. arm 2: Dose Level 1: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (36 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (36 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (36 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6.

Dose Level 1: Carfilzomib IV (1 dose level above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (1 dose level above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (1 dose level above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Dose Level 2: Carfilzomib IV (2 dose levels above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (2 dose levels above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (2 dose levels above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib. arm 3: Dose Level 2: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (45 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (45 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (45 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6. arm 4: Dose Level 3: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (56 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (56 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (56 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6. arm 5: Cohort 0: Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib. arm 6: Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.
Interventions: intervention 1: carfilzomib intervention 2: pegylated liposomal doxorubicin (PLD) intervention 3: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
Amendment 4 12/04/15 
 
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A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone 
for the Treatment of Relapsed/Refractory Multiple Myeloma 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Box 8007 
St. Louis, MO 63110 
 
HRPO #: 201102043 
IND #: 111755 
 
 
 
 
ClinicalTrials.gov # NCT01246063 
 
Principal Investigator: 
Ravi Vij, M.D. 
 
 
 
 
660 S. Euclid Avenue 
 
 
 
 
Campus Box 8007 
 
 
 
 
St Louis, MO 63110  
 
 
 
 
 
Telephone: 314-454-8323  
 
 
 
 
 
Fax: 314-454-7551 
 
 
 
 
 
Email: rvij@dom.wustl.edu 
 
 
Sub-Investigators: 
 
Camille Abboud, MD  
John DiPersio, MD, PhD 
Timothy Graubert, MD 
Keith Stockerl-Goldstein, MD 
Michael Tomasson, MD 
 
Geoffrey Uy, MD 
Matthew Walter, MD 
Peter Westervelt, MD, PhD 
 
Statistician:  
 
Feng Gao, Ph.D. 
 
 
 
Study Drugs:  
 
Carfilzomib 
 
 
 
 
 
Pegylated liposomal doxorubicin (Doxil® or Lipodox)  
 
 
 
 
 
Dexamethasone   
 
Protocol Version Date:  
Amendment 4 12/04/2015 
 
 
 
 
 
  
 
 
 
A Phase I/II Trial of Carfilzomib and Pegylated Liposomal Doxorubicin for the Treatment 
of Refractory/Relapsed Multiple Myeloma 
 


 
Amendment 4 12/04/15 
 
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SCHEMA 
 
Carfilzomib will be administered on Days 1, 2, 8, 9, 15, and 16 during Cycles 1 through 6, and 
on Days 1, 8, 15, and 22 beginning on Cycle 7 until disease progression or clinical relapse. 
 
Pegylated liposomal doxorubicin (PLD) will be administered on Day 8 during Cycles 1 through 
6. 
 
Dexamethasone (Dex) will be administered on the same schedule as Carfilzomib (for patients in 
part 2 of phase 1 and phase 2.)  
 
Phase I 
 
Part 1- A maximum of 24 participants eligible for Maximal Tolerated Dose (MTD) analysis will 
be enrolled to determine the MTD of carfilzomib in combination with pegylated liposomal 
doxorubicin (PLD) in participants with relapsed or refractory multiple myeloma. 
 
Dose Level 
Carfilzomib (mg/m2) 
IV  
PLD (mg/m2) IV 
-2  
20  
20 
-1  
20 on D1 and D2* 
27 starting on D8 
20 
0 (Start) 
20 on D1 and D2* 
27 starting on D8 
30 
1 
20 on D1 and D2* 
36 starting on D8 
30 
2 
20 on D1 and D2* 
45 starting on D8 
30 
3 
20 on D1 and D2* 
56 starting on D8 
30 
*- Please note that the D1 and D2 carfilzomib dose of 20mg/m2 will only occur during Cycle 1. 
For all subsequent cycles, patients will receive the same dose of carfilzomib throughout at what 
is noted in this table to be the D8 dose.  
 
Part 2- After the MTD of carfilzomib in combination with PLD has been determined, dose 
escalation will resume at the MTD of carfilzomib and PLD with the addition of dexamethasone. 
A maximum of 12 participants eligible for Maximal Tolerated Dose (MTD) analysis will be 
enrolled.  
 
 
Screening 
Screening 
• D-21 to D1 
Cycle 1 through 6
Cycle 1 through 6
• Carfilzomib and 
Dex on D1, 2, 8, 9, 
15, 16 
• PLD on D8
Cycles 3-6
Cycles 3-6
• Carfilzomib and 
Dex on D1, 8, 15, 
22
• PLD on D8
Cycles 7 and beyond 
until progression
Cycles 7 and beyond 
until progression
• Carfilzomib and 
Dex on D1, 8, 15, 
22


 
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Dose Level 
Carfilzomib (mg/m2) 
IV  
PLD (mg/m2) IV 
Dex (mg) IV or PO  
-1  
1 dose level below the 
MTD 
1 dose level below the 
MTD 
20 
0 (Start) 
MTD 
MTD 
20 
 
Phase II 
 
Seventeen participants will be treated at the MTD of carfilzomib in combination with PLD and 
dexamethasone to evaluate the efficacy and toxicity in participants with relapsed or refractory 
multiple myeloma. Participants treated in phase 1 at the MTD will be counted as part of the 
phase two accrual.  
  
 
 
 


 
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A Phase I/II Trial of Carfilzomib and Liposomal Doxorubicin for the Treatment of 
Refractory/Relapsed Multiple Myeloma 
 
TABLE OF CONTENTS 
 
1.0 BACKGROUND AND RATIONALE .............................................................................................. 6 
1.1 MULTIPLE MYELOMA ...................................................................................................................... 6 
1.2 PROTEASOME INHIBITION AND BORTEZOMIB (VELCADE®) ............................................................ 7 
1.3 CARFILZOMIB ................................................................................................................................... 8 
1.4 PEGYLATED LIPOSOMAL DOXORUBICIN (DOXIL® OR LIPODOX) .................................................. 15 
1.5 DEXAMETHASONE .......................................................................................................................... 16 
1.6 RATIONALE .................................................................................................................................... 16 
1.7 CORRELATIVE STUDIES BACKGROUND ......................................................................................... 17 
2.0 OBJECTIVES .................................................................................................................................. 17 
2.1 PRIMARY OBJECTIVES .................................................................................................................... 17 
2.2 SECONDARY OBJECTIVES............................................................................................................... 17 
3.0 PARTICIPANT SELECTION ........................................................................................................ 18 
3.1 INCLUSION CRITERIA ..................................................................................................................... 18 
3.2 EXCLUSION CRITERIA .................................................................................................................... 19 
3.3 INCLUSION OF WOMEN AND MINORITIES ...................................................................................... 21 
4.0 REGISTRATION PROCEDURES ................................................................................................ 21 
4.1 CONFIRMATION OF PATIENT ELIGIBILITY ...................................................................................... 21 
4.2 PATIENT REGISTRATION IN THE SITEMAN CANCER CENTER DATABASE ...................................... 21 
4.3 ASSIGNMENT OF UPN .................................................................................................................... 21 
5.0 TREATMENT PLAN ...................................................................................................................... 22 
5.1 OVERVIEW ..................................................................................................................................... 22 
5.2 PHASE I........................................................................................................................................... 22 
5.3 PHASE II ......................................................................................................................................... 23 
5.4 REQUIREMENTS TO START TREATMENT (CYCLE 1 DAY 1) ........................................................... 24 
5.5 ACCRUAL ....................................................................................................................................... 24 
6.0 DOSE-LIMITING TOXICITIES/DOSE MODIFICATIONS ..................................................... 24 
6.1 DEFINITION OF DOSE-LIMITING TOXICITY ..................................................................................... 24 
6.2 DOSING MODIFICATIONS ............................................................................................................... 25 
6.3 MISSED DOSES ............................................................................................................................... 30 
6.4 CHANGES IN BODY SURFACE AREA (BSA) ................................................................................... 30 
7.0 AGENT ADMINISTRATION ........................................................................................................ 30 
7.1 CARFILZOMIB ................................................................................................................................. 30 
7.2 PEGYLATED LIPOSOMAL DOXORUBICIN (DOXIL® OR LIPODOX) .................................................. 34 
7.3 DEXAMETHASONE .......................................................................................................................... 36 
7.4 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................. 37 
8.0 DURATION OF THERAPY ........................................................................................................... 39 
8.1 CRITERIA FOR REMOVAL FROM STUDY ......................................................................................... 39 
8.2 DURATION OF FOLLOW-UP ............................................................................................................ 39 
9.0 CRITERIA FOR RESPONSE ........................................................................................................ 39 
9.1 COMPLETE RESPONSE .................................................................................................................... 39 
9.2 STRINGENT COMPLETE RESPONSE ................................................................................................. 40 
9.3 NEAR-COMPLETE RESPONSE ......................................................................................................... 40 
9.4 VERY GOOD PARTIAL RESPONSE ................................................................................................... 40 
9.5 PARTIAL RESPONSE ........................................................................................................................ 40 
9.6 MINIMAL RESPONSE ...................................................................................................................... 41 


 
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9.7 STABLE DISEASE ............................................................................................................................ 41 
9.8 PROGRESSIVE DISEASE .................................................................................................................. 41 
9.9 CLINICAL RELAPSE ........................................................................................................................ 42 
9.10 
RELAPSE FROM COMPLETE RESPONSE ...................................................................................... 42 
10.0 
STUDY CALENDAR .................................................................................................................. 43 
11.0 
DATA SUBMISSION SCHEDULE ........................................................................................... 44 
12.0 
CORRELATIVE STUDIES ........................................................................................................ 45 
13.0 
SAFETY MONITORING, DATA AUDITING, AND REQUIRED REPORTING OF 
EVENTS .................................................................................................................................................... 46 
13.1 
ADVERSE EVENTS ...................................................................................................................... 46 
13.2 
UNANTICIPATED PROBLEMS ...................................................................................................... 47 
13.3 
NONCOMPLIANCE ...................................................................................................................... 47 
13.4 
SERIOUS NONCOMPLIANCE ....................................................................................................... 47 
13.5 
PROTOCOL EXCEPTIONS ............................................................................................................ 47 
13.6 
PREGNANCY ............................................................................................................................... 48 
13.7 
REPORTING TO THE HUMAN RESEARCH PROTECTION OFFICE (HRPO) AND THE QUALITY 
ASSURANCE AND SAFETY MONITORING COMMITTEE (QASMC) AT WASHINGTON UNIVERSITY ........ 48 
13.8 
REPORTING TO THE FDA ........................................................................................................... 48 
13.9 
REPORTING TO AMGEN ............................................................................................................ 49 
13.10 TIMEFRAME FOR REPORTING REQUIRED EVENTS ..................................................................... 50 
14.0 
DATA AND SAFETY MONITORING PLAN ......................................................................... 50 
14.1 
EXTERNAL DATA AUDITING ...................................................................................................... 51 
15.0 
ENDPOINTS ................................................................................................................................ 51 
15.1 
PRIMARY OUTCOME ANALYSES ................................................................................................ 51 
15.2 
SECONDARY OUTCOME ANALYSES ........................................................................................... 51 
16.0 
STATISTICAL ANALYSIS ....................................................................................................... 52 
17.0 
REFERENCES ............................................................................................................................. 53 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE ............................................................... 56 
APPENDIX B:  KARNOFSKY PERFORMANCE STATUS SCALE ................................................ 57 
APPENDIX C: COCKCROFT-GAULT FORMULA ........................................................................... 58 
APPENDIX D: NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
VERSION 4.0 ............................................................................................................................................ 59 
APPENDIX E: MEDWATCH 3500 ........................................................................................................ 60 
 
 


 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Multiple Myeloma 
 
Multiple myeloma (MM) is a multifocal plasma cell neoplasm resulting from the clonal 
expansion of terminally differentiated B-cells.  The disease is characterized by a serum or 
urine monoclonal protein and skeletal destruction with osteolytic lesions, bone pain, 
pathologic fractures and hypercalcemia. Recurrent infections from depressed normal 
immunoglobulin production, renal dysfunction from light chain production, and anemia 
from generalized marrow involvement are also common.  In the United States, MM is the 
second most common hematologic malignancy behind non-Hodgkin’s lymphomas with 
an estimated 15,270 new cases and 11,070 deaths in 2004.[1]  
 
Progress in the management of MM has been modest since the introduction of melphalan 
more than 25 years ago. Melphalan combined with prednisone produces an objective 
response of 50-60% although median survival remains approximately 3 years with 5-10% 
of patients surviving 10 or more years[2]. More aggressive chemotherapy regimens, 
though associated with higher response rates, have had little impact on improving 
survival [3-8]. However, corticosteroids when used alone can induce a response in 
approximately 30% of patients, similar to rates seen with combination chemotherapy in 
refractory patients [9, 10].   Interferon  (IFN-) in combination with chemotherapy is 
known to prolong the plateau phase of remission[11, 12]. The combination of IFN- and 
corticosteroids has been shown to be better than IFN- alone in improving progression 
free survival[13].  
 
High dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) has 
resulted in a higher rate of complete response (CR) (22% vs. 5%) and longer progression 
free survival (PFS) and overall survival (OS) (18-27 months and 37-60+ months, 
respectively) compared to standard dose chemotherapy [14]. However, high dose 
chemotherapy with transplant is not curative and currently there is great interest in 
developing therapies that prolong the remission duration following autologous 
transplantation for MM. 
 
With the advent of novel targeted agents, the majority of patients have experienced 
improved survival outcomes in recent years.  The immunodulatory agents thalidomide 
and lenalidomide and the proteasome inhibitor bortezomib are routinely used as first line 
therapy and have thus improved the outcomes for myeloma patients.  However, despite 
the availability of these newer therapies, the overall prognosis of patients with myeloma 
remains poor.  Furthermore, patients who do respond and survive salvage chemotherapy 
will almost invariably relapse, underscoring the need for additional effective agents 
against myeloma. 
 
 


 
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1.2 
Proteasome Inhibition and Bortezomib (Velcade®) 
 
1.2.1 The Proteasome  
 
The ubiquitin-proteasome pathway plays an essential role in cellular homeostasis. 
Eukaryotic cells target specific proteins for destruction by tagging them with 
ubiquitin. Polyubiquitinated proteins bind to the proteasome. The 26 S 
proteasome is an adenosine triphosphate-dependent multicatalytic protease which 
consists of a core 20S particle, which contains the catalytic proteinase function. 
This is symmetrically bound to 2 copies of a regulatory 19S particle, which 
recognizes the ubiquitinated substrates. The 26S proteasome performs a 
“housekeeping” role that acts to dispose of used up or damaged proteins and 
create antigenic peptides for presentation to immune effector cells.  
 
In addition, the ubiquitin-proteasome pathway plays an important role in 
regulating the cell cycle, neoplastic growth and metastases.[15, 16]  A number of 
key regulatory proteins are temporally degraded during the cell cycle by the 
ubiquitin-proteasome pathway. The orderly degradation of these proteins is 
required for the cell to progress through the cell cycle and undergo mitosis. One 
of the targets is the tumor suppressor gene p53, which is required for the 
transcription of a number of genes involved in cell cycle progression and also 
plays an important role in apoptosis.  Cyclins and cyclin-dependent kinase 
inhibitors p21 and p27 are other growth regulatory proteins degraded by the 
ubiquitin proteasome pathway. 
 
The ubiquitin-proteasome pathway is also required for transcriptional regulation. 
Nuclear factor kappa-B is a key transcription factor, whose activation is regulated 
by the proteasome-mediated degradation of the inhibitor protein I-kappa B. NF-
κB regulates the expression of adhesion molecules such as E-selectin, intercellular 
adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM 1).  
These adhesion molecules in turn direct the adhesion and extravasation of tumor 
cells.  NF-κB is also required by a variety of cells to maintain cell viability due to 
the production of anti-apoptotic proteins like bcl-2 or growth factors such as 
interleukin-6. 
 
1.2.2 Bortezomib (Velcade®) 
 
Bortezomib is the first proteasome inhibitor developed to be used in routine 
clinical practice for myeloma treatment. It is a reversible inhibitor of the 
proteasome blocking signal transduction pathways mediated by NF-κB resulting 
in the stimulation of apoptosis by inhibiting the proteasome degradation of IκB.  It 
has been shown to be effective in the first line setting as well as in patients with 
relapsed and refractory myeloma.   
 
In newly diagnosed elderly patients, the phase III VISTA trial compared 


 
Amendment 4 12/04/15 
 
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bortezomib plus melphalan plus prednisone versus melphalan plus prednisone and 
demonstrated a 52% reduction in the risk of disease progression and a median 
time to progression (TTP) of 24 months versus 16.6 months (P<0.001).  After a 
median follow-up of 25.9 months, the 3-year survival rates were also better with 
the bortezomib-containing regimen (72% vs. 59%, p-0.003).[17]   
 
In the relapsed/refractory population, the phase III APEX trial demonstrated the 
superiority of a bortezomib plus high dose dexamethasone versus high-dose 
dexamethasone alone.  The median TTP was longer (6.2 vs. 3.5 months), 
p<0.001), more patients experienced a >PR (38% vs. 18%; p<0.001) and CR (6% 
vs. <1%, p<0.001), and the overall 1 year survival was improved (80% vs. 66%; 
p=0.003).[18]  
 
1.3 
Carfilzomib 
 
1.3.1 Overview of Carfilzomib 
 
Carfilzomib is a novel inhibitor of the proteasome.  It is an irreversible 
tetrapeptide ketoepoxide-based inhibitor of the chymotrypsin-like activity of the 
20S proteasome, which is structurally and mechanistically different from the 
dipeptide boronic acid reversible proteasome inhibitor bortezomib.  It is more 
selective for the chymotrypsin-like protease, having less inhibitory activity 
against the other two active subunits.  In addition, when measured against a broad 
panel of proteases including metallo, aspartyl, and serine proteases, carfilzomib 
demonstrated less reactivity against non-proteasomal proteases when compared to 
bortezomib.   
 
1.3.2 Pre-clinical Studies of Carfilzomib  
 
Based upon in vitro and in vivo studies, it is anticipated that more intense and 
longer duration of proteasome inhibition can be achieved with carfilzomib relative 
to bortezomib, resulting in enhanced anti-tumor activity.  Continuous (72-hour) 
exposure to carfilzomib was associated with potent cytotoxic and pro-apoptotic 
activity across a broad panel of tumor-derived cell lines in culture [19].  
Incubation of hematologic tumor cell lines with carfilzomib for as little as 1 hour 
led to rapid inhibition of proteasome activity followed by accumulation of 
polyubiquinated proteins and induction of apoptotic cell death.  Carfilzomib was 
also cytotoxic in bortezomib-resistant tumor cell lines.[20] 
 
Preclinical studies in rats and monkeys have been performed administering 
carfilzomib intravenously (IV) for 5 consecutive days followed by 9 days of rest 
for 2 cycles.  Proteasome inhibition of more than 80% was achieved, suggesting 
that high-level inhibition of the proteasome with the epoxyketone class is 
possible, affording new opportunities to escalate dose to optimize anti-tumor 
effects.  This finding was in contrast to preclinical testing with the boronic class 
of inhibitors that prohibited uninterrupted daily dosing due to lethal toxicity.   


 
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1.3.3 Non-Clinical Pharmacodynamics and Pharmacokinetics of 
Carfilzomib  
 
1.3.3.1    Pharmacodynamics 
 
The in vivo pharmacodynamics (PDn) and efficacy of carfilzomib have 
been evaluated using direct measurement of proteasome enzyme activity 
in a variety of tissues and determination of the antitumor response in mice 
bearing established subcutaneous tumors. 
 
The PDn of carfilzomib has been determined by measurement of 
chymotrypsin-like proteasome activity in tissue extracts following IV 
bolus administration in rats. Dose-dependent proteasome inhibition was 
observed 1 hour after dose administration in all tissues examined, with the 
exception of brain (Demo 2007). Proteasome activity recovered in 
nucleated tissues with a half-life of approximately 24 hours.  With a 12 
mg/m2 (2 mg/kg) dose (the STD10 on a QDx5 schedule), proteasome 
inhibition exceeded 80% in multiple tissues (blood, adrenal, heart, lung, 
and bone marrow). Equivalent levels of proteasome inhibition were seen 
in blood and tissues when carfilzomib was delivered as a bolus 
administration or a 30-minute infusion indicating that the biodistribution 
and PDn of carfilzomib are a function of the total dose administered and 
not the maximum plasma concentration (Cmax).  
 
1.3.3.2    Pharmacokinetics 
 
The pharmacokinetics (PK) of carfilzomib was examined following IV 
bolus administration to Sprague-Dawley rats and cynomolgus monkeys. 
There was a dose-dependent increase in the area under the curve (AUC) 
and a biphasic distribution profile following administration. The terminal 
half-life (t1/2) was calculated to be 5 to 17 minutes in rats and 7 minutes in 
monkeys. The plasma clearance of carfilzomib is 195 to 319 mL/min/kg in 
rats and 187 to 286 mL/min/kg in monkeys, which is higher than the liver 
blood flow for both species, indicating that clearance occurred largely 
extrahepatically in these species.  
 
When carfilzomib was given as 30-minute IV infusion at 8 mg/kg to rats, 
the concentration at steady state was approximately 28-fold lower than the 
Cmax with IV bolus at the equivalent doses. Other PK parameters 
(clearance, AUC, and t1/2) were comparable between bolus and infusion 
dosing. Similar PDn (proteasome inhibition in blood and tissues) between 
bolus and infusion dosing supported accessibility of carfilzomib to target 
tissues using the 30-minute infusion protocol. 
 
 


 
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1.3.3.3 Metabolism, Distribution, and Excretion 
 
1.3.3.3.1 Metabolism 
 
 
 
 
 
Carfilzomib is rapidly and extensively metabolized following IV 
administration to rats, monkeys, and humans. The predominant 
metabolites are carfilzomib diol as well as peptide fragments and 
amino acids derived from carfilzomib, with no unique metabolites 
identified in humans, suggesting that peptidase cleavage and 
epoxide hydrolysis are the principal pathways of metabolism in all 
these species. The metabolites do not inhibit proteasome activity. 
Cytochrome P450-mediated pathways are not significant in the 
overall metabolism of carfilzomib. 
 
Carfilzomib is also rapidly metabolized by peptidases and epoxide 
hydrolases in vitro upon incubation with rat blood and tissue 
homogenates derived from the lung, kidney, and liver, further 
corroborating the extrahepatic mechanisms of metabolism in vivo. 
 
1.3.3.3.2 Distribution 
 
The Vss was 0.3 to 2.0 L/kg and 0.3 to 1.1 L/kg, respectively, for 
rats and monkeys. Due to metabolism in a variety of tissues and 
the irreversible, covalent binding of carfilzomib to the 20S 
proteasome, the Vss values may underestimate the extent of tissue 
distribution of carfilzomib. Potent proteasome inhibitory effects in 
a variety of tissues following IV administration to rats at different 
dose levels and detection of radioactivity in a variety of tissues 
with an IV administration of [3H-Phe]-carfilzomib to rats at 2 
mg/kg (12 mg/m2) indicated rapid and wide distribution of 
carfilzomib to tissues except brain. 
 
An in vitro protein-binding study using equilibrium dialysis 
demonstrated that approximately 97% of carfilzomib is bound to 
human plasma proteins, similar to rats and monkeys. 
 
1.3.3.3.3 Elimination 
 
Excretion of [3H-Phe]-carfilzomib was determined by quantitative 
whole-body autoradiography in rats receiving a single IV bolus 
administration of 2 mg/kg (12 mg/m2). Urine and feces accounted 
for 14.1% and 18% of the dosed radioactivity, respectively, at 168 
hours post-dose. Approximately 44% of the administered 
radioactivity remained in tissues, indicating slow elimination of 
drug-derived radioactivity, likely due to incorporation of 3H-


 
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phenylalanine into cellular proteins. 
 
Excretion was also determined in bile duct-cannulated rats 
following a single IV bolus administration of 2 mg/kg. Carfilzomib 
was excreted mainly in the form of metabolites, with less than 1% 
of the dose excreted intact. About 57% of the dose was recovered 
within 24 hours of dosing in both bile and urine samples. The 
limited recovery was likely due to target binding in cells unable to 
synthesize new proteasomes (e.g., red blood cells [RBCs]) and 
peptidic metabolites that cannot be differentiated from endogenous 
components. 
 
1.3.4 Clinical Pharmacokinetics, Metabolism, Distribution, and Excretion 
 
1.3.4.1  Pharmacokinetics 
 
Following IV administration of carfilzomib at ≥ 15 mg/m2 to patients with 
hematological malignancies (PX-171-001 and PX-171-002), carfilzomib 
was rapidly cleared from the systemic circulation with a half-life < 1 hour. 
The systemic clearance, which ranged from 2.7 to 30 L/minute, exceeded 
liver blood flow, suggesting that carfilzomib is largely cleared non-
hepatically. 
 
Assessment of the PK of carfilzomib in MM patients with varying levels 
of renal dysfunction, including those on dialysis, is currently ongoing (PX-
171-005). As of the data transfer cutoff date of 10 July 2009, 16 patients 
have been evaluated for PK and there has been no apparent effect of renal 
dysfunction on PK in preliminary analysis. Based on currently available 
data, carfilzomib can be administered to patients with MM and substantial 
renal dysfunction without need for dose adjustment. 
 
Carfilzomib was also rapidly cleared in patients with solid tumors 
following IV administration (PX-171-007) with a half life of < 1 hour and 
systemic clearance exceeding hepatic blood flow. There was no systemic 
accumulation of carfilzomib after repeat doses. Both Cmax and AUC 
increased dose-proportionally from 20 to 36 mg/m2, indicating linear PK 
in the dose range tested. 
 
1.3.4.2 Metabolism 
 
Similar to the metabolic profile in rats and monkeys, the most abundant 
metabolites of carfilzomib in human plasma and urine collected from the 
patients with hematological malignancies were peptide and amino acid 
fragments of carfilzomib and carfilzomib diol, indicating that peptidase 
cleavage and epoxide hydrolysis are the principal pathways of metabolism 
of IV administered carfilzomib in humans. No significant oxidative 


 
Amendment 4 12/04/15 
 
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metabolites mediated by cytochrome P450 enzymes were detected. None 
of these metabolites have significant proteasome inhibition (or other 
known biological) activity. 
 
1.3.4.3 Distribution 
 
The Vss of carfilzomib ranged from 10 L to 228 L in patients with 
hematological cancers. However, due to metabolism in tissues and 
irreversible binding of carfilzomib to the 20S proteasome, the Vss value 
may underestimate the actual tissue distribution of carfilzomib. The potent 
proteasome inhibitory effects in a variety of tissues in rats and broad 
distribution of the radioactivity in the quantitative whole body 
autoradiography study in rats following IV administration demonstrated 
wide tissue distribution of carfilzomib except brain. The in vitro binding 
of carfilzomib to human plasma proteins averaged 94% over the 
concentration range of 0.5–5 μM. 
 
1.3.4.4 Excretion 
 
Carfilzomib is eliminated primarily in the form of inactive metabolites 
(mainly as peptide fragments). Renal excretion accounts for 20%–30% of 
the total dose and appears not to be affected by renal dysfunction (PX-
171-005).  
 
1.3.5 Current Clinical Experience with Carfilzomib  
 
1.3.5.1 Summaries of Phase I Studies 
 
Two Phase 1 studies have been completed; both evaluated carfilzomib in 
subjects with refractory or relapsed hematologic malignancy following at 
least 2 prior therapies. In the first study (Study PX-171-001, N = 29), the 
MTD was established at 15 mg/m2 as an IV bolus over 1 to 2 minutes. At 
the 20 mg/m2 dose, 2 of 5 subjects experienced DLTs of Grade 3 febrile 
neutropenia and chills (1 subject) and Grade 4 thrombocytopenia (1 
subject) during Cycle 1. In the second study (Study PX-171-002, N = 48), 
DLTs of renal failure, fatigue, and hypoxia were observed at different 
dose levels; no dose level (through 27 mg/m2) met the criteria for the 
MTD of carfilzomib. However, based on the safety information available, 
further dose escalation beyond 27 mg/m2 as an IV bolus over 2 minutes 
was not pursued. The expansion cohort received starting doses of 20 
mg/m2 in Cycle 1 on Days 1, 2, 8, 9, 15, and 16, escalating up to 27 
mg/m2 in Cycle 2 as tolerated on Days 1, 2, 8, 9, 15, and 16. 
 
Three Phase 1 studies are ongoing. One study is being conducted in 
multiple myeloma subjects with end stage renal disease and another in 
subjects with relapsed advanced malignancies who have varying degrees 


 
Amendment 4 12/04/15 
 
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of hepatic impairment, both testing the 56 mg/m2 dose (by Cycle 2 and 
beyond in subjects that tolerate the 20 and 27 mg/m2 doses) administered 
as a 30-minute infusion. The third study is evaluating once-weekly 
carfilzomib in combination with lenalidomide and dexamethasone in 
subjects with newly diagnosed or relapsed multiple myeloma.  
 
1.3.5.2 Phase 2 Experience with Carfilzomib as a monotherapy 
 
The initial Phase 1 studies administered carfilzomib as monotherapy on 5 
consecutive days with a 14-day cycle; this resulted in sustained 
proteasome inhibition and a favorable safety profile[22].  Subsequent 
Phase 1 and 2 studies of carfilzomib monotherapy utilized twice-weekly 
dosing for 3 weeks in a 28-day cycle and have achieved higher tolerated 
doses with promising anti-tumor activity.  The most common adverse 
events have been non-hematologic, including fatigue, nausea, diarrhea, 
upper respiratory tract infection, and reversible elevations in creatinine.  
Severe peripheral neuropathies were rare: 2 cases of grade 3 in >200 
myeloma 
patients 
treated, 
most 
with 
pre-existing 
neuropathy.  
Hematologic 
toxicities 
were 
seen, 
including 
anemia, 
transient 
thrombocytopenia (cyclical, similar to bortezomib), and neutropenia with 
or without fever.  The level of grade 3 neutropenia is ~10% and appears to 
be lower than that observed with bortezomib.   
 
Two Phase 2 clinical studies are ongoing with carfilzomib in MM patients, 
PX-171-003-A0 (N=46) in relapsed and refractory MM and PX-171-004 
(N=39) in relapsed MM.  In both studies, patients were dosed with 20 
mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  In these 
studies there were four cases of suspected or documented TLS prior to 
institution of the prophylaxis guidelines.  No further cases of TLS have 
been reported.  In both studies, the most common adverse events were 
fatigue, anemia, thrombocytopenia (primarily cyclical), gastrointestinal, 
and dyspnea.  Almost all were Grades 1 or 2.  There were reported cases 
of increased in serum creatinine that were primarily < Grade 2 and were 
transient, rapidly reversible, and non-cumulative.  A very low rate of 
treatment-emergent peripheral neuropathy, 2.2% Grade 3/4, was observed 
in PX-171-003-A0 despite the fact that 78% of patients had Grade 1/2 
neuropathy upon study entry[23].   
 
The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD 
in these patients that entered the study with progressive disease and were 
refractory to their most recent therapy, often including bortezomib and/or 
an immunomodulatory drug (usually lenalidomide).  The median time to 
progression on the PX-171-003-A0 study was 5.1 months with a DOR of 
7.4 months (mean follow up of 7.6 months).  A “stepped up” dosing 
schedule, referred to as 20/27 mg/m2, has subsequently been incorporated 
into the PX-171-003 study (referred to as PX-171-003-A1) in order to 


 
Amendment 4 12/04/15 
 
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maximize the clinical benefit of carfilzomib.  Patients receive 20 mg/m2 
for the first cycle and 27 mg/m2 thereafter.  To date, this dosing schedule 
has been well tolerated.  An independent Safety Oversight Group (SOG) 
evaluated the safety data from the 40 of 250 patients to be enrolled on the 
20/27 schedule and agreed that the trial should proceed without 
modification.  No cases of TLS were observed.  The most common 
adverse events were similar to the A0 portion of the study. A decrease in 
cases of renal impairment was observed from 47% all grades with 15% 
Grade 3/4 in A0 to 35% all grades and 2.2% Grade 3/4 in A1.  This is 
most likely due to the implementation of guidelines for hydration.  
Treatment-emergent peripheral neuropathy remains low on this portion of 
the study with 15% Grade 1/2 and no Grade 3 or 4 reported to date on PX-
171-003-A1.  In addition, anemia rates in the PX-171-003-A1 (higher 
dose) were lower than those reported in the PX-171-003–A0 portion of the 
study, possibly indicating that the higher dose of carfilzomib is achieving 
better clearing of neoplastic cells in the bone marrow.  Rates of 
thrombocytopenia and neutropenia were similar in the two cohorts, with 
Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date[23].   
As of May 2009, over 160 patients with relapsed and refractory multiple 
myeloma have received the 20/27 stepped-up dosing schedule in the PX-
171-003-A1 study.  Phase 1b/2 solid tumor study patients are also 
receiving a stepped up dosing schedule using 20/36 mg/m2. In this study, 
the stepped up dose is administered on Day 8 of Cycle 1 and for all 
subsequent doses.  As of April 2009, no MTD has been reached in this 
study and dose escalation to 45 mg/m2 is to be initiated. 
 
In PX-171-004, the subset of patients (N=14) that had not seen bortezomib 
had an ORR of 57% (7% CR, 14% VGPR and 36% PR), while the 
bortezomib treated patients (N=17) had an ORR of 18% (18% PRs)[24].  
The median TTP was 11.1 and 8.3 months in these two groups, 
respectively.  Thus, carfilzomib can induce very high levels of response in 
patients who have not previously been treated with bortezomib, and 
substantial anti-tumor activity is observed even in bortezomib-treated 
patients.  Of note, disease control (PR + MR + SD) was achieved in ~65% 
of patients with progressive MM entering the study.  Patients on these 
studies have been treated for >12 cycles with good tolerability, and 
cumulative toxicity (e.g., bone marrow, severe fatigue, or neuropathy) 
have not been observed. 
 
Based on the results of these trials, in July 2012 carfilzomib received FDA 
approval for patients who had relapsed/refractory multiple myeloma who 
have received at least two prior therapies, including bortezomib and an 
immunomodulatory agent, and have demonstrated disease progression on 
or within 60 days of the completion of the last therapy.[40] 
  
 
 


 
Amendment 4 12/04/15 
 
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1.4 
Pegylated Liposomal Doxorubicin (Doxil® or Lipodox) 
 
Pegylated liposomal doxorubicin (PLD) was first compared with conventional 
doxorubicin in a randomized, phase III multicenter trial of metastatic breast cancer 
(MBC).  Two hundred ninety-seven patients with MBC and no prior chemotherapy for 
metastatic disease were randomized to receive either 60 mg/m2 of PLD or conventional 
doxorubicin, in combination with 600 mg/m2 of cyclophosphamide, every 3 weeks until 
disease progression or unacceptable toxicity.  The study showed an improved toxicity 
panel compared to doxorubicin with significantly reduced cardiotoxicity and less grade 4 
neutropenia, while providing comparable antitumor efficacy.[25]  This was confirmed in 
subsequent trials as O’Brien and colleagues compared the use of PLD at a dose of 50 
mg/m2 (every 4 weeks) to doxorubicin 60 mg/m2 (every 3 weeks).  Cardiac event rates 
were based on reductions in left ventricular ejection fraction as a function of cumulative 
anthracycline dose.  This study demonstrated that in first-line treatment of women with 
MBC, the efficacy of [progression-free survival (PFS)] of PLD is non-inferior to 
doxorubicin with significantly less cardiotoxicity, myelosuppression, nausea, and 
vomiting.[26] 
 
Multicenter randomized phase III trials in multiple myeloma showed that PLD-containing 
chemotherapy regimens (DVD – PLD (Doxil), vincristine (Oncovin), dexamethasone) 
compared to a similar doxorubicin-containing regimen (VAD – vincristine (Oncovin), 
doxorubicin (Adriamycin), dexamethasone) provided similar responses and survival, but 
that the DVD regimen was associated with significantly less toxicity and supportive 
care.[27,28]  PLD was associated with significantly less grade 3/4 neutropenia or 
neutropenic fever (10% vs. 24%; p=0.01), less antibiotic use, lower incidence of sepsis, 
decreased need for central venous access (p<0.0001) and growth factor support (p=0.03) 
and less alopecia compared to the doxorubicin regimen.[27]  A similar decreased toxicity 
and equivalent tumor response was seen in phase II trials incorporating PLD for 
doxorubicin in the CHOP regimen for older patients with aggressive (stage III/IV) NHL, 
in low-grade NHL and in previously untreated aggressive diffuse large B cell 
lymphoma[28-31] 
 
In a Phase III international study comparing the efficacy and safety of a combination of 
pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy 
in patients with relapsed or refractory multiple myeloma, 646 patients were randomly 
assigned to receive either intravenous bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 of 
an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on Day 4.  
Median time to progression was increased from 6.5 months for bortezomib alone to 9.3 
months with the PLD + bortezomib combination (P = 0.000004; hazard ratio, 1.82 
[monotherapy v combination therapy]; 95% CI, 1.41 to 2.35).  The 15 month survival rate 
for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P=0.03).  The 
complete plus partial response rate was 41% for bortezomib and 44% for PLD + 
Bortezomib, a difference that was not statistically significant.  Median duration of 
response was increased from 7 to 10.2 months (P=0.0008) with PLD + bortezomib.  


 
Amendment 4 12/04/15 
 
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Grade 3 and 4 adverse events were more frequent in the combination group (80% vs. 
64%), with safety profiles consistent with the known toxicities of the two agents.   
 
Based on the results of this trial the combination of bortezomib and liposomal 
doxorubicin (Doxil) received FDA approval for patients who had relapsed/refractory 
multiple myeloma who had failed at least one line of therapy and had not received prior 
bortezomib therapy.[17]  
 
In response to a critical shortage of (Doxil), the FDA approved temporary importation of 
a replacement drug Lipodox (doxorubicin hydrochloride liposome injection) in Febuary 
2012. Lipodox has not been approved by the FDA, and therefore, cannot be considered a 
“generic” of Doxilbut has the same active ingredient, dosage, strength, and route of 
administration. Lipodox is manufactured in a facility that has been inspected by the FDA 
and found to be in compliance with current good manufacturing practices.  
 
1.5 
Dexamethasone 
 
There is increasing data on the superiority of three-drug regimens in the treatment of 
relapsed and refractory multiple myeloma.  Dexamethasone is commonly incorporated in 
these three-drug regimens because of its ability to improve response rates and duration of 
response without adding toxicity.  
 
The combination of bortezomib, PLD, and dexamethasone (VDD) has been shown to be 
efficacious and well tolerated. The overall response and duration of response of VDD 
exceeds that of the two drug regimens bortezomib-PLD, and bortezomib-dexamethasone 
suggesting a synergistic effect.[42]  
 
Dexamethasone has been added to carfilzomib, with and without additional agents, in 
many ongoing clinical trials. These clinical trials have indicated that adding 
dexamethasone may increase efficacy and tolerability of carfilzomib containing 
regimens. Many clinical trials that have incorporated dexamethasone into carfilzomib 
regimens have exceeded the MTD of the single-agent carfilzomib studies.   
 
1.6 
Rationale 
 
Based on the further need to improve the therapeutic interventions for multiple myeloma, 
the previous experience with proteasome inhibition, the potentially improved efficacy of 
carfilzomib over bortezomib, and the success of bortezomib combination with PLD, the 
natural next step is to combine carfilzomib with PLD.  Furthermore, proteasome 
inhibitors have the ability to enhance the chemosensitivity in both in vitro and in vivo 
preclinical models.[32]  Mechanistic studies have indicated that this effect is at least in 
part due to the inhibition of NF-κB, since many chemotherapeutics activate NF-κB, 
which can lead to the induction of anti-apoptotic survival proteins such as members of the 
Bcl-2 family[33].  Several models utilizing anthracyclines in combination with a 
proteasome inhibitor have shown enhanced anti-tumor activity, including solid tumor 
models as well as multiple myeloma.  Our aim would be to first determine the maximal 


 
Amendment 4 12/04/15 
 
Page 17 of 60 
 
tolerated dose of the combination in participants with relapsed/refractory myeloma and 
then to establish the efficacy of this novel combination[34, 35].  
 
1.7 
Correlative Studies Background 
 
The correlative studies will focus on two areas: 
(1) evaluation of markers of response 
(2) evaluation of effects of carfilzomib, PLD, and dexamethasone on clonogenic 
myeloma cells 
 
In order to do so, we will collect bone marrow, peripheral blood, and plasma samples 
prior to treatment, at time of response, and/or at end of study. The first objective is to 
determine tumor characteristics that predict at least very good partial response (VGPR). 
VGPR has been associated with longer progression survival and overall survival. The 
second objective is to investigate the effects of carfilzomib and PLD on clonogenic 
myeloma cells. It is hypothesized that inability to cure the disease is related to the 
inability of eradicating chemoresistant clonogenic myeloma cells or myeloma stem cells. 
The effect of carfilzomib and its combinations on these cells is not known.  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
  
• Phase 1: Part 1- To determine the Maximal Tolerated Dose (MTD) of carfilzomib in 
combination with pegylated liposomal doxorubicin (PLD), in participants with 
relapsed or refractory multiple myeloma. Part 2- To determine the Maximal 
Tolerated Dose (MTD) of carfilzomib in combination with PLD and dexamethasone, 
in participants with relapsed or refractory multiple myeloma. 
• Phase 2: To evaluate the efficacy and toxicity of carfilzomib in combination with 
PLD and dexamethasone in participants with relapsed or refractory multiple 
myeloma.   
 
2.2 
Secondary Objectives 
  
• To evaluate the safety of carfilzomib in combination with PLD and dexamethasone in 
participants with relapsed or refractory multiple myeloma.   
• To evaluate the effect of dexamethasone co-administration on the MTD of 
carfilzomib and PLD    
• To evaluate time to tumor progression, progression-free survival, and overall survival 
in this population treated with carfilzomib in combination with PLD and 
dexamethasone. 
 
 
 


 
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3.0 
PARTICIPANT SELECTION 
 
3.1 
Inclusion Criteria 
 
A participant must meet all of the following criteria to be eligible for enrollment.  
 
3.1.1 Histologically confirmed diagnosis of multiple myeloma with a 
measurable disease parameter at time of screening. A measurable disease 
parameter is defined as one or more of the following: 
• Serum monoclonal protein > 0.5 g/dl. 
• 24 hour urine monoclonal protein > 0.2 g/24 hour  
• Serum free light chain ratio > 5x normal ratio with an absolute 
difference of 10mg/dl between the involved and uninvolved free light 
chain. 
• Soft tissue plasmacytoma > 2 cm measurable by either physical 
examination and/or applicable radiographs (e.g. MRI, CT, etc).  
 
• Bone Marrow Plasma Cells >30%. 
  
3.1.2 Documentation of at least one line of prior myeloma therapy now with 
relapsed or refractory disease requiring re-treatment.   
 
3.1.3 > 18 years of age at time of signing the informed consent.  
 
Note: No dosing or adverse event data are currently available on the use of 
carfilzomib in combination with PLD in participants < 18 years of age. 
Thus, children and adolescents are excluded from this study but will be 
eligible for future pediatric phase 2 combination trials. 
 
3.1.4 Performance status of ECOG < 2 or Karnofsky > 60 % (see Appendix A 
and B). 
 
Note: Participants with lower performance status based solely on bone 
pain secondary to multiple myeloma will be eligible. 
 
3.1.5 Required Laboratory Values 
• ALT (SGPT) and AST (SGOT) < 2.5 x the upper limit of the 
institutional normal value (ULN). 
• Total bilirubin < 1.5 x ULN. 
• ANC > 1,000. 
• Hemoglobin > 8 g/dl. 
• Platelets > 50,000. 
• Creatinine clearance > 15 ml/minute using Cockcroft-Gault formula 
(See Appendix C). 
• For those participants receiving warfarin (Coumadin), unfractionated 
heparin, or low-molecular weight heparin therapy, the applicable 


 
Amendment 4 12/04/15 
 
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coagulation parameter that is being monitored must be within the 
accepted therapeutic ranges for those indications.  
 
Note: Transfusions and/or growth factor dependent participants are not 
excluded if the above parameters can be achieved with such support. 
 
3.1.6 Females of childbearing potential (FCBP) must agree to refrain from 
becoming pregnant while on study drug and for 3 months after 
discontinuation from study drug, and must agree to use adequate 
contraception including hormonal contraception, (i.e. birth control pills, 
etc), barrier method contraception (i.e. condoms), or abstinence during 
that time frame.   
 
FCBP must agree to regular pregnancy testing during this timeframe (see 
section 10.1). Inclusion of FCBP requires two negative pregnancy tests 
prior to enrollment. 
 
Note: all women, regardless of age, should be considered FCBP unless 
they are surgically sterile (post hysterectomy, post bilateral oophorectomy, 
etc) or have been naturally post menopausal for > 24 consecutive months.  
 
3.1.7 Men engaging in sexual intercourse with a FCBP must agree to use 
adequate contraception including hormonal contraception, (i.e. birth 
control pills, etc), barrier method contraception (i.e. condoms), or 
abstinence while on study drug and for 3 months after discontinuation 
from study drug 
 
3.1.8 Ability to understand and willing to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
A participant must not meet any of the following criteria to be eligible for enrollment. 
 
3.2.1 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein, and skin changes). 
 
3.2.2 Plasma Cell Leukemia. 
 
3.2.3 Waldenstrom’s macroglobulinemia. 
 
3.2.4 Pregnant or lactating females. 
 
3.2.5 Use of any anti-myeloma drug therapy within 14 days of initiation of 
study drug treatment excluding corticosteroids if given for an indication 
other than myeloma.  


 
Amendment 4 12/04/15 
 
Page 20 of 60 
 
 
Note: Bisphosphonates are not considered anti-myeloma drugs.   
 
3.2.6 Participation in an investigational therapeutic study within 14 days of 
initiation of study drug treatment. 
 
3.2.7 Radiotherapy to multiple sites or immunotherapy within 14 days of 
initiation of study drug treatment (localized radiotherapy to a single site at 
least 7 days before start is permissible). 
 
3.2.8 Major surgery within 14 days of initiation of study drug treatment. 
 
3.2.9 Participants in whom the required program of PO and IV fluid hydration is 
contraindicated. 
 
3.2.10 Prior history of a hypersensitivity reaction to PLD, doxorubicin, 
bortezomib, carfilzomib, or liposomal drug formulations other than PLD.  
 
History of reactions to liposomal drug formulations other than PLD should 
be evaluated individually and if their reactions were felt to have been due 
to the encapsulated agent, rather than the liposomal component itself they 
should be excluded at the discretion of the investigators. 
 
3.2.11 Participants who are known to have active hepatitis A, B, or C viral 
infection may not participate in this study.  Active disease is defined as 
participants with a known viral hepatitis whose liver function tests are 
elevated beyond the criteria indicated in Section 3.1.5. 
 
3.2.12 Known HIV-seropositive and are taking anti-retrovirals may not 
participate in this study because of potential interactions between these 
medications and the investigational agent. Participants who are HIV-
seropositive and not on anti-retroviral therapy and who otherwise meet the 
inclusion/exclusion criteria will be eligible for the study. 
 
3.2.13 Compromised cardiovascular function defined as any of the following: 
• EKG evidence of acute ischemia. 
• EKG 
evidence 
of 
medically 
significant 
conduction 
system 
abnormalities. 
• History of myocardial infarction within the last 6 months. 
• Unstable angina pectoris or cardiac arrhythmia. 
• History of Class 3 or Class 4 New York Heart Association Congestive 
Heart Failure  
• Left ventricular ejection fraction (LVEF) < 55% by either 
echocardiography or radionuclide-based multiple gated acquisition 
(Echo or MUGA). 


 
Amendment 4 12/04/15 
 
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3.2.14 Uncontrolled concurrent illness including: other hematologic or non-
hematologic malignancy, active infection, or uncontrolled diabetes 
 
3.2.15 Any significant psychological, medical, or surgical condition thought to 
compromise the participant, the study, or prevent informed consent.   
 
3.3 
Inclusion of Women and Minorities  
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
  
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
All patients must be registered through the Siteman Cancer Center database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
Patients will also be identified by first, middle, and last initials.  If the patient has no 
middle initial, a dash will be used on the case report forms (CRFs).  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
 


 
Amendment 4 12/04/15 
 
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5.0 
TREATMENT PLAN 
 
5.1 
Overview 
 
Carfilzomib will be administered on Days 1, 2, 8, 9, 15, and 16 during Cycles 1 through 
6, and on Days 1, 8, 15, and 22 beginning on Cycle 7 until disease progression or clinical 
relapse. Participants treated prior to approval of amendment 1, will have carfilzomib 
administered on Days 1, 2, 8, 9, 15, and 16 during Cycles 1 and 2 and on Days 1, 8, 15, 
and 22 beginning on Cycle 3.  PLD will be administered on Day 8 during Cycles 1 
through 6. Dexamethasone will be administered on the same schedule as carfilzomib 
(patients treated in part 2 of phase 1 or phase 2). 
 
 
Participants that have PLD or dexamethasone discontinued for toxicity may remain on 
study to receive the planned study drug doses at the PI’s discretion. 
 
5.2 
Phase I 
 
Part 1- A phase I dose escalation of carfilzomib and PLD will be performed using a 
standard 3 + 3 design with a maximum of 4 dose levels (24 participants). The carfilzomib 
dose will be determined using a modified Fibonacci dose escalation, with a goal of three 
participants at each dose level.  
 
Dose Level 
Carfilzomib (mg/m2) 
IV  
PLD (mg/m2) IV 
-2  
20  
20 
-1  
20 on D1 and D2* 
27 starting on D8 
20 
0 (Start) 
20 on D1 and D2* 
27 starting on D8 
30 
1 
20 on D1 and D2* 
36 starting on D8 
30 
2 
20 on D1 and D2* 
45 starting on D8 
30 
3 
20 on D1 and D2* 
56 starting on D8 
30 
*- Please note that the D1 and D2 carfilzomib dose of 20mg/m2 will only occur during 
Cycle 1. For all subsequent cycles, patients will receive the same dose of carfilzomib 
throughout at what is noted in this table to be the D8 dose.  
 
Part 2- After the MTD of carfilzomib in combination with PLD has been determined, 
dose escalation will resume at the MTD of carfilzomib and PLD with the addition of 
dexamethasone. A maximum of 12 participants eligible for Maximal Tolerated Dose 
(MTD) analysis will be enrolled.  
 
 


 
Amendment 4 12/04/15 
 
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Dose Level 
Carfilzomib (mg/m2) 
IV  
PLD (mg/m2) IV 
Dex (mg) IV or PO  
-1  
1 dose level below the 
MTD 
1 dose level below the 
MTD 
20 
0 (Start) 
MTD 
MTD 
20 
 
5.2.1  Dose Escalation Rule 
 
 
 
 
Only after the last participant on at each dose level completes one cycle of 
treatment will the first participant in the next dose level be enrolled. 
 
5.2.2 Definition of Maximum Tolerated Dose 
 
The maximum tolerated dose (MTD) is defined as the dose level immediately 
below the dose level at which 2 participants of a cohort  (of 2 to 6 participants) 
experience dose limiting toxicity (DLT) during the first cycle of treatment.  (See 
Section 6.0 for information on what constitutes a DLT.)  Dose escalation will 
proceed until the MTD has been reached. 
  
5.3 
Phase II 
 
Having established an MTD in phase I, phase II will be conducted to assess the efficacy 
and toxicity of carfilzomib in combination with PLD and dexamethasone in participants 
with relapsed or refractory multiple myeloma.  
 
Seventeen participants will be treated at the MTD of carfilzomib in combination with 
PLD and dexamethasone. Participants treated in phase 1 at the MTD will be counted as 
part of the phase two accrual. If < 5 successes (CR, VGPR, or PR) are observed, we will 
Number of Participants 
with a DLT at a Dose Level 
Escalation Decision Rule 
0 
Enter 3 participants at the next dose level. 
1 out of 3 
Enter 3 more participants at this dose level. 
 
If none of the additional participants 
experiences a DLT, then proceed to the next 
dose level.  If > 1 of the additional 
participants experiences a DLT, then dose 
escalation is stopped and the level below is 
declared the MTD. 
> 2 
Dose escalation is stopped.  Enter 3 more 
participants at the next lower dose level if 
only 3 participants had previously been 
treated at that dose level. 


 
Amendment 4 12/04/15 
 
Page 24 of 60 
 
consider this regimen ineffective in this participant population and will not recommend 
further testing. 
 
5.4 
Requirements to Start Treatment (Cycle 1 Day 1) 
 
• ALT (SGPT) and AST (SGOT) < 2.5 x the upper limit of the institutional normal 
value (ULN). 
• Total bilirubin < 1.5 x ULN. 
• ANC > 0.5. 
• Platelets > 25,000. 
• Creatinine clearance > 15 ml/min using Cockcroft-Gault formula (See Appendix C). 
 
5.5 
Accrual  
 
The anticipated accrual rate for the phase I portion is 1 participant per calendar month, 
with a total accrual time of two years. The anticipated accrual rate for the phase II portion 
is 1-2 participants per calendar month, with a total accrual time of one year. 
 
 
6.0 
DOSE-LIMITING TOXICITIES/DOSE MODIFICATIONS 
 
6.1 
Definition of Dose-limiting Toxicity  
 
Participants will be evaluated for toxicity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 4.0.  A DLT 
is defined as any of the below treatment emergent toxicities with attribution to one or 
both of the study drugs that occur during Cycle 1.   Toxicities that occur in subsequent 
cycles will be handled through dose modifications (Section 6.2) but will not be 
considered DLTs or figure into the definition of MTD.   
 
As the study uses a lead in dose of 20mg/m2 of Carfilzomib for days 1 and 2 for all dose 
levels, toxicity that requires dose reduction or doses to be held prior to Day 8 of cycle 1 
will not be considered a DLT, but will result in the participant being ineligible for MTD 
analysis. The participant may remain on protocol therapy at the PI’s discretion, and an 
additional participant will be enrolled into the cohort for MTD analysis. 
 
In Phase 1, inability to receive  >80% of Carfilzomib doses and 100% of PLD doses in 
Cycle 1 for reasons other than toxicity will result in the participant being ineligible for 
MTD analysis. The participant may remain on protocol therapy at the PI’s discretion, and 
an additional participant will be enrolled into the cohort for MTD analysis.  
 
Inability to receive >80% of Dex doses for reasons other than toxicity will result in the 
participant being ineligible for MTD analysis (only patients treated in part 2). 
 
Hematologic DLTs 
• > Grade 4 thrombocytopenia 


 
Amendment 4 12/04/15 
 
Page 25 of 60 
 
• > Grade 4 neutropenia 
• > Grade 3 febrile neutropenia (fever > 38.5 degrees C and ANC <1000k/cumm) 
 
Non-Hematologic DLTs 
• ≥ Grade 2 neuropathy with pain 
• ≥ Any grade 3 non-hematologic toxicity (excluding nausea, vomiting, diarrhea) 
• ≥ Grade 3 nausea, vomiting, or diarrhea for > 3 days despite maximal 
antiemetic/antidiarrheal therapy 
• Any non-hematologic toxicity requiring a dose reduction within Cycle 1 
• Inability to receive Day 1 dose of Cycle 2 due to drug-related toxicity persisting 
from Cycle 1 or drug-related toxicity newly encountered on Day 1 of Cycle 2 
• Delay of > 14 days in initiating Day 1 of Cycle 2 due to drug-related toxicity 
 
6.2 
Dosing Modifications 
 
6.2.1 Overview  
 
Dose modifications for hematologic and non-hematologic toxicities are 
summarized in sections 6.2.2 and 6.2.3 respectively. Participants who have 
treatment delayed for greater than four weeks should discontinue protocol 
therapy.   
 
A maximum of 2 dose reductions of carfilzomib or Dex and 1 dose reduction of 
PLD will be allowed for each participant. More than two dose reductions of Dex 
or one dose reduction of PLD will require the agent be discontinued. Participants 
that permanently discontinue Dex or PLD due to toxicity can remain on study and 
receive the other planned study drug doses at the investigator’s discretion. 
Participants requiring a third dose reduction of carfilzomib will have treatment 
discontinued. 
 
If the participant tolerates the reduced dose for one cycle, the participant may be 
dose escalated to the study drug dose(s) prior to reduction at the discretion of the 
Investigator. 
 
Dose modifications should be followed directly for Cycle 1 for all patients treated 
in the phase I portion of the study. In Cycles 2+ for patients treated in the phase I 
portion, and for any cycle for patients treated in the phase II portion, dose 
modifications and delays different from those stated in the protocol for 
management of toxicities will be permitted at the discretion of the Principal 
Investigator. 
 
6.2.2 Dosing Modifications for Hematologic Toxicities 
 
6.2.2.1 Thrombocytopenia 
 
Only thrombocytopenia determined to be related to one or both study 


 
Amendment 4 12/04/15 
 
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drugs require dose reductions or adjustments as described in this section. 
Platelet transfusion support is permissible at the discretion of the treating 
physician.  Participants who have treatment delayed for greater than four 
weeks should discontinue protocol therapy.   
 
Dose modifications for thrombocytopenia should be instituted as follows: 
 
Grade  Platelet 
           Modification 
4 
< 25,000 
First episode: Hold therapy until platelets resolve 
to grade < 1 or baseline, then reduce carfilzomib by 
one dose level 
  
Second episode: Hold therapy until platelets 
resolve to grade < 1 or baseline, then further reduce 
carfilzomib by one more dose level and reduce PLD 
by one dose level 
  
  
Third episode: Discontinue protocol therapy. 
 
6.2.2.2 Neutropenia 
 
Only neutropenia determined to be related to one or both study drugs 
require dose reductions or adjustments as described in this section. 
Colony-stimulating factor support (such as G-CSF or GM-CSF) for 
neutropenia is permissible at the discretion of the treating physician, but 
should not be given prophylactically. Participants who have treatment 
delayed for greater than four weeks should discontinue protocol therapy.  
 
Dose modifications for neutropenia should be instituted as follows: 
 
 
 
 
 
 
 
 
 
 
6.2.2.3 F
ebrile Neutropenia (Fever > 38.5 degrees Celsius and ANC < 
1000) 
 
Colony-stimulating factor support (such as G-CSF or GM-CSF) for 
neutropenia is permissible at the discretion of the treating physician, but 
should not be given prophylactically. Participants who have treatment 
delayed for greater than four weeks should discontinue protocol therapy.   
 
 
Grade  
ANC 
           Modification 
4 
< 500 
First episode: Hold therapy until ANC resolves to 
grade < 1 or baseline, then reduce carfilzomib by one 
dose level 
  
Second episode: Hold therapy until ANC resolves to 
grade < 1 or baseline, then further reduce carfilzomib 
by one more dose level and reduce PLD by one dose 
level 
  
  
Third episode: Discontinue protocol therapy. 


 
Amendment 4 12/04/15 
 
Page 27 of 60 
 
 
Dose modifications for febrile neutropenia should be instituted as follows: 
 
Grade    
           Modification 
> 3 
First episode: Hold therapy until participant recovers, 
then reduce carfilzomib by one dose level 
  
Second episode: Hold therapy until participant 
recovers, then further reduce carfilzomib by one more 
dose level and reduce PLD by one dose level 
  
  
Third episode: Discontinue protocol therapy. 
 
6.2.3 Dosing Modifications for Non-Hematologic Toxicities 
 
Dose modification guidelines for treatment related non-hematologic toxicities are 
as follows: 
 
Toxicity 
Grade  
           Modification 
Allergic 
reaction/hypersensitivity 
2 or 3 
First episode: Hold suspected drug(s) 
until ≤ grade 1, resume treatment at full 
dose. 
  
  
Second episode: Discontinue 
suspected drug(s).  
Allergic 
reaction/hypersensitivity 
4 
Discontinue suspected drug(s).  
Congestive heart failure 
(CHF) 
 Any 
Any participant with new symptoms of 
CHF worsening symptoms of baseline 
CHF or LVEF < 45% should have all 
drugs held until resolution or return to 
baseline regardless of attribution, once 
resolved Carfilzomib may continue at 
the original dose, reduced dose or 
discontinued 
at 
the 
investigator's 
discretion, 
but 
PLD 
must 
be 
discontinued 
Creatinine Clearance  < 
15 mL/min (by Cockcroft-
Gault formula, see 
Appendix C) 
 N/A 
Hold all drugs until > 15mL/min 
regardless of attribution, then reduce 
suspected drug(s) by one dose level.  
Herpes simplex virus 
(HSV) or herpes zoster 
Any 
Hold all drugs until HSV lesions are 
dry then resume treatment at full dose. 


 
Amendment 4 12/04/15 
 
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Infection 
> 3 
Hold all drugs until infection is 
adequately controlled with systemic 
therapy regardless of attribution, then 
resume treatment at full doses. Patients 
with recurrent infection should have 
carfilzomib or PLD dose reduced at the 
investigator's discretion. 
Nausea, Vomiting, or 
Diarrhea 
  
  
persisting < 3 days 
following adequate 
treatment of antiemetics or 
antidiarrheals 
3 
No dose modification required. 
  
  
  
persisting > 3 days 
following adequate 
treatment of antiemetics or 
antidiarrheals 
3 
Hold suspected study drug(s) until 
toxicity resolves to < grade 1 or 
baseline, then reduce suspected drug(s) 
by one dose level. 
Neuropathy 
  
  
Moderate symptoms; 
limiting instrumental ADL 
but not painful 
2 
Continue treatment. Patients on 
Pyridoxine should have it discontinued 
Moderate symptoms with 
associated pain; limiting 
instrumental ADL   
 
2 
Continue treatment. Patients on 
Pyridoxine should have it discontinued. 
If neuropathy persists for more than 
two weeks, hold suspected drug(s) until 
resolved to < grade 2 without pain, then 
reduce suspected drug(s) by one dose 
level. 
  
  
  
Severe symptoms; limiting 
self care ADL  
3 
Continue treatment. Patients on 
Pyridoxine should have it discontinued. 
If neuropathy persists for more than 
two weeks, hold suspected drug(s) until 
resolved to < grade 2 without pain, then 
reduce suspected drug(s) by one dose 
level. 
  
  
Life-threatening 
consequences; urgent 
intervention indicated  
4 
Discontinue treatment. 
 
 


 
Amendment 4 12/04/15 
 
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Palmar-Plantar 
Erythrodysthesia (PPE) 
Erythema, desquamation, 
or swelling interfering with 
but not precluding normal 
physical activities; small 
blisters or ulcerations less 
than 2 cm in diameter 
2 
 First episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume at the same 
dose. 
Second episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume carfilzomib at 
same dose level a reduce PLD by one 
dose level. 
Third episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume carfilzomib at 
same dose and discontinue PLD 
Blistering, ulceration, or 
swelling interfering with 
walking or normal daily 
activities; cannot wear 
regular clothing 
3 
First episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume carfilzomib at 
same dose level a reduce PLD by one 
dose level. 
  
  
Second episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume carfilzomib at 
same dose and discontinue PLD. 
  
  
  
Diffuse or local process 
causing infectious 
complications, a bed-
ridden state or 
hospitalization 
4 
First episode: Hold all drugs until 
resolved to < grade 1 regardless of 
attribution, then resume carfilzomib at 
same dose and discontinue PLD. 
Stomatitis 
Painful erythema, edema, 
or ulcers, but can eat 
2 
First episode: Hold all drugs until 
resolved to < grade 1 then resume at 
the same dose. 
Second episode: Hold all drugs until 
resolved to < grade 1 then resume 
carfilzomib at the same dose and PLD 
at 20 mg/m2. 
Third episode: Hold all drugs until 
resolved to < grade 1 then discontinue 
PLD and resume carfilzomib at the 
same dose. 
 
Painful erythema, edema, 
or ulcers, and cannot eat 
3 
First episode: Hold all drugs until 
resolved to < grade 1 then resume 
carfilzomib at the same dose and PLD 
at 20 mg/m2. 
  
  
Second episode: Hold all drugs until 
resolved to < grade 1 then discontinue 
PLD and resume carfilzomib at the 


 
Amendment 4 12/04/15 
 
Page 30 of 60 
 
same dose. 
  
  
  
Requires parenteral or 
enteral support 
4 
Hold all drugs until resolved to < grade 
1, then discontinue PLD and resume 
carfilzomib at the same dose.   
Tumor lysis syndrome, 
defined as > 3 of 
following: 
Any 
Hold all drugs until all abnormalities in 
serum chemistries have resolved to 
baseline, then resume treatment at full 
doses. 
> 50% increase in 
creatinine 
  
  
> 50% increase in uric acid 
> 50% increase in 
phosphorus 
  
  
> 30% increase in 
potassium 
> 20% decrease in calcium 
> 2-fold increase in LDH 
  
  
Other non-hematologic 
toxicity 
> 3 
Hold suspected study drug(s) until 
toxicity resolves to < grade 1 or 
baseline, then reduce suspected drug(s) 
by one dose level. 
 
6.3 
Missed Doses 
 
Missed doses will not be replaced during a cycle. Doses can be adjusted by +/- 2 days to 
allow for holidays, travel issues, etc. Additional adjustments may be granted at the PI’s 
discretion. Everything possible should be done to prevent adjustments from in the study 
schedule during Cycle 1.  
 
6.4 
Changes in Body Surface Area (BSA)  
 
Dose adjustments do not need to be made for weight gains/losses of ≤ 20% from baseline.  
Participants with a Body Surface Area (BSA) of greater than 2.2 m2 will receive a capped 
dose using 2.2 m2 as the cut-off value. 
 
 
7.0 
AGENT ADMINISTRATION 
 
7.1 
Carfilzomib 
 
7.1.1 Accountability 
 
Instructions for the receipt, inspection, storage, preparation, administration, and 
disposal of Carfilzomib for Injection are provided in the Pharmacy Manual at 
each clinical site. 


 
Amendment 4 12/04/15 
 
Page 31 of 60 
 
 
7.1.2 Availability 
 
Carfilzomib for injection is supplied as a lyophilized parenteral product in single-
use vials. Before use, the lyophilized product is reconstituted with water for 
injection to a final concentration of 2 mg/mL. 
 
7.1.3 Storage, Stability, and Preparation 
 
Lyophilized Carfilzomib for Injection is stored in a refrigerator at 2°C to 8°C. 
Carfilzomib doses are based on BSA. In a typical dose of carfilzomib, 27 mg/m2 
in a participant with a BSA of 2.0 m2, the dose delivered would be 54 mg 
carfilzomib in a volume of 27 mL. Participants with a BSA of 2.2 m2 or higher 
receive a dose based upon 2.2 m2 BSA.  After addition of the appropriate amount 
of Water for Injection and vigorous mixing, the solution is administered as an IV 
infusion.   
 
7.1.4 Administration 
 
The dosing schedule of carfilzomib will be on Days 1, 2, 8, 9, 15, and 16 in a 28-
day cycle for 6 cycles and then weekly (Days 1, 8, 15, and 22) thereafter until 
disease progression or clinical relapse. Participants treated prior to approval of 
amendment 1, will have carfilzomib administered on Days 1, 2, 8, 9, 15, and 16 
during Cycles 1 and 2 and on Days 1, 8, 15, and 22 beginning on Cycle 3.  
Carfilzomib dose levels being investigated are: 20mg/m2, 20/27mg/m2, 
20/36mg/m2, 20/45mg/m2, and 20/56mg/m2.   
 
Current clinical experience indicates that carfilzomib can be safely administered 
as an IV push at rates of approximately 10 mL/minute for doses of 20-27mg/m2.  
Higher doses (> 27 mg/m2) should be administered as a 30-minute infusion. For 
IV infusion over 30 minutes, carfilzomib should be diluted into 50cc of 5% 
Dextrose Injection. USP (D5W). Based on preclinical studies, these adjustments 
in infusion rate and time should not affect the PDn effects in humans. 
 
Each dose will consist of carfilzomib for injection administered on a mg/m2 basis, 
and should be based on the participant’s actual calculated body surface area 
(BSA) at baseline.  Participants with a BSA > 2.2 m2 will receive a dose based on 
a 2.2 m2 BSA. 
 
IV hydration will be given immediately before carfilzomib dose during Cycle 1.  
This will consist of 250 to 500 mL normal saline or other appropriate IV fluid.  
The goal of the hydration program is to maintain robust urine output (e.g., ≥ 2 
L/day).  Participants should be monitored periodically during this period for 
evidence of fluid overload. 
 
Patients not receiving dexamethasone as part of the regimen (those treated in part 


 
Amendment 4 12/04/15 
 
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1 of phase 1) should receive 4mg dexamethasone premedication >30 minutes 
prior to all carfilzomib doses in cycle 1. Dexamethasone premedication can 
continue beyond cycle 1 at the discretion of the treating physician. Patients being 
treated with 10 or 20 mg dexamethasone as part of their regimen should not 
receive an additional 4mg as premedication.   
 
Complete blood counts (CBC) with platelet count should be obtained and 
reviewed prior to carfilzomib dosing. See section 6.2.2 for guidelines for dose 
reductions, adjustments and delays for hematologic toxicities. 
 
Appropriate chemistries, including creatinine should be obtained and reviewed 
prior to carfilzomib dosing during cycles 1 and 2. Electrolyte abnormalities that 
are National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) > 2 or clinically significant should be corrected prior to dosing.  
Renal function must be monitored closely during treatment with carfilzomib. 
Carfilzomib must be held for participants with a creatinine clearance (by 
Cockcroft-Gault formula see Appendix C) < 15 mL/min at any time during study 
participation.  
 
Participants with laboratory abnormalities consistent with TLS should not receive 
the scheduled dose. Lab abnormalities consistent with TLS is defined as > 3 of 
following: serum creatinine ≥ 50% increase, uric acid ≥ 50% increase, phosphorus  
≥ 50% increase, potassium ≥ 30% increase, calcium ≥ 20% decrease, LDH ≥ 2-
fold increase prior to dosing should not receive the scheduled dose.  Participants 
with such abnormalities should be re-evaluated again within the next 24 hours (or 
sooner, if clinically indicated) and then periodically as clinically indicated.    
 
Participants should have a dedicated line for carfilzomib administration.  Before 
and after administration, the line must be flushed with a minimum of 20 mL of 
normal saline.  If a dedicated line is not possible, the existing line must be flushed 
with a minimum of 20 mL of normal saline before and after drug administration.     
 
Participants may experience stinging, burning, or a painful sensation at the 
injection site during the IV push administration of carfilzomib. This generally is 
mild and subsides shortly following the infusion. Slowing the IV push to the 
maximum allowed time (10 minutes) can help with minimize such a reaction.  
 
Carfilzomib is considered an irritant. Nonetheless, care should be taken to avoid 
extravasation. If any signs or symptoms of extravasation occur, the infusion 
should be terminated and restarted in another vein. Apply ice immediately for 30-
60 minutes, subsequently alternating on and off every 15 minutes for 24 hours. 
The extremity should be monitored for 24-48 hours, then the participant may 
resume normal activity as tolerated. Do not apply heat or sodium bicarbonate. If 
pain, erythema or swelling persists beyond 48 hours the participant should be 
referred to a plastic surgeon for possible debridement at the treating physician’s 
discretion. 


 
Amendment 4 12/04/15 
 
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The dose will be administered at a facility capable of managing hypersensitivity 
reactions. Medications to treat infusion-related reactions, as well as emergency 
equipment should be available for immediate use. If a patient develops a grade > 
2 infusion-related reaction, the infusion should be stopped and appropriate 
symptomatic treatment per institutional guidelines should be started immediately. 
The participant should be observed for at least 30 to 60 minutes depending on the 
severity of the reaction. At the discretion of the treating physician, treatment may 
be resumed. Discontinue treatment if subsequent infusion-related reaction occurs. 
 
In the event of > grade 2 infusion-related or hypersensitivity reaction during 
carfilzomib infusion, discontinue the carfilzomib injection. Begin appropriate 
symptomatic treatment immediately per institutional guidelines. The participant 
should be observed for at least 30 to 60 minutes depending on the severity of the 
reaction. At the discretion of the treating physician, treatment may be resumed. 
Discontinue treatment if subsequent infusion-related reaction occurs. 
 
Procedures for dose reductions, adjustments and delays are summarized in 
Section 6.0. 
 
7.1.5 Guidelines for Monitoring and Treatment of Tumor Lysis Syndrome  
 
Tumor Lysis Syndrome (TLS), which may be associated with multiorgan failure, 
has been observed in treatment Cycles 1 and 2 in some participants with MM who 
have been treated with carfilzomib.  
 
7.1.5.1 Laboratory Monitoring 
 
Participants with laboratory abnormalities consistent with TLS should not 
receive the scheduled dose. Lab abnormalities consistent with TLS is 
defined as > 3 of following: serum creatinine ≥ 50% increase, uric acid ≥ 
50% increase, phosphorus  ≥ 50% increase, potassium ≥ 30% increase, 
calcium ≥ 20% decrease, LDH ≥ 2-fold increase prior to dosing should not 
receive the scheduled dose.  Participants with such abnormalities should 
be re-evaluated again within the next 24 hours (or sooner, if clinically 
indicated) and then periodically as clinically indicated.    
 
7.1.5.2 Clinical Monitoring 
 
Inform participants of signs and symptoms that may be indicative of TLS, 
such as fevers, chills/rigors, dyspnea, nausea, vomiting, muscle tetany, 
weakness, or cramping, seizures, and decreased urine output.  Advise 
participants to report such symptoms immediately and seek medical 
attention.  
 
7.1.5.3 Treatment of Tumor Lysis Syndrome 


 
Amendment 4 12/04/15 
 
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If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring 
should be instituted.  Correct electrolyte abnormalities, monitor renal 
function and fluid balance, and administer therapeutic and supportive care, 
including dialysis, as clinically indicated. 
 
A “first-dose effect” has been seen, which is notable for fever, chills, 
and/or rigors occurring during the evening following the first day of 
infusion and an increase in creatinine on Day 2, which may be the clinical 
sequelae of rapid tumor lysis and/or cytokine release.  Should a “first 
dose” effect occur at any point during Cycle 1 or 2, treatment with high 
dose 
glucocorticoids 
(e.g. 
methylprednisolone 
50–100 
mg) 
is 
recommended.  In addition, intravenous fluids, vasopressors, oxygen, 
bronchodilators, and acetaminophen should be available for immediate use 
and instituted, as medically indicated.  
 
7.2 
Pegylated Liposomal Doxorubicin (Doxil® or Lipodox) 
 
7.2.1 Accountability 
 
Instructions for the receipt, inspection, storage, preparation, administration, and 
disposal of pegylated liposomal doxorubicin (PLD) are provided in the Pharmacy 
Manual at each clinical site. 
 
7.2.2 Availability 
 
Pegylated liposomal doxorubicin (PLD) is supplied in 20mg and 50mg vials as a 
liposomal dispersion at a concentration of 2mg/ml. Vials are intended for single 
use.  
 
7.2.3 Storage and Stability  
 
Intact vials of pegylated liposomal doxorubicin (PLD) should be stored under 
refrigeration (2-8ºC). Prolonged freezing may adversely affect liposomal drug 
products, but freezing for less than one month doesn’t seem to do so. Pegylated 
liposomal doxorubicin (PLD) diluted for infusion is stable for 48 hours under 
refrigeration or 24 hours at room temperature.   
 
7.2.4 Preparation  
 
The desired volume of liposomal dispersion should be withdrawn and must be 
added to 250ml D5W for IV infusion.   
 
 


 
Amendment 4 12/04/15 
 
Page 35 of 60 
 
 
7.2.5 Administration   
 
PLD will be administered on Day 8 of each 28-day cycle for a maximum of 6 
cycles. PLD dose levels being investigated are: 20mg/m2, and 30mg/m2.   
 
Pegylated liposomal doxorubicin (PLD) will be administered as an IV infusion 
over 1 hour beginning one hour after the beginning of the carfilzomib infusion.  
On days when carfilzomib is held, PLD should also be held. PLD may be 
administered through the same line as carfilzomib. Rapid flushing of the infusion 
line should be avoided post PLD administration.  
 
Pegylated liposomal doxorubicin (PLD) is considered an irritant. This is in 
contrast to conventional doxorubicin which can cause severe tissue damage on 
extravasation, Nonetheless, care should be taken to avoid extravasation. If any 
signs or symptoms of extravasation occur, the infusion should be terminated and 
restarted in another vein. Apply ice immediately for 30-60 minutes, subsequently 
alternating on and off every 15 minutes for 24 hours. The extremity should be 
monitored for 24-48 hours, then the participant may resume normal activity as 
tolerated. Do not apply heat or sodium bicarbonate. If pain, erythema or swelling 
persists beyond 48 hours the participant should be referred to a plastic surgeon for 
possible debridement at the treating physician’s discretion. 
 
Infusion-related reactions have been seen in up to 10% of participants per the 
manufacturer. Participants who experience this reaction generally do so during the 
first infusion and not with subsequent dosing. Symptoms may include fever, 
flushing, dyspnea, facial swelling, headache, chills, back pain, tightness in the 
chest and throat, rash, pruritus, chest pain, hypotension, syncope, sinus 
tachycardia, apnea, bronchospasm/wheezing, cyanosis, and asthma. Serious and 
sometimes life-threatening or fatal anaphylactic shock/anaphylactoid reactions 
have been reported. 
 
Rapid infusion may increase the risk of some infusion-related reactions, and it is 
suggested that first infusion be initiated at a rate of 1 mg/min. If no reactions are 
observed after 5-10 minutes, the rate can be increased to complete the infusion 
over 1 hour.   
 
The dose will be administered at a facility capable of managing hypersensitivity 
reactions. Medications to treat infusion-related reactions, as well as emergency 
equipment, should be available for immediate use. If a participant develops a 
grade > 2 infusion-related reaction, the infusion should be stopped and 
appropriate symptomatic treatment per institutional guidelines should be started 
immediately. The participant should be observed for at least 30 to 60 minutes 
depending on the severity of the reaction. At the discretion of the treating 
physician, treatment may be resumed with administration of H1-blockers and/or 
steroids. Discontinue treatment if subsequent infusion-related reaction occurs. 


 
Amendment 4 12/04/15 
 
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Procedures for dose reductions, adjustments and delays are summarized in 
Section 6.0. 
 
7.2.6 Palmar-Plantar Erythrodysesthesia (PPE)  
 
The onset of PPE is often preceded by exposure of the affected area to friction 
and/or heat. All participants should therefore be advised to avoid contact with 
heated objects or bathing and washing with hot water during therapy.  
 
Pyridoxine (vitamin B6) has been reported to decrease the severity of PPE and 
may decrease its incidence if used in a prophylactic setting. Participants in this 
study should receive pyridoxine starting on or before Day 1 of Cycle 1[36, 37] 
(See section 6.3.2 for details). 
 
Management of PPE once it has appeared is predominantly supportive, with use 
of treatments such as topical wound care, cold compresses, and elevation. Non-
steroidal anti-inflammatory drugs are beneficial in some, and topical 99% 
dimethyl-sulfoxide has been reported to be of benefit as well, but none of these 
studies have been studied in a randomized, blinded, prospective fashion. 
Pyridoxine will be continued in the event that PPE develops despite prophylaxis 
[38].  
 
7.3 
Dexamethasone 
 
7.3.1 Accountability 
 
Dexamethasone is not provided by the study. It will be sourced from a 
commercial pharmacy.   
 
7.3.2 Availability 
 
Dexamethasone is commercially available in 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 
1.5mg, 4 mg, and 6 mg tablets. It is also available as a 0.5 mg/5mL elixir, and as 4 
mg/mL, 10 mg/mL, and 20 mg/mL solution for injection. Please refer to the FDA 
approved package insert for dexamethasone for product information, extensive 
preparation instructions, and a comprehensive list of adverse events.  
 
7.3.3 Storage and Stability  
 
Dexamethasone tablets should be stored at room temperature. Solution for 
injection may be administered diluted in IV fluids over 10-20 minutes.   
 
7.3.4 Administration   
 
Dexamethasone will be administered on the same dosing schedule as carfilzomib 


 
Amendment 4 12/04/15 
 
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(Days 1, 2, 8, 9, 15, and 16 for 6 cycles and then Days 1, 8, 15, and 22 thereafter 
until disease progression or clinical relapse). Dexamethasone dose levels being 
investigated are: 10 mg and 20mg.  
 
Dexamethasone should be taken IV or PO > 30 minutes prior to Carfilzomib 
injection.  
 
After cycle 2, participants enrolled into part 1 of phase 1 (those not receiving 
dexamethasone) can have dexamethasone 20mg added at the discretion of the 
treating physician. If dexamethasone is added, the dose modification guidelines 
(section 6.2) should be followed.  
 
7.4 
General Concomitant Medication and Supportive Care Guidelines 
 
7.4.1 HSV Prophylaxis 
 
Acyclovir, or valacyclovir, should be given to all participants, per institutional 
prophylaxis guidelines, unless contraindicated. 
 
7.4.2 Pyridoxine 
 
It is recommended that all participants be initiated on pyridoxine (vitamin B6) at 
200 mg PO QD for prophylaxis against palmar plantar erythrodysesthesia (PPE) 
starting on or before Day 1 of Cycle 1. Pyridoxine will be continued in the event 
that PPE develops despite prophylaxis  
 
Vitamin B6 has been reported to cause neuropathy[39]. Therefore any participants 
who develop a neuropathy more severe than grade 1 while on study should first 
have this agent discontinued.   
 
7.4.3 Glucocorticoids  
 
Glucocorticoids (other than those required per protocol) are permitted for non-
malignant conditions (i.e. asthma, IBD, etc.) but should not be used unless 
completely necessary. Glucocorticoids have anti-myeloma effect that may lead to 
confusion of the response data for this study. Glucocorticoid use while one study 
should be kept minimal.   
 
7.4.4 Bisphosphonates  
 
Participants should receive therapy with bisphosphonates as per institutional 
guidelines. The choice of agents in this category will be left to the discretion of 
the treating physicians.   
 
 


 
Amendment 4 12/04/15 
 
Page 38 of 60 
 
 
7.4.5 Erythropoietins   
 
Participants may develop new or worsening anemia and may require either 
initiation of an erythropoietin preparation or an increased dose of the agent they 
are already receiving. The choice of preparations to be used will be left to the 
discretion of the treating physicians. 
 
7.4.6 Filgrastim (G-CSF), Peg-Filgrastim, and Sargramostim (GM-CSF)  
 
Participants may develop neutropenia and may benefit from initiation of some 
type of colony stimulating factor, but they should not be given prophylactically. 
The choice of preparations to be used will be left to the discretion of the treating 
physicians.  
 
7.4.7 Platelet, RBC, Whole blood, or FFP Transfusions  
 
Participants may receive platelet, red blood cell (RBC), whole blood, or fresh 
frozen plasma (FFP) transfusions if clinically indicated.   
 
7.4.8 Antiemetics and Antidiarrheals  
 
Carfilzomib and PLD treatment can cause nausea, vomiting, or diarrhea, 
sometimes requiring the use of antiemetics or antidiarrheals, but these agents 
should not be started prophylactically. If needed, the choice of preparations to be 
used will be left to the discretion of the treating physicians.  
 
Participants with severe nausea, vomiting, or diarrhea should have fluid and 
electrolyte replacement administered to prevent dehydration per institutional 
guidelines.   
 
7.4.9 Palliative Radiation 
 
Palliative radiation while on study is allowed at the discretion of the treating 
physician as long as the definition of progressive disease is not met (see section 
9.8). Participants meeting the definition of progressive disease should be 
discontinued from study.  
 
7.4.10 Anti-Myeloma Therapy 
 
The concurrent use of any approved or investigative drug with known or 
suspected anti-myeloma effect outside the scope of this trial is prohibited, with 
exception to those specifically permitted in section 7.4.   
 
 


 
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7.4.11 Investigational Agents 
 
Other investigative agents (e.g., antibiotics or antiemetics) should not be used 
during the study.  
 
 
8.0 
DURATION OF THERAPY 
 
8.1 
Criteria for Removal from Study 
  
Treatment may continue until disease progression or clinical relapse, as defined in 
Sections 9.8 and 9.9 respectively, or until one or more of the following criterion applies: 
 
• Participant withdraws consent 
• Holding study drug(s) > 2 continuous weeks for adverse event(s) 
• Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 
• General or specific changes in the participant’s condition render the 
participant unacceptable for further treatment in the judgment of the 
investigator 
• Suspected or confirmed pregnancy 
• Major violation of the study protocol 
• Participant lost to follow-up 
• The PI decides to remove the participant from study for any reason 
• Death 
• The treating center decides to close the study 
 
8.2 
Duration of Follow-Up 
 
Participants will be followed for 18 months after removal from study or until death, 
whichever occurs first.  Participants removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event, even if the follow-
up exceeds 18 months. 
 
 
9.0 
CRITERIA FOR RESPONSE 
  
9.1 
Complete Response  
 
Complete response (CR) requires all of the following: 
  
• Disappearance monoclonal protein by both protein electrophoresis and 
immunofixation studies from the blood and urine on at least two 
determinations, performed a minimum of six weeks apart 
• <5% plasma cells in the bone marrow 


 
Amendment 4 12/04/15 
 
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• Disappearance of soft tissue plasmacytomas for at least six weeks 
  
9.2 
Stringent Complete Response  
 
Stringent complete response (sCR) requires all of the following: 
 
• CR as defined above 
• Normal free light chain ratio 
• Absence of clonal cells in the bone marrow by immunohistochemistry or 
immunofluorescence 
 
9.3 
Near-Complete Response  
 
Near-complete response (nCR) requires all of the following: 
 
• The presence of a residual monoclonal protein that is visible only on 
immunofixation studies, and not on serum or urine protein electrophoresis  
• All other criteria are met for complete response.  
 
9.4 
Very Good Partial Response 
 
Very good partial response (VGPR) requires all of the following: 
 
• Serum and urine monoclonal protein detectable by immunofixation but not on 
electrophoresis for at least two determinations, performed a minimum of six 
weeks apart  
 
 
 
 
 
OR   
> 90% reduction in serum monoclonal protein with urine monoclonal protein 
< 100 mg per 24 hours for at least two determinations, performed a minimum 
of six weeks apart. 
• If present, > 50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examinations) for at least six weeks.  
 
9.5 
Partial Response 
 
Partial response (PR) requires all of the following: 
 
• > 50% reduction in the level of the serum monoclonal protein for at least two 
determinations performed a minimum of six weeks apart.  
• Reduction in urine monoclonal protein by either > 90% or to < 200 mg for at 
least two determinations performed a minimum of six weeks apart.  
• If present, > 50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examinations) for at least six weeks.  
• If serum and urine monoclonal protein are unmeasurable, a >50% decrease in 
difference between the involved and uninvolved free light chain levels is 
required in place of monoclonal protein criteria (The absolute decrease must 


 
Amendment 4 12/04/15 
 
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be > 10 mg/dl) 
• If serum and urine monoclonal protein are unmeasurable and serum free light 
chain is unmeasurable,  a > 50% reduction in plasma cells is required in place 
of monoclonal protein provided that baseline bone marrow plasma cell 
percentage was > 30%  
 
9.6 
Minimal Response  
 
Minimal response (MR) requires all of the following: 
 
• > 25% to < 49% reduction in the level of serum monoclonal protein for at 
least two determinations six weeks apart.  
• If present, a 50 to 89% reduction in 24-hour urine monoclonal protein  which 
still exceeds 200 mg/24hr, for at least two determinations six weeks apart.  
• 25-49% reduction in the size of plasmacytomas (by clinical or radiographic 
examinations) for at least six weeks.   
• No increase in size or number of lytic bone lesions (development of 
compression fracture dose not exclude response). 
 
Note: MR includes participants in whom some but not all criteria for PR are fulfilled 
providing the remaining criteria satisfy the requirements for MR. 
 
9.7 
Stable Disease  
 
Stable disease (SD) is defined as not meeting criteria for any other response as defined in 
this section. 
 
9.8 
Progressive Disease  
 
Progressive disease (PD) requires one or more of the following: 
  
• > 25% increase in the level of serum monoclonal protein, which must also be 
an absolute increase of at least 0.5 g/dL, and confirmed on a repeat 
investigation.   
• > 25% increase in 24-hour urine monoclonal protein, which must also be an 
absolute increase of at least 200 mg/24hr and confirmed on a repeat 
investigation.   
• > 25% increase in plasma cells in a bone marrow aspirate or on trephine 
biopsy, which must also be an absolute increase of at least 10%.  
• > 25% increase in the difference between involved and uninvolved free light 
chain levels (The absolute increase must be >10 mg/dl)  
• Definite increase in the size of existing lytic bone lesions or soft tissue 
plasmacytomas. A definite increase is defined as at least 50% (and at least 1 
cm) increase as measured serially as the sum of the products of the cross-
diameters of the lesions. 
• Development of new bone lesions or soft tissue plasmacytomas (not including 


 
Amendment 4 12/04/15 
 
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compression fracture).  
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 
mmol/L not attributable to any cause other than progressive multiple 
myeloma).  
 
Note: A response of progressive disease nullifies any other concurrent response. For 
example, at a given time point a participant meets criteria for VGPR but has development 
of new bone lesions the response is PD not VGPR. 
 
 
9.9 
Clinical Relapse 
 
Clinical relapse (i.e. progressive disease requiring alternate myeloma treatment) requires 
one or more of the following: 
 
• Decrease in hemoglobin > 2 g/dl not attributable to any cause other than 
progressive multiple myeloma 
• Increase in creatinine  by > 2 mg/dl not attributable to any cause other than 
progressive multiple myeloma 
• Other worsening laboratory result, or clinical condition that the treating 
physician determines is not attributable to any cause other than progressive 
multiple myeloma 
 
9.10 
Relapse from Complete Response 
 
Relapse from a complete response requires a prior CR or sCR as described above and 
subsequently developing one or more of the following: 
 
• Reappearance of serum or urinary paraprotein on immunofixation or routine 
electrophoresis excluding oligoclonal immune reconstitution for at least two 
determinations.  
• > 5% plasma cells in the bone marrow aspirate or biopsy. 
 


 
Amendment 4 12/04/15 
 
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10.0 
STUDY CALENDAR 
 
Assessment * 
Screening a 
Cycles 1 through 6 
Cycles 7 and beyond 
End of 
Study b 
Follow-
up c 
D1 
D2 
D8 
D9 
D15 
D16 
D1 
D8 
D15 
D22 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & treatment history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical exam e 
X 
X1 
 
 
 
 
 
X 
 
 
 
 
 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/ differential 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Chemistries f  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT/INR & PTT 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
SPEP & IFIX g 
X 
X1 
 
 
 
X2 
 
X 
 
 
 
X 
 
24-hour urine total protein, UPEP, & IFIX  gh 
X 
X1 
 
 
 
X2 
 
X 
 
 
 
X 
 
Serum free light chains 
X 
X1 
 
 
 
X2 
 
X 
 
 
 
X 
 
Quantitative immunoglobulins (IgA, IgG, IgM) 
X 
X1 
 
 
 
X2 
 
X 
 
 
 
X 
 
Beta-2 microglobulin 
X 
X1 
 
 
 
 
 
X 
 
 
 
X 
 
Serum HCG j 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
EKG & Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or Echo m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging for plasmacytoma assessment km 
X 
 
 
 
 
 
 
 
 
 
 
X3 
 
Skeletal survey m 
X 
 
 
 
 
 
 
 
 
 
 
X3 
 
Bone marrow biopsy & aspirate n 
X 
 
 
 
 
 
 
 
 
 
 
X3 
 
Correlative samples o 
X 
 
 
 
 
 
 
 
 
 
 
X3 
 
Carfilzomib administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PLD administration  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Dexamethasone administration p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Follow-up for survival 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* All assessments allowed a window of +/- 2 days for scheduling issues (such as holidays) 
a: Screening period is D-21 though D1 prior to Carfilzomib dose 
b: End of study must be within 30 days of last dose of study drug 
c: Follow-up takes place every 3 months for up to 18 months or until resolution or stabilization of adverse events, whichever is longer 
d: To be done within 1 hour prior to carfilzomib administration. 
e: Physical exam includes height, weight, BSA, performance status, neurological assessment and plasmacytoma assessment if indicated . 
f: Chemistries include Complete Metabolic Panel with Renal and Hepatic Panels, LDH, Magnesium, Phosphorous, Uric Acid. 
g: SPEP = serum protein electrophoresis, IFIX=immunofixation, UPEP= urine protein electrophoresis. 
h: All participants must complete 24 hour urine at screening and for confirmation of CR or VGPR if necessary. Additional serial 24-hour urines only required for participants with > 0.2g/24 hours of 
monoclonal protein at screening.   
j: Required only in women of childbearing potential; 2 negative test results required before study drug dosing on Cycle 1 Day 1. 
k: Only required if clinically indicated. Imaging can include X-ray, CT, MRI, PET, etc.  
m: To be repeated on study when clinically indicated. 
n: Bone marrow aspirate and core biopsy for differential, cytogenetics, and fluorescent in situ hybridization (FISH) studies. To be repeated on study for confirmation of CR or sCR. 
o: To be repeated on study whenever a bone marrow biopsy and aspirate is performed. 
p: Only for patients treated in part 2 of phase 1 or phase 2.  
1: Not required to be repeated in Cycle 1 if screening assessment was within 7 days of Day 1. 
2: Only during Cycle 1. 
3. Optional. If patient is willing and able.  


 
Amendment 4 12/04/15 
 
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11.0 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent 
Registration 
Eligibility Checklist 
Medical History  
Treatment History  
Radiation History  
Transplant History  
Vital Signs 
Labs – Hematology 
Labs – Chemistry 
Disease Assessment  
Skeletal Survey/Plasmacytoma Evaluation 
Bone Marrow Biopsy  
Original Consent: Before initiation of any 
non-standard of care procedures 
 
Registration and Eligibility Checklist: At 
time of enrollment  
 
All others: Within 28 days of enrollment 
 
Vital Signs 
Labs – Hematology 
Labs – Chemistry 
Disease Assessment  
Response Assessment  
Skeletal Survey/Plasmacytoma Evaluation 
Bone Marrow Biopsy  
Study Drug Dosing Record 
Within 28 days of end of each cycle 
 
Note: Some forms must be completed 
multiple times per cycle 
 
Correlative Studies 
Within 28 days of sample collection 
 
Adverse Events 
To be completed throughout study 
participation; as per guidelines in section 
13.1 
 
Off Study  
Vital Signs 
Labs – Hematology 
Labs – Chemistry 
Disease Assessment Form 
Response Assessment Form 
Skeletal Survey/Plasmacytoma Evaluation 
Bone Marrow Biopsy Form 
Within 28 days of end of study visit 
 
Survival Form 
Within 28 days of follow-up 
 
 
 


 
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12.0 
CORRELATIVE STUDIES 
 
Bone marrow and peripheral blood samples will be taken prior to treatment, at time of 
complete response, and/or at end of study. 
 
The following samples will be collected at all time points: 
• Bone marrow aspirate: 6-10 mL divided between two EDTA (lavender top) tubes. 
• Peripheral blood for viable PBMC: 60 mL collected in 6 large EDTA (lavender 
top) tubes. 
• Peripheral blood for plasma: 10 mL collected in 1 EDTA (lavender top) tube. 
 
Bone marrow aspirate samples will be pooled, and mononuclear cells will be purified 
over Ficoll.  Resulting BM mononuclear cells will be divided into 1) viable cells 
cryopreserved at 107/vial, and 2) cell pellet for nucleic acid.  Plasma and from bone 
marrow will be divided into 2mL aliquots and frozen at -80oC.   
 
Peripheral blood mononuclear cells (PBMC) will similarly be isolated by Ficoll 
preparation from the pooled peripheral blood lavender top tubes and will be viably 
cryopreserved.   
 
Plasma will be divided into 2mL aliquots and frozen at -80oC.   
 
Fresh PBMC or BM mononuclear cells may also be used for correlative studies at the 
discretion of the principal investigator.   
 
All samples are to be delivered to the Siteman Cancer Center Tissue Procurement Core 
(Dr. Mark Watson, Director) during their normal operating hours.  Specimens will be 
identified by initials and study number at the Tissue Procurement Core, and samples will 
be processed appropriately.  
 
Contact information for questions regarding sample procurement only:   
 
Mark Watson, M.D., Ph.D. 
Siteman Cancer Center Tissue Procurement Facility 
BJC Institute of Health 
5th Floor, Rooms 5120, 5113, and 5205St Louis, MO 63110 
Phone: 314-454-7615 
Fax: 314-454-5525 
Email: tbank@wudosis.wustl.edu 
 
 


 
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13.0 
SAFETY MONITORING, DATA AUDITING, AND REQUIRED 
REPORTING OF EVENTS 
 
13.1 
Adverse Events  
 
Definition:  any unfavorable medical occurrence in a human subject including 
any abnormal sign, symptom, or disease. 
 
Grading:  the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 
Health and Human Services’ Office for Human Research Protections (OHRP).  A 
copy of this guidance can be found on OHRP’s website: 
(http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm).   
 
All AEs, regardless of relationship to study drug, will be followed from first day 
of study treatment until 30 days following the last day of study treatment or until 
the start of a new chemotherapy, whichever is sooner. All AEs resulting in death 
within 30 days following the last day of study treatment will be recorded without 
regards to new chemotherapy. Thereafter, any death while off study but 
reasonably related to study drug(s) will be recorded, regardless of the proximity to 
study treatment.  
 
All AEs should be recorded in the Case Report Forms (CRFs). The CRFs should 
include the duration, outcome, intensity, attribution, dose delays/dose 
modifications, and seriousness.   
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for all toxicity reporting (see Appendix D). 
 
13.1.1 Regulatory Reporting of Internal AEs 
 
When a trend of unexpected and reasonably related non-serious AEs is 
identified by the PI, these events are required to reported to Amgen, 
HRPO, QASMC, and the FDA in a written report (Medwatch 3500 form, 
see Appendix E). The events should be then added to the consent form. 
 
All grade 3 and 4 AEs that are serious and/or unexpected and reasonable 
related must be reported to Amgen, HRPO, QASMC, and the FDA in a 
written report (Medwatch 3500 form, see Appendix E).  
 


 
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All grade 5 (death) AEs must be reported to Amgen, HRPO, QASMC, and 
the FDA in a written report (Medwatch 3500 form, see Appendix E). 
 
13.1.2 Regulatory Reporting of External AEs 
 
Any event or summary of adverse events that are provided to the 
investigator or study chair should be submitted to QASMC and/or HRPO 
for review.  
 
13.2 
Unanticipated Problems 
 
Definition: 
 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• 
related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. 
 
13.3 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
13.4 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to participants or others, or that materially compromises the 
rights or welfare of participants. 
 
13.5 
Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a 
singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event, unless 


 
Amendment 4 12/04/15 
 
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taken to avoid or eliminate immediate harm to a participant/participants. If taken 
to avoid or eliminate immediate harm to a participant report within 24 hours.  
 
13.6 
Pregnancy 
 
Pregnancy of a female participant or the female partner of a male participant 
while enrolled on this clinical trial or up to three months following administration 
of study drug(s) is a reportable event (Medwatch 3500 form, See Appendix E). If 
the participant is on study drug(s) at the time of pregnancy it must be discontinued 
immediately.  
 
The pregnant female will be followed until completion of the pregnancy.  The 
Investigator will be required to report the results of the pregnancy (follow-up to 
the original Medwatch 3500 form). 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
grade 5 event—spontaneous abortion (any congenital anomaly detected in an 
aborted fetus is to be documented), stillbirth, neonatal death, or congenital 
anomaly—the Investigator should report the event per the guidelines below. 
 
13.7 
Reporting to the Human Research Protection Office (HRPO) and the 
Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which 
occur at WU, any BJH or SLCH institution, or that impacts participants or 
the conduct of the study. 
• Noncompliance with federal regulations or the requirements or 
determinations of the IRB. 
• Receipt of new information that may impact the willingness of participants 
to participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the 
occurrence of the event or notification to the PI of the event.  The death of a 
research participant that qualifies as a reportable event should be reported within 
1 working day of the occurrence of the event or notification to the PI of the 
event. 
 
13.8 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 


 
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is the responsibility of the investigator to report any unanticipated problem to the 
FDA as follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences 
associated with use of the drug (i.e., there is a reasonable possibility that 
the experience may have been caused by the drug) by telephone or fax no 
later than 7 calendar days after initial receipt of the information.  A life-
threatening adverse experience is defined as any adverse drug experience 
that places the subject (in the view of the investigator) at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
• Report any serious, unexpected adverse experiences, as well as results 
from animal studies that suggest significant clinical risk within 15 
calendar days after initial receipt of this information.  A serious adverse 
drug experience is defined as any adverse drug experience occurring at 
any dose that results in any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
An unexpected adverse drug experience is defined as any adverse drug 
experience, the specificity or severity of which is not consistent with the 
current investigator brochure (or risk information, if an IB is not required 
or available). 
 
All MedWatch forms will be sent by the investigator or investigator’s team to the 
FDA at the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
13.9 
Reporting to Amgen 
 
All required forms will be sent to Amgen Global Safety by Fax: (1-888) 814-
8653, or at the following email address (with secure email connection with 
Amgen only): svc-ags-in-us@amgen.com.  
 


 
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13.10 Timeframe for Reporting Required Events  
 
Deaths 
Any reportable death while on study or within 30 
days of study 
Immediately, within 24 hours, 
to PI, FDA, Amgen, and the 
IRB 
Any reportable death while off study  
Immediately, within 24 hours, 
to PI, FDA, Amgen, and the 
IRB 
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described in 
Sections 12.1 and 12.2 (other than death) 
Immediately, within 24 hours 
to PI, FDA, and within 10 
working days to the IRB 
All adverse events regardless of grade and attribution 
should be submitted cumulatively  
Include in DSM report 
Non-Compliance and Serious Non-Compliance 
All noncompliance and serious noncompliance as 
described in Sections 12.3 and 12.4 
Immediately, within 24 hours, 
to PI and within 10 working 
days to the IRB 
Pregnancy 
Pregnancy 
Immediately, within 24 hours, 
to PI, FDA, Amgen, and the 
IRB 
 
 
14.0 
DATA AND SAFETY MONITORING PLAN 
 
In compliance with the Washington University Institutional Data and Safety Monitoring 
Plan, the Principal Investigator will provide a Data and Safety Monitoring (DSM) report 
to the Washington University Quality Assurance and Safety Monitoring Committee 
(QASMC) semi-annually beginning six months after accrual has opened (if at least five 
patients have been enrolled) or one year after accrual has opened (if fewer than five 
patients have been enrolled at the six-month mark). 
 
During the phase I dose escalation, the Principal Investigator will review all patient data 
at least monthly (or before each dose-escalation if occurring sooner than monthly), and 
provide a semi-annual report to the Quality Assurance and Safety Monitoring Committee 
(QASMC).  During the phase II, the Principal Investigator will review all patient data at 
least every six months, and provide a semi-annual report to the QASMC. This report will 
include: 
• HRPO protocol number, protocol title, Principal Investigator name, data 
coordinator name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO 
approval/revision, date of HRPO expiration, date of most recent QA audit, study 
status, and phase of study 


 
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• History of study including summary of substantive amendments; summary of 
accrual suspensions including start/stop dates and reason; and summary of 
protocol exceptions, error, or breach of confidentiality including start/stop dates 
and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants 
who have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities separated by cohorts with the number of dose-limiting 
toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for 
serious toxicities on an ongoing basis. Once the principal investigator or Research Patient 
Coordinator becomes aware of an adverse event, the AE will be reported to the HRPO 
and QASMC according to institutional guidelines. 
 
14.1 
External Data Auditing 
 
The study data will be audited by a member of the QASMC office on annual basis 
as per institutional guidelines.  
 
 
15.0 
ENDPOINTS 
 
15.1 
Primary Outcome Analyses 
 
The primary endpoint for each arm of the phase II portion of this trial is the 
proportion of confirmed tumor responses.  A confirmed response is defined to be 
a CR, VGPR, or PR noted as the objective status.  Response will be evaluated 
using up to 12 cycles of treatment.  All participants meeting the eligibility criteria 
who have signed a consent form and have begun treatment will be evaluable for 
response.  
  
15.2 
Secondary Outcome Analyses 
 
Survival time is defined as the time from registration to death due to any cause.  
The distribution of survival time will be estimated using the method of Kaplan-
Meier for the participants included in evaluating the decision criteria. 
   


 
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Progression-free survival time is defined as the time from registration to disease 
progression, clinical relapse, or death due to any cause.  The distribution of 
progression-free survival will be estimated using the method of Kaplan-Meier.   
 
Duration of overall response is defined for all participants who have achieved a 
confirmed response as the date at which the participant’s objective status is first 
noted to be a CR, sCR, nCR, VGPR, or PR to the earliest date progression or 
clinical relapse is documented.  The distribution of duration of response will be 
estimated using the method of Kaplan-Meier.  
 
 
16.0 
STATISTICAL ANALYSIS 
 
In the Phase 2 portion, the largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 20%, and the smallest 
success proportion that would warrant further treatment is 40%.  The following one-stage 
design uses 24 participants to test the null hypothesis that the true success proportion is at 
most 20%.   
 
Enter 24 participants into the phase 2 portion of the study.  If 7 or fewer successes are 
observed, we will consider this treatment ineffective in this participant population.  If 8 or 
more successes are observed, we may recommend further testing of the regimen in 
subsequent studies in this population. 
 
Power and Significance Level:  Assuming that the number of successes is binomially 
distributed, the significance level is 0.10, i.e. there is a 10% chance of finding the drug to 
be effective when it truly is not.  The probability of declaring that this regimen warrants 
further study (i.e. statistical power) under various success proportions, and the probability 
of stopping after the first stage can be tabulated as a function of the true success 
proportion. 
 


 
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17.0 
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Mandelli, F., et al., Maintenance treatment with recombinant interferon alfa-
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Browman, G.P., et al., Randomized trial of interferon maintenance in multiple 
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Salmon, S.E., et al., Interferon versus interferon plus prednisone remission 
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Attal, M., et al., A prospective, randomized trial of autologous bone marrow 
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Adams, J., et al., Proteasome inhibitors: a novel class of potent and effective 
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16. 
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Dimopoulos, M.A., et al., Prospective randomized comparison of vincristine, 
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injection and VAD with liposomal doxorubicin as first-line treatment in 
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5022.  
 
 


 
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APPENDIX A: ECOG Performance Status Scale  
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  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 
In bed <50% of the time.  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 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 


 
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APPENDIX B:  Karnofsky Performance Status Scale  
 
DEFINITIONS  
 
RATING (%)   
CRITERIA 
Able to carry on normal activity and to work; 
no special care needed. 
  100   Normal no complaints; no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care 
for most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of his 
personal needs. 
50 
Requires considerable assistance 
and frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital 
admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead 
 
 


 
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APPENDIX C: Cockcroft-Gault Formula  
 
 
 
 
 


 
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APPENDIX D: NCI Common Terminology Criteria for Adverse Events Version 4.0 
 
Adverse Events will be scored using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0.  
 
A copy of the NCI CTCAE Version 4.0 can be downloaded from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
  
 
 


 
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APPENDIX E: Medwatch 3500 
 
Reportable adverse events and pregnancies will be reported to the appropriate on a 
Medwatch 3500 form. The most recent Medwatch 3500 Form can be retrieved from  
http://www.fda.gov/medwatch/safety/FDA-3500_fillable.pdf