Clinical trial NCT01690143
Conditions: Multiple Myeloma
Sponsor: University of Alabama at Birmingham
Start date: 2012-05-01; Completion date: 2017-11-01
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for patients that have multiple myeloma that has come back or relapsed and their condition indicates a procedure called an Autologous Hematopoietic Stem Cell Transplantation (AHSCT). AHSCT is a procedure when stem cells from bone marrow or blood are removed before high-dose chemotherapy. Afterwards, the removed stem cells are put back into the patient's body to form a new population of blood cells.

The high-dose chemotherapy administered before the AHSCT is called "Conditioning Therapy." The FDA has approved the use of the drug melphalan as a conditioning therapy. This research study will look at whether adding the study drug called carfilzomib will improve participant outcomes. Carfilzomib is considered investigational and is not approved by the FDA for the treatment of relapsed multiple myeloma.

This study is divided into two phases.

Phase I: Dose Escalation Phase:

The main purpose of Part I of this study is to examine the safety of the study drug, carfilzomib, and determine the safest amount of the study drug that can be given to subjects who have multiple myeloma. Subjects on this study will receive different dose levels of the study drug. If you are one of the first three subjects to receive the study drug, it will be at what is called the 'starting dose' for the study which is the lowest dose that is expected to be tolerated based on prior research. After the first set of participants receive the study drug, the study doctor will review their health to see how they are tolerating the treatment. This will decide if the study drug dosage will be increased or decreased for the next set of subjects who join the study. It is anticipated that 12- 18 participants will enroll in the Phase I portion of this study.

Phase II: Safety Confirmation Phase:

Once the study doctor has discovered the highest possible dose of study drug that subjects can tolerate, up to 28 more subjects may be enrolled at that dose level. The main purpose of the Phase II portion of the study is look at how effective the combination of carfilzomib and melphalan when given before your stem cell transplantation is in treating multiple myeloma. This expansion phase will also include evaluation of two single agent carfilzomib maintenance therapy regimens for patients without disease progression at day 100.

Detailed description:
This is a phase 1/2a trial. Since this is an AHSCT conditioning regimen trial, only one cycle of therapy will be administered for each subject.

PHASE 1 The phase 1 component has a typical 3+3 design.

* Initially up to three subjects will be enrolled in each cohort starting at cohort 0 in the table below.
* If no dose limiting toxicity (DLT) is noted among the 3 initial subjects, 3 additional patients will be accrued at the subsequent cohort.
* If 1/3 subjects experience DLT, 3 additional subjects will be accrued at the cohort. If no additional DLT occur, accrual will continue at the subsequent cohort.
* If 2 or more subjects experience DLT in a given cohort, the dose will be considered higher than the maximum tolerated dose (MTD) and the immediately lower dose will be considered the MTD.
* If accrual is completed in cohort 4 with 0/3 or 1/6 DLT, the MTD will be considered "not reached" and cohort 4 will be expanded in the phase 2 of the trial.
* If 2 subjects experience DLTs in cohort 0, patients will be accrued in cohort -1, one subject at a time, with the subsequent subject only being accrued once the current subject has completed the DLT period (transplant day 30). The doses in cohort -1 will be considered the MTD if 0/3 or 1/6 subjects experience DLT.
* If ≥ 2 subjects experience DLT in cohort -1 the study will be interrupted without proceeding to phase 2a and the combination of carfilzomib and high dose melphalan will be considered too toxic.

PHASE 2 Once the MTD for the combination of carfilzomib and high dose melphalan with AHSCT is found, there will be expansion of the MTD cohort so that 28 individuals will be treated at the MTD of carfilzomib and high dose melphalan.

Screening - Subjects likely to meet eligibility criteria will be offered participation in the study after the investigator verifies with the registration system that there is a current available slot (phase 1). Subjects will sign informed consent prior to any protocol associated procedure. Screening procedures are outlined in Table 3 and will 1) ensure that subject meets all the eligibility criteria, 2) obtain disease assessment to allow efficacy measurements, 3) assess baseline toxicity and 4) provide initial biological samples for pharmacodynamic and correlative studies.

Treatment- Subjects will receive the appropriate dose of carfilzomib (according to assigned cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will be infused over 30 minutes. On day -2, with 60 to 120 minutes of the end of infusion of carfilzomib, subjects will receive 200 mg/m2 of intravenous melphalan as an intravenous push or a fast infusion. Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines.

Infusion of autologous cells- Infusion of autologous hematopoietic stem cells will occur on day 0 and follow institutional SOP.

Follow up phase - On day 1 following HSCT patients will receive pegfilgrastim 6 mg subcutaneously as per institutional standard of care aiming at faster engraftment. The follow up phase will last 100 days and will consist of standard post transplantation supportive care and monitoring of adverse events (AE's). For the phase 1 component of the study, dose-limiting toxicities will be captured during the first 30 days after transplantation (DLT period). Patients without progression may continue with carfilzomib maintenance therapy.

Patients will either be randomized in blocks of two to either maintenance therapy Arm 1= AB (two cycles of A followed by two cycles of B), or maintenance therapy Arm 2= BA (two cycles of B followed by two cycles of A). Maintenance regimen A will consist of carfilzomib 36 mg/m2 infused over 30 minutes on days 1,8,15. Maintenance regimen B will consist of carfilzomib 36 mg/m2 infused over 30 minutes on days 1, 2, 15 and 16. Each cycle will have 4 week duration. The first four maintenance therapy cycles will be dictated by a randomized assignment at time of study registration to maintenance therapy. For both maintenance therapy arms, a patient preference questionnaire will be administered to the patient upon completion of the 4th cycle. The remaining 8 cycles (cycles 5-12) will be administered according to the regimen schedule preferred by the patient as documented on the patient preference questionnaire.

Disease assessment- Disease assessment will occur at day 100 (+/- 7 days) and will consist of serum protein electrophoresis, serum and urine immunofixation, 24h urine protein electrophoresis, serum free light chains, bone marrow aspiration and biopsy, complete blood counts and metabolic panel.

Arms: arm 1: Single arm.
Interventions: intervention 1: Carfilzomib intervention 2: Melphalan
Intervention descriptions: intervention 1: Subjects will receive the appropriate dose of carfilzomib (according to assigned cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will be infused over 30 minutes. Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs. intervention 2: Subjects will receive 200 mg/m2 of intravenous melphalan on Day -2. Administered as an intravenous push or a fast infusion according to institutional standard operating procedure (SOP). Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs.

Protocol documents:
Prot_000.pdf: 
PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA 
 
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PROTOCOL INFORMATION 
Study Title:  PHASE I/IIA STUDY CARFILZOMIB  +  HIGH DOSE MELPHALAN AS 
PREPARATIVE REGIMEN  FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL 
TRANSPLANTATION IN MULTIPLE MYELOMA 
 
NCT #: 0169014 
UAB # 1467 
Onyx #: IST-CAR-536 
 
Institution Names: University of Alabama at Birmingham Medical Center, Medical 
University of South Carolina (MUSC), Medical College of Wisconsin, and Memorial Sloan 
Kettering Cancer Center (MSKCC) 
 
Co-Principal Investigator Information: 
Name: Luciano J. Costa, MD, PhD 
Address:  1802 6th Avenue South, North Pavilion NP 2552, Birmingham, AL  35294 
Phone No:  (205) 934-9695 
Fax No:  (205) 975-8394 
Email Address:  ljcosta@uabmc.edu 
 
Co-Principal Investigator Information: 
Name: Sergio Giralt, MD 
Address: 1275 York Ave, Box 235, New York, NY 10065 
Phone No: (212) 639-6009 
Fax No: (212) 639-3861 
Email Address: giralts@mskcc.org 
 
Co-Investigators: 
Name: Saurah Chhabra, MD 
Address: 173 Ashley Avenue, Charleston, SC 29425 
Phone No: (843) 792-2300  
Fax No: (843) 792-0644  
Email Address: Chhabra@musc.edu 
 
Co-Investigators: 
Name: Yubin Kang, MD 
Address: 2400 Pratt St., Durham, NC  27710 
Phone No: (919) 668-2331  
Fax No: (919) 668-1091  
Email Address: yubin.kang@duke.edu 
 
Co-Investigators: 
Name: Parameswaran Hari, MD 
Address:9200 West Wisconsin Avenue, Milwaukee, WI 53226 


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Phone No: (414) 805-4600 
Fax No: (414) 805-4606 
Email Address: phari@mcw.edu 
 
 
 
 
Statistician: 
Name: Elizabeth Garrett-Mayer, PhD 
Associate Professor 
Director of Biostatistics – Hollings Cancer Center 
Address: 86 Jonathan Lucas St., Charleston, SC 29425, Room 118G 
Phone No: (843) 792-7764 
Fax No: (843) 792-4233 
Email Address: garrettm@musc.edu  
 
 
University of Alabama at Birmingham, Clinical Trials Network and Monitoring Office – 
UAB CTNMO 
(Multicenter Operations) 
 
Name: Pam Dixon, RN, OCN, CCRP 
Address: 1824 6th Avenue South; WTI 110C, Birmingham, AL 35294 
Phone:  (205) 975-5387 
Fax No:   (205) 975 9875 
Email Address: pamdixon@uab.edu 
 
Name: Trina Lucas-Chancey 
Address: 1824 6th Avenue South; WTI 110X3, Birmingham, AL 35294 
Phone:   (205) 996-5976 
Fax No: (205) 975-9875 
Email Address  : tlucas@uab.edu 
 
 
 
Protocol Version History:  
 
Amendment #6 dated November 21, 2014 
 
Replaces:  
Amendment #5 dated May 22, 2014 
Amendment #3 August 23, 2013 
Amendment #2 dated June 29, 2012 
Amendment #1 dated June 1, 2012 
Original dated December 21, 2011 
  


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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PROTOCOL SYNOPSIS 
TITLE: 
Phase I/IIa Study of Carfilzomib  +  High Dose Melphalan as 
Preparative Regimen  for Autologous Hematopoietic Stem Cell 
Transplantation in Multiple Myeloma 
 
OBJECTIVES: 
PRIMARY OBJECTIVE 
Phase I:  To determine the MTD of carfilzomib when added to 
standard melphalan conditioning for AHSCT in relapsed MM. 
Phase IIa: To evaluate the anti-myeloma activity and the toxicity 
of carfilzomib + high dose melphalan conditioning in relapsed 
MM.  
SECONDARY OBJECTIVES 
 
To describe the pharmacodynamic effects of carfilzomib + high 
dose melphalan in terms of changes in expression of fanconi 
anemia/BRCA DNA repair genes and DNA fragmentation. 
To provide preliminary pharmacodynamic, safety and patient 
preference data on two schedules of carfilzomib maintenance 
therapy after AHSCT. 
 
STUDY DESIGN: 
The study has a phase I/IIa design.  Phase I will be a standard 3+3 
dose escalation. The phase IIa portion of the study will expand the 
MTD cohort, (or cohort 4 if no MTD is identified), to enroll a total 
of 28 patients using a single stage design.  This expansion phase 
will also include evaluation of two single agent carfilzomib 


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maintenance therapy regimens for patients without disease 
progression at day 100. See section 3 Experimental Plan for more 
detail.  
STUDY 
POPULATION: 
Patients with relapsed MM and indication for autologous HSCT. 
 
INCLUSION 
CRITERIA: 
 
1. Age ≥ 18 years (or age of majority at participating site, 
whichever is greater) and ≤ 70 years. 
2. Life expectancy ≥ 12 months. 
3. Eastern Cooperative Oncology Group (ECOG) performance 
status 0–2. 
4. Diagnosis of symptomatic multiple myeloma, relapsed after 
initial therapy. 
5. At least minimal response (defined as 25% decrease in the M 
protein in serum or urine) to the most recent treatment 
regimen. 
6. Evaluable disease prior to the most recent reinduction regimen 
as defined by at least one of the following: 
-Serum monoclonal (M) protein ≥0.5 g/dl by protein 
electrophoresis  
->200 mg of M protein in the urine on 24 hour 
electrophoresis   
- Serum immunoglobulin free light chain ≥10 mg/dL 
AND abnormal serum immunoglobulin kappa to 
lambda free light chain ratio 
 
 
- Monoclonal bone marrow plasmacytosis ≥30%  
7. Adequate hepatic function, with serum ALT ≤ 3.5 times the 
upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 
µmol/L) within 14 days prior to registration. 
8. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to start of 
therapy (subjects may be receiving red blood cell [RBC] 
transfusions in accordance with institutional guidelines).  
9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 14 days 
prior to start of therapy, either measured or calculated using a 
standard formula (eg, Cockcroft and Gault). 
10. Prior storage of at least 2 x 106 CD34+ cells/kg available for 
autologous transplantation. During the phase I component of 


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the study, at least the same amount of cells is required as 
“back up” in the unlikely event of non-engraftment. 
11. Subjects may have had a prior AHSCT for the treatment of 
MM as long as it was performed greater than 12 months from 
study registration. 
12. Subjects must meet institutional general eligibility criteria for 
autologous transplantation. 
13. Written informed consent in accordance with federal, local, 
and institutional guidelines.  
 
14. Females of childbearing potential (FCBP) must agree to 
ongoing pregnancy testing and to practice contraception. Male 
subjects must agree to practice contraception. 
 
EXCLUSION 
CRITERIA: 
 
1. Pregnant or lactating females. 
2. Major surgery within 30 days prior to start of treatment. 
3. Acute active infection requiring treatment (systemic 
antibiotics, antivirals, or antifungals) within 14 days prior to 
registration. 
4. Known human immunodeficiency virus infection. 
5. Active hepatitis B or C infection. 
6. Unstable angina or myocardial infarction within 4 months 
prior to registration, NYHA Class III or IV heart failure, 
uncontrolled angina, history of severe coronary artery disease, 
severe uncontrolled ventricular arrhythmias, sick sinus 
syndrome, or electrocardiographic evidence of acute ischemia 
or Grade 3 conduction system abnormalities unless subject has 
a pacemaker. 
7. Uncontrolled hypertension or uncontrolled diabetes within 14 
days prior to registration. 
8. Nonhematologic malignancy within the past 3 years with the 
exception of a) adequately treated basal cell carcinoma, 
squamous cell skin cancer, or thyroid cancer; b) carcinoma in 
situ of the cervix or breast; c) prostate cancer of Gleason 
Grade 6 or less with stable prostate-specific antigen levels; or 
d) cancer considered cured by surgical resection or unlikely to 
impact survival during the duration of the study, such as 
localized transitional cell carcinoma of the bladder or benign 
tumors of the adrenal or pancreas. 


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9. Significant neuropathy (Grades 3–4, or Grade 2 with pain) 
within 14 days prior to registration. 
10. Known history of allergy to Captisol® (a cyclodextrin 
derivative used to solubilize carfilzomib). 
11. Subjects with pleural effusions requiring thoracentesis or 
ascites requiring paracentesis within 14 days prior to 
registration.  
12. Any other clinically significant medical disease or condition 
that, in the Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent. 
 
STUDY 
PROCEDURES: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients enrolled during the Phase I portion of the study will only 
follow procedures related to conditioning therapy and autologous 
HSCT (day -30 screening through day 100 disease assessment). 
Patients enrolled during the Phase IIa portion of the study will 
follow procedures related to conditioning therapy at the MTD and 
autologous HSCT (day -30 screening through day 100 disease 
assessment). In addition, for eligible patients, single agent 
carfilzomib maintenance therapy will be administered for a 
maximum of 12 cycles (one cycle equals 28 days). 
 
CONDITIONING THERAPY AND AUTOLOGOUS HSCT  
(day -30 screening through day 100 disease assessment) 
Applicable during Phase I and Phase IIa study activity 
Screening – Subjects likely to meet eligibility criteria will be 
offered participation in the study after the investigator verifies 
UAB CTNMO registration. During the phase I portion, 
investigators should have confirmed with MUSC availability of a 
cohort slot prior to offering study participation.  Subjects will sign 
informed consent prior to any protocol associated procedure. 
Screening procedures are outlined in Table 7 and will 1) ensure that 
subject meets all the eligibility criteria, 2) obtain disease 


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assessment to allow efficacy measurements, 3) assess baseline 
toxicity, and 4) provide initial biological samples for 
pharmacodynamic and correlative studies. 
Conditioning Treatment- Subjects will receive the appropriate 
dose of carfilzomib on days -3 and -2. The Phase I portion of the 
study was completed and data was reviewed on October 28, 2013. 
There were no DLT even at the highest dose cohort and the MTD 
was not identified. Therefore, phase II enrollment is ongoing at the 
maximum tested dose of 27 mg/m2 on day -3 and 56 mg/m2 on day 
-2. Carfilzomib will be infused over 30 minutes (±10 minutes) as 
described in section 6.1.1. On day   -2, with 60 to 120 minutes of 
the end of infusion of carfilzomib, subjects will receive 200 mg/m2 
of intravenous melphalan as an intravenous push or a fast infusion, 
according to institutional standard operating procedure (SOP) (also 
see section 6.1.2). Prophylaxis of chemotherapy induced nausea 
and vomiting will follow institutional guidelines and SOPs. 
Infusion of autologous cells- Infusion of autologous hematopoietic 
stem cells will occur on day 0 and follow institutional SOP.  
Post AHSCT Follow-up phase – On day 1 following AHSCT, 
patients will receive pegfilgrastim 6 mg subcutaneously (single 
dose) or start filgrastim 5 mcg/kg/day subcutaneously that will 
continue daily at least until absolute neutrophil count > 500/mm3 
for 2 consecutive days as per institutional standard of care aiming 
at faster engraftment. The post AHSCT follow-up phase will last 
100 days (+/- 7 days) and will consist of standard post 
transplantation supportive care and monitoring of AEs. For the 
phase I component of the study, dose-limiting toxicities will be 
captured during the first 30 days after transplantation (DLT period).  


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Post AHSCT Disease assessment- Disease assessment will occur 
at day 100 (+/- 7 days) and will consist of interim medical history 
and physical exam assessment, serum protein electrophoresis, 
serum and urine immunofixation, 24h urine protein electrophoresis, 
serum free light chains, bone marrow aspiration and biopsy, 
complete blood counts and metabolic panel including uric acid and 
phosphorus. Disease response will be categorized according to 
appendix B. Patients enrolled to the Phase I portion of the study 
will only be followed until the disease assessment visit at day 100 
(+/- 7 days) and resolution of any treatment related toxicities to 
baseline or until toxicities have been deemed irreversible by the 
investigator. 
 
MAINTENANCE THERAPY 
(post day 100 disease assessment through a maximum of twelve 
28 day maintenance cycles) 
Applicable only to phase IIa study activity 
 
Screening for Maintenance Therapy- Patients must undergo Day 
100 disease assessment and be without disease progression in order 
to continue with maintenance therapy. Patients must be registered 
by UAB CTNMO prior to starting any maintenance therapy. 
Maintenance registration forms are included in the UAB CTNMO 
case report form packet. Registration can occur any time after day 
100 assessments are completed, but subjects must start 
maintenance therapy by day 120 after transplantation. At the time 
of registration, patients will be randomized to Arm 1 or Arm 2. 


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Maintenance therapy – Maintenance regimen A will consist of 
carfilzomib 36 mg/m2 infused over 30 minutes (±10 minutes) on 
days 1,8,15. Maintenance regimen B will consist of carfilzomib 
36mg/m2 infused over 30 minutes (±10 minutes) on days 1, 2, 15 
and 16. Each cycle will have 4 week duration. The first four 
maintenance therapy cycles will be dictated by a randomized 
assignment at time of study registration to maintenance therapy. 
Patients will either be randomized in blocks of two to either 
maintenance therapy Arm 1= AABB (two cycles of A followed by 
two cycles of B), or maintenance therapy Arm 2= BBAA (two 
cycles of B followed by two cycles of A). For both maintenance 
therapy arms, a patient preference questionnaire will be 
administered to the patient upon completion of the 4th cycle. The 
remaining 8 cycles (cycles 5-12) will be administered according to 
the regimen schedule preferred by the patient as documented on the 
patient preference questionnaire. 
Maintenance Therapy Disease Assessment- During maintenance 
therapy, disease assessments will occur at the end of each even 
cycle and consist of medical history and physical exam assessment, 
serum protein electrophoresis, serum and urine immunofixation, 
24h urine protein electrophoresis, serum free light chains, complete 
blood counts and metabolic panel including uric acid and 
phosphorus. Bone marrow aspiration and biopsy will only be 
performed if needed to confirm complete response. Patients will 
complete Quality of Life assessments at the end of each even cycle. 
Maintenance Therapy Follow-Up- For the phase IIa portion of 
the study, patients will be followed until the completion of the last 
4-week cycle of maintenance carfilzomib therapy (up to a 
maximum of twelve cycles) and resolution of all treatment 


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associated toxicity to  baseline or until the toxicity is deemed 
irreversible by the investigator. 
PRIMARY 
ENDPOINT: 
 
Phase I – The primary endpoint in phase I is the occurrence of a 
dose-limiting toxicity as defined in section 3.1.1.1. 
Phase IIa – Rate of very good partial response (VGPR) + complete 
response (CR) in patients with relapsed MM treated with the 
melphalan + MTD of Carfilzomib (or maximum tested dose if 
MTD is not reached) as determined in the phase 1 component of 
the study.  
 
SECONDARY 
ENDPOINTS: 
Phase I and IIa –  Pharmacodynamic effects of this combination at 
the proposed doses and schedule: changes in expression of Fanconi 
anemia/BRCA DNA repair genes and DNA fragmentation.  
Phase IIa – Rate of overall response, defined as CR+VGPR+PR 
(Appendix B). Rate of PFS 12 months after AHSCT in the setting 
of carfilzomib + melphalan conditioning and carfilzomib 
maintenance therapy. Pharmacodynamic effect of maintenance 
regimens A and B assessed by proteasome inhibition in peripheral 
blood mononuclear cells. Subject’s preference for maintenance 
regimens A and B. 
STATISTICAL 
METHODS: 
 
Phase I will be a standard 3+3 dose escalation study to include 
between 9 and 30 patients.  However, it is highly unlikely that 30 
patients will be enrolled (this would occur if dose expansion to 6 
patients per level occurred at all dose levels 0 through 4) and 
expected enrollment is 18 or fewer.  The phase IIa portion of the 
study will expand the MTD cohort, (or cohort 4 if no MTD is not 
reached), to enroll a total of 28 patients using a single stage design. 
More specifically, N=28 provides a halfwidth of <0.20 for the 95% 


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confidence interval for any response rate.  This precision will 
provide sufficient information to determine if the regimen is 
sufficiently promising, in conjunction with the safety information 
learned in the phase IIa portion. Due to the 100 day lag between 
treatment and evaluation, an interim analysis for the primary 
endpoint is not feasible.  PFS will be graphically displayed using 
Kaplan-Meier curves and 12 month PFS will be estimated with its 
95% confidence interval. For those patients in the maintenance 
phase of the phase IIa portion of the study, proteasome inhibition 
will be treated as a continuous variable and summarized by 
treatment arm using graphical displays and summary statistics.  
Preference for A vs. B and completion rates will be estimated by 
proportions with exact 95% confidence intervals.  Given that the 
number of patients in the maintenance portion of the study is 
expected to be small (20-22), hypothesis testing will not be 
performed to compare patients who receive A first versus those 
who receive B first.  
 


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SCHEMA 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..........................................................................................................3 
SCHEMA .................................................................................................................................12 
TABLE OF CONTENTS .........................................................................................................13 
1 
INTRODUCTION .......................................................................................................19 
1.1 
Disease Specific Background ..........................................................................19 
1.2 
Proteasome Background ..................................................................................20 
1.3 
Carfilzomib Background ..................................................................................20 
1.4 
Dose Rationale .................................................................................................26 
1.5 
Study Rationale ................................................................................................29 
2 
OBJECTIVES ..............................................................................................................31 
2.1 
Primary Objective ............................................................................................31 
2.2 
Secondary Objectives.......................................................................................31 
3 
EXPERIMENTAL PLAN ...........................................................................................32 
3.1 
Study Design ....................................................................................................32 
3.2 
Number of Centers ...........................................................................................35 
3.3 
Number of Subjects..........................................................................................35 
3.4 
Estimated Study Duration ................................................................................35 
3.5 
Treatment Schema ...........................................................................................35 
3.6 
Pharmacodynamic and correlative assays ........................................................40 
4 
SUBJECT SELECTION ..............................................................................................45 
4.1 
Inclusion Criteria .............................................................................................45 
4.2 
Exclusion Criteria ............................................................................................46 
4.3 
Criteria for registration for maintenance (PHASE IIa ONLY) ........................46 
5 
SUBJECT ENROLLMENT.........................................................................................48 
6 
TREATMENT PROCEDURES ..................................................................................50 
6.1 
Drug Preparation and Administration ..............................................................50 
6.2 
Dose Reductions/Adjustments .........................................................................51 
6.3 
Safety Considerations ......................................................................................54 
6.4 
Concomitant Medications ................................................................................56 
7 
STUDY TESTS AND OBSERVATIONS ..................................................................58 
8 
STUDY DISCONTINUATION ..................................................................................62 


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9 
ADVERSE EVENTS ...................................................................................................63 
9.1 
Adverse Events Definitions .............................................................................63 
9.2 
Causality ..........................................................................................................64 
9.3 
Adverse Events Reporting Procedures .............................................................65 
9.4 
Serious Adverse Events Definitions ................................................................66 
9.5 
Serious Adverse Event Reporting and Documentation Requirements ............66 
9.6 
Pregnancy .........................................................................................................68 
10 
STATISTICAL ANALYSIS .......................................................................................69 
10.1 
Study Design ....................................................................................................69 
10.2 
Study Endpoints ...............................................................................................69 
10.3 
Sample Size Considerations .............................................................................70 
10.4 
Interim and safety Analysis .............................................................................70 
10.5 
Planned Methods of Analysis ..........................................................................71 
11 
INVESTIGATIONAL PRODUCT ..............................................................................73 
11.1 
Carfilzomib Description...................................................................................73 
11.2 
Carfilzomib Formulation .................................................................................73 
11.3 
carfilzomib Storage ..........................................................................................73 
11.4 
carfilzomib Accountability ..............................................................................73 
11.5 
melphalan Description .....................................................................................74 
11.6 
melphalan formulation .....................................................................................74 
11.7 
Melphalan Storage ...........................................................................................74 
11.8 
melphalan supplier ...........................................................................................74 
12 
REGULATORY OBLIGATIONS...............................................................................75 
12.1 
Informed Consent.............................................................................................75 
12.2 
Compliance with Laws and Regulations..........................................................75 
12.3 
Pre-study Documentation Requirements .........................................................76 
12.4 
Subject Confidentiality ....................................................................................78 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................79 
13.1 
Protocol Amendments and Study COMPLETION ..........................................79 
13.2 
Study Documentation and Archive ..................................................................79 
13.3 
Study Monitoring and Data Collection ............................................................80 
14 
REFERENCES ............................................................................................................83 
APPENDIX A:  NCI-CTCAE VERSION 4.0 .........................................................................86 


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APPENDIX B:  RESPONSE CRITERIA FOR MULTIPLE MYELOMA ............................87 
APPENDIX C:  PATIENT PREFERENCE QUESTIONNAIRE ...........................................89 
APPENDIX D:  QUALITY OF LIFE QUESTIONNAIRE (QLQ-C30) ................................91 
APPENDIX E:  QUALITY OF LIFE QUESTIONNAIRE (QLQ-MY20) .............................95 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
C 
degrees Centigrade 
F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
AST 
aspartate aminotransferase 
bid 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 
h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 


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IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
MR 
minimal response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SPEP 
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
Tumor lysis syndrome 
TTP 
time to tumor progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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VGPR 
very good partial response 
WBC 
white blood count 
 


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1 
INTRODUCTION   
1.1 
DISEASE SPECIFIC BACKGROUND 
 
Multiple Myeloma (MM) is a malignant plasma cell disorder with no standard curative therapy.1 
Symptomatic MM is characterized by a clonal proliferation of plasma cells preceding clinical 
findings that include bone lesions, fractures, anemia, renal failure and hypercalcemia.2 MM 
affects 4.3 per 100,000 individuals yearly3 and accounts for about 1% of all cancers and 10% of 
all hematological malignancies in the United States.2  
 
For decades, low doses of melphalan and prednisone was the cornerstone of MM treatment. 
However, complete responses under this regimen are rare, and the median time for progression is 
not higher than 15 months4,5. A first significant advance in the management of MM was the 
upfront use of high doses of melphalan with autologous hematopoietic stem cell transplantation 
(AHSCT). Such treatment has allowed for improved response rates, progression free survival 
and, in some trials, prolonged survival in MM6-9. High dose melphalan with AHSCT is 
considered a fundamental therapeutic modality to be explored by younger patients upfront (after 
response to conventional induction therapy) and/or at the time of disease progression. 
 
The advent of new “biological” agents in treatment regimens for MM has led to marked 
improvement in the depth and duration of the responses obtained. The immunomodulatory drugs 
thalidomide and lenalidomide, along with the first proteasome inhibitor, bortezomib, have shown 
efficacy in the management of both newly diagnosed as well as relapsed and refractory MM 
patients 1,10-12. Treatment of MM patients with combination regimens, containing one or more 
biological agents, followed by autologous HSC transplantation consolidation have resulted in the 
highest response rates ever reported in the management of newly diagnosed MM patients13-18.  
 
 
 


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1.2 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a 
wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation 
system.  Ubiquitinated proteins are cleaved within the proteasome by one or more of three 
separate threonine protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a 
caspase-like activity.   
 
1.3 
CARFILZOMIB BACKGROUND 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsin-like active site of the 20S proteasome.  Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib 
(Velcade®).  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 bortezomib19,20. 
 
1.3.1 
CARFILZOMIB TOXICOLOGY STUDIES 
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by the drug maker, 
Onyx, carfilzomib was administered to rats and monkeys as two complete two-week cycles of 
QDx5 for five days with nine days rest21.  Administration to rats at 12 mg/m2, the severely toxic 
dose in 10% of animals (STD10) caused > 90% proteasome inhibition in red blood cells one hour 
after dosing.  Overall, stronger inhibition of the proteasome and longer duration of inhibition was 
tolerated with carfilzomib compared with bortezomib.  Daily administration of bortezomib at 
anti-tumor doses is not tolerated in animals, and therefore daily bortezomib has not been given in 
the clinic.  A dose-dependent decrease in proteasome activity was demonstrated in animals, and 
equivalent levels of proteasome inhibition were achieved with administration of carfilzomib as 
either an intravenous (IV) push or an IV infusion.  The dose-limiting toxicities (DLTs) of 
carfilzomib in both the rat and monkey 28 day GLP toxicity studies included toxicity to the 
gastrointestinal tract, bone marrow, pulmonary, and cardiovascular systems.  No behavioral or 


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histopathological signs of neurotoxicity were observed, and carfilzomib does not cross the blood-
brain barrier. 
In 6-month rat and 9-month chronic toxicity studies, carfilzomib was administered on Days 1, 2, 
8, 9, 15, and 16 of a 28-day cycle, mimicking the active anti-tumor regimen being used in 
ongoing Phase II studies in myeloma and solid tumors21.  Tolerability was excellent, with no 
evidence of peripheral (or central) neurotoxicity, including neuropathology, observed, even at 
high doses.  This is in stark contrast to that observed with bortezomib14,22. DLTs included effects 
on the gastrointestinal, renal, pulmonary, and cardiovascular systems and appeared to be related 
to Cmax effects.  Of note, neutropenia was not observed; rather, transient neutrophilia was seen 
following acute dosing.  Renal, cardiovascular and gastrointestinal toxicities were similar to 
those observed with bortezomib.  Finally, cyclical thrombocytopenia, likely due to inhibition of 
platelet budding from megakaryocytes, was similar to that seen with bortezomib.  Proteasome 
inhibition in the blood in excess of 90% was achievable at well-tolerated doses, which contrasts 
with the ~70% proteasome inhibition achieveable with bortezomib at its maximum tolerated dose 
(MTD).  In summary, these animal toxicity studies support the tolerability of carfilzomib in 
clinical studies, even on intensive dosing schedules and at doses achieving proteasome inhibition 
in excess of what can be achieved with bortezomib at its MTD on a less intensive schedule. 
1.3.2 
CARFILZOMIB PRECLINICAL ANTITUMOR ACTIVITY 
Based upon the results of in vitro and in vivo studies, it is anticipated that the more intense and 
longer duration of proteasome inhibition that can be achieved with carfilzomib will result in 
enhanced anti-tumor activity relative to bortezomib.  Continuous (72 hr) exposure to carfilzomib 
is associated with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-
derived cell lines in culture12,19.  Incubation of hematologic tumor cell lines with carfilzomib for 
as little as one hour leads to rapid inhibition of proteasome activity followed by accumulation of 
polyubiquitinated proteins and induction of apoptotic cell death.  Carfilzomib has also been 
demonstrated to be cytotoxic in bortezomib-resistant tumor cell lines12,19. 
The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice implanted 
with a variety of tumor cell lines.  In a human colorectal adenocarcinoma model HT-29, 
administration of carfilzomib on a twice-weekly Day 1, Day 2 schedule resulted in significant 


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reduction in tumor size and was superior to a twice-weekly Day 1, Day 4 schedule using the 
same dose of carfilzomib, and a once-weekly dosing schedule using twice the dose level.  
Bortezomib at its MTD has no activity in this xenograft model using the standard Day 1, Day 4 
schedule19. 
 
1.3.3 
PHASE 1 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed23.  During the dose escalation portion of the trial, 
36 subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with 
Multiple Myeloma (MM), Non-Hodgkin’s Lymphoma (NHL), Waldenström’s 
Macroglobulinemia, and Hodgkin’s Lymphoma (HL) were enrolled on the study.   
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 
1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 dose level, one of eight patients had a 
Grade 3 renal failure at Cycle 1, Day 2 which was considered possibly related to study drug and 
lasted for six days.  The patient continued on study for the remainder of Cycle 1 before having 
disease progression.   At the 27 mg/m2 dose level, one of six subjects experienced a DLT during 
Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing.  In 
subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome 
(TLS) and/or cytokine release.  This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion.  On the second day, three of five subjects 
with multiple myeloma experienced an increase in creatinine to Grade 2 (including the subject 
with the DLT).  This elevation was rapidly reversible and all three subjects were rechallenged 
with carfilzomib without recurrence of the events.  Interestingly, all three subjects had a rapid 
decline in serum and/or urine M-protein levels; two subjects achieved a PR and the third subject 
achieved a minimal response (MR).  There were no consistent changes in potassium, calcium, 
phosphorous, or uric acid levels although some increases in LDH and other markers of tumor 
lysis were noted.  Because of the possible TLS and reversible creatinine elevations, hydration 
and very-low dose dexamethasone prophylaxis were instituted in subsequent studies and have 


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essentially eliminated clinically significant TLS/creatinine elevations and the other “first-dose” 
effects.   
Hematologic toxicities were primarily mild or moderate.  The thrombocytopenia reported with 
carfilzomib is cyclical and similar to that reported with bortezomib.  The cause and kinetics of 
the thrombocytopenia following treatment are different from those of standard cytotoxic agents.  
To maximize the likely benefit of carfilzomib, subjects with thrombocytopenia should be 
supported as clinically indicated rather than having treatment reduced due to thrombocytopenia. 
Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM7.  Four MM patients achieved 
a partial response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 mg/m2 dose, and 
two of five at the 27 mg/m2 dose.  The responses have been rapid in onset, beginning in some 
subjects after 1-2 doses.  The duration of response (DOR) ranged from 134 to 392 days. The 
minimal effective dose was 15 mg/m2 wherein >80% proteasome inhibition in peripheral blood 
and mononuclear cells was observed one hour after dosing.  The median number of prior 
therapies for subjects on this trial was five, and responses were seen in subjects who had relapsed 
from (including some refractory to) bortezomib and/or immunomodulatory agents.  Stable 
disease also occurred in four NHL and five MM subjects, with subjects on therapy for up to 409 
days.  Such prolonged therapy, at “full” twice-weekly doses, is not possible with bortezomib.  
These results led to the initiation of two Phase 2 studies. 
 
1.3.4 
PHASE 2 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
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.  Since these guidelines were implemented, no further cases of TLS have 
been reported including in >350 additional patients with relapsed or refractory MM treated in 
ongoing Phase II studies.  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 serum creatinine that were primarily 


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< 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 entry24.   
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)24.   
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 maximize the clinical 
benefit of carfilzomib.  Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  
The study completed enrollment of 266 patients by the end of 2009.  To date, this dosing 
schedule has been well tolerated7.  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 and rates of BUN 
and creatinine elevation dropped sharply, with Grade 3/4 renal impairment dropping to 2.2% in 
A1 (from 15% in A0), most likely due to hydration and very low dose dexamethasone.  The 
other most common adverse events were similar to the A0 portion of the study.  Treatment-
emergent peripheral neuropathy remains low on this portion of the study with 15% Grade 1/2 
and one (0.7%) Grade 3/4 event reported to date on PX-171-003-A124.  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 allowing superior normal marrow reconstitution.  
Rates of thrombocytopenia and neutropenia were similar in the two cohorts, with Grade 3 
neutropenia in ~5% without any Grade 4 neutropenia to date24.  
In PX-171-004, a first cohort of patients received 20 mg/m2.  The subset of patients (N=54) that 
had not seen bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the 
bortezomib treated patients (N=33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR)25,26.  
The median TTP was 7.6 and 5.3 months in these two groups, respectively.  Thus, carfilzomib 


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can induce very high levels of response in patients who have not previously been treated with 
bortezomib and, even in bortezomib-treated patients, substantial anti-tumor activity is observed.  
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 no cumulative toxicities (e.g., bone marrow, severe fatigue, or neuropathy) have 
been observed. The protocol was amended to allow patients to increase to 27 mg/m2 in Cycle 2 
or later based on tolerability, similar to that used in PX-171-003 – A1.   
Based on its single agent activity, carfilzomib received FDA accelerated approval on July 20, 
2012 for “the treatment of patients with 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”. 
1.3.5 
EXPERIENCE WITH CARFILZOMIB IN COMBINATION WITH 
LENALIDOMIDE AND DEXAMETHASONE  
PX-171-006 is an ongoing Phase 1b study in patients with relapsed multiple myeloma in which 
carfilzomib is administered in combination with lenalidomide (Revlimid®) and dexamethasone.  
“Low-dose” dexamethasone 40 mg/day is given on Days 1, 8, 15, and 22 in all cases.  
Carfilzomib is administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide is administered PO 
on Days 1 through 21.   
Enrollment has closed in this study, and no MTD was reached.  The maximum per protocol 
doses of carfilzomib (27 mg/m2) with lenalidomide 25 mg and low dose dexamethasone are 
being used27.  After 8 patients tolerated these doses well, an additional 44 patients were enrolled 
in an “expansion” cohort at this level, and this regimen is being taken into Phase III in study PX-
171-009.   
 
 To date, 40 patients were treated in cohorts 1-6 and 44 in the cohort 6 expansion. 27/32 patients 
in cohorts 1–5 are evaluable for safety and 29/32 for response. Patients were heavily pre-treated; 
72% received prior BTZ and 87.5% received prior LEN or thalidomide (Thal). 47% of patients 
were refractory to their last therapy (typically lenalidomide + high dose dexamethasone; > 84% of 
patients had a history of neuropathy with 67% BTZ- or Thal-related. No treatment emergent 


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fatigue, neuropathy, or thrombotic events ≥ Grade (G) 3 were observed. Hematological AEs ≥ G3 
(thrombocytopenia [n=6], anemia [n=4], and neutropenia [n=6]) were reversible. Four patients had 
drug-related SAEs as follows: transient G3 sinus bradycardia, G3 upper respiratory tract infection, 
febrile neutropenia, and G3 diarrhea + G3 urinary infection. ORR and CBR for the 29 evaluable 
patients are 59% and 72%, respectively. Response data is shown in the table below. Initial 
responses improved with continued therapy (up to 18 cycles). Median duration of response has not 
been reached (median follow-up 5.2 months). No dose-limiting toxicities or deaths attributed to 
study treatment have been observed. Several patients have completed the study (in the lower dose 
cohorts) after 18 cycles and are continuing in an extension study.  Updated efficacy data are 
presented in the following table: 
 
 
Table 1 
 
CRd: Cohorts 1–5 
(CFZ: 15 to 20 mg/m2; LEN: 10 to 25 mg)  
Response 
Relapsed (n=16) 
Refractory 
(n=13) 
Overall  
(n=29) 
   ≥ CR/nCR 
5 (31) 
1 (8) 
6 (21) 
   ≥ VGPR 
7 (44) 
4 (31) 
11 (38) 
   ≥ PR 
9 (56) 
8 (62) 
17 (59) 
   ≥ MR 
11 (67) 
10 (77) 
21 (72) 
 
 
Together, these results suggest that carfilzomib, lenalidomide, and low-dose dexamethasone 
(CRd) in combination are active and well tolerated and that there are no significant overlapping 
toxicities (in the dose ranges tested). Importantly, lenalidomide-associated neutropenia and 
thrombocytopenia do not appear to be exacerbated by concurrent treatment with carfilzomib, even 
up to 27 mg/m2, suggesting that carfilzomib will combine well with other anti-cancer agents.   
1.4 
DOSE RATIONALE 
Preliminary data suggest that carfilzomib, as a single agent, can produce substantial response 
rates in myeloma subjects across a variety of dosing cohorts.  Responses were seen over a wide 
therapeutic window, from 15 to 27 mg/m2.  Maximum proteasome inhibition was seen at doses 
11 mg/m2 and higher in whole blood samples taken 1 hour after the first dose.  The final analysis 
of the human pharmacokinetic (PK) data is ongoing but appears to be rapid and similar to the 
results from the animal studies.  Carfilzomib is rapidly cleared from plasma with an elimination 


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half life of < 60 minutes at the 20 mg/m2 dose.  Large, single arm studies of the 27 mg/m2 dose 
are ongoing and suggest that this dose is very well tolerated with patients being treated for >10 
cycles without cumulative toxicities. 
 
By the end of 2009, 269 patients with relapsed and refractory multiple myeloma have been enrolled 
in the PX-171-003-A1 study. The goal of dose escalating to 27 mg/m2 beginning with Cycle 2 is 
to improve ORR, DOR, and TTP. 
 
In multiple preclinical studies, the tolerability of carfilzomib in rats has been shown to be 
significantly higher when administered as a 30 minute infusion as compared to a rapid IV 
bolus.  Toxicities observed with IV bolus injection of carfilzomib above the MTD at a dose of 48 
mg/m2 include evidence of prerenal azotemia (transient increases in BUN > creatinine) as well as 
lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred in ~50% 
of animals at 48 mg/m2 when carfilzomib was given as a bolus. Administration of the same dose 
(48 mg/m2) as a 30 minute continuous infusion was well tolerated, with no changes in BUN and 
creatinine and substantially reduced signs of lethargy, piloerection, or dyspnea.  Moreover, all 
animals in the infusion treatment groups survived.  The only toxicity observed following infusion 
of carfilzomib for 30 minute was gastrointestinal bleeding.  The reduced toxicity seen with 
dosing by infusion may reflect the reduced Cmax of carfilzomib versus that with bolus 
dosing.  Inhibition of the pharmacological target of carfilzomib (the chymotrypsin-like activity 
of the proteasome) was equivalent in the bolus and infusion treatment groups.   
 
In the clinic, the MTD of carfilzomib has not been reached in the multiple myeloma (MM) setting, 
particularly when administered as a 30 minute infusion.  27 mg/m2 of carfilzomib (bolus 
administration over 2-10 minutes) is well tolerated in MM patients overall and can be tolerated for 
>12 cycles in late stage MM patients with substantial comorbidities.  
 
A phase 1 dose escalation study (PX-171-007) of single agent carfilzomib administered is ongoing 
and as of 10 July 2009, over 65 patients with solid tumors had started treatment in the initial Phase 
2 portion of the study at 36 mg/m2 (bolus administration over 2-10 minutes). A review of the 
tolerability of 36 mg/m2 carfilzomib in these patients  indicates that this regimen was very well 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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tolerated with only one DLT (fatigue) and an overall adverse event profile similar to that seen with 
the 27 mg/m2 carfilzomib experience with bolus dosing (see IB for details). Three patients 
completed > 12 cycles of therapy at 36 mg/m2 with no evidence of cumulative toxicity.  There 
were no significant DLTs observed. The majority of discontinuations on the study were due to 
progressive disease. Because of the long-term tolerability of carfilzomib, the Phase 1b portion of 
this study was reopened, and a separate arm for multiple myeloma was added.  
More recently in the PX-171-007 trial, patients have been treated with carfilzomib given as a 30-
minute infusion in order to potentially minimize Cmax-related infusion events. The protocol was 
amended and doses of 20/36 (20 mg/m2 given on Days 1 and 2 of cycle 1 only; followed by 36 
mg/m2 for all subsequent doses), 20/45, 20/56 mg/m2 and so forth are being investigated.  Doses 
of 20/56 mg/m2 are currently being given in two separate cohorts of patients with advanced MM 
and advanced solid tumors with the lower doses being well tolerated.  Preliminary tolerability 
information at this dose level (20/56 mg/m2) indicated that it is reasonably well tolerated with 
minimal infusion reactions.  In some cases at 20/56 mg/m2, dexamethasone was increased from 4 
mg/dose to 8mg with the 56mg/m2 doses in order to reduce fevers and hypotension.  As of March 
20, 2010, seven patients had received 20/56 mg/m2 and were tolerating it.  Patients with 
advanced, refractory MM being treated at 36 mg/m2 and 45 mg/m2 have shown very good 
tolerability (> 6 months in some cases) with documented minimal and partial responses in these 
heavily pretreated patients. These data indicate that carfilzomib 30-minute infusion can be given 
at very high levels, with >95% inhibition of blood proteasome levels achievable and with (at 
least) acute tolerability.  All protocols using ≥ 36 mg/m2 carfilzomib are now administering the 
drug as a 30-minute infusion. 
In addition to the above observations, a phase I study of carfilzomib in patients with relapsed and 
refractory multiple myeloma was reported in abstract form at the 2009 American Society of 
Hematology meeting which demonstrated that carfilzomib can be safely administered to patients 
with substantial renal impairment (CrCl < 30, including patients on dialysis) without dose 
adjustment28.  These data indicate that carfilzomib does not exacerbate underlying renal 
dysfunction, and confirm the “pre-renal” etiology of the BUN/creatinine elevations observed 
with IV bolus carfilzomib. 
 


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As part of recent continuous evaluations of product safety information performed by Onyx, 4 case 
reports consistent with Posterior Reversible Encephalopathy Syndrome (PRES) have been 
associated with the use of carfilzomib. PRES is a rare, potentially fatal neurological disorder, 
which can present with headaches, altered mental status, seizures, visual disturbances, and 
hypertension. If diagnosed early, the symptoms of PRES may be reversible. One case was reported 
from a company-sponsored clinical trial (of the approximately 2,621 subjects treated in company 
sponsored trials), one case was reported from an investigator-sponsored trial (of the approximately 
1,719 subjects treated in IST studies), and the remaining two cases were reported in the post-
marketing setting (of the approximately 16,500 patients treated). Also noted is that 2 of the events 
of PRES occurred during the use a high dose (36 and 56 mg/m2) carfilzomib. In this study patients 
will be informed about the risk of PRES and instructed to contact the  investigator immediately if 
seizures, confusion, severe headaches, fainting, blurred vision or blindness develops   
1.5 
STUDY RATIONALE 
  
Proteasome inhibitors (PI) have been shown in vitro to impair the fanconi/BRCA pathway of 
DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM 
cells29. Clinically, regimens combining alkylating agents with the PI bortezomib have resulted in 
high rates of overall response and responses ≥ VGPR, particularly in untreated, newly diagnosed 
patients14,30,31.  
The alkylating agent melphalan, given in high (myeloablative) doses preceding AHSCT is part of 
the upfront management of younger patients with MM6-8. AHSCT has also been utilized in the 
salvage setting32,33 (late transplantation) and can be repeated (retransplantation) in patients 
deriving meaningful benefit from the first transplantation procedure34. Melphalan at the dose of 
200 mg/m2 is the most frequently utilized conditioning regimen for autologous transplantation in 
MM. The proteasome inhibitor bortezomib has been successfully combined with high-dose 
melphalan leading to apparently greater reduction in disease burden without significant 
enhancement of the post transplantation toxicity35. As a proteasome inhibitor, carfilzomib may 
intensify the anti-myeloma effect of melphalan and be potentially more synergistic than 
bortezomib in combination with high dose melphalan due to the irreversible nature of 
proteasome inhibition. Also, contrary to bortezomib, carfilzomib has minimal neurologic 


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toxicity. We intend to find the maximal tolerated dose (MTD) of carfilzomib that can be safely 
combined with standard high-dose  (200 mg/m2) melphalan as preparative regimen prior to 
AHSCT for MM and obtain additional data on the efficacy and safety of this combination.  
Patients who undergo autologous transplantation for mm in the relapse setting will often have 
short duration of remission and post-transplant therapy, either as maintenance or consolidation. 
Due to its favorable efficacy and side effect profile, carfilzomib is a suitable drug for 
maintenance therapy. An ideal regimen for carfilzomib maintenance therapy would combine 
minimal toxicity, adequate drug exposure and convenience. Currently, there is not a “standard” 
regimen for carfilzomib maintenance therapy. Therefore, the phase iia of the present study will 
assess the toxicity, pharmacodynamics and convenience of two schedules in individuals who 
have not progressed on day 100 assessment. The intercalation of regimens within the same 
subject will minimize inter-patient variability and better characterize the tolerance, 
pharmacodynamics and convenience of the two regimens. 


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2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
Phase I:  To determine the MTD of carfilzomib when added to standard melphalan conditioning 
for AHSCT in relapsed MM. 
Phase IIa: To evaluate the anti-myeloma activity and the toxicity of carfilzomib + high dose 
melphalan conditioning in relapsed MM.  
2.2 
SECONDARY OBJECTIVES 
 
To describe the pharmacodynamic effects of carfilzomib + high dose melphalan in terms of 
changes in expression of fanconi anemia/BRCA DNA repair genes and DNA fragmentation. 
To provide preliminary pharmacodynamic, safety and patient preference data on two schedules 
of carfilzomib maintenance therapy after AHSCT. 


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3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a phase I/IIa trial. Since this is an AHSCT conditioning regimen trial, only one cycle of 
therapy will be administered for each subject during the phase 1. During the phase IIa subjects 
will undergo 12 cycles of maintenance therapy with carfilzomib..  
3.1.1 
PHASE 1 
The phase I component has a typical 3+3 design36. 
-Initially up to three subjects will be enrolled in each cohort starting at cohort 0 in the 
table below.  
-If no dose limiting toxicity (DLT) is noted among the 3 initial subjects, 3 additional 
patients will be accrued at the subsequent cohort.  
-If 1/3 subjects experience DLT, 3 additional subjects will be accrued at the cohort. If no 
additional DLT occur, accrual will continue at the subsequent cohort.  
-If 2 or more subjects experience DLT in a given cohort, the dose will be considered 
higher than the maximum tolerated dose (MTD) and the immediately lower dose will be 
considered the MTD.  
-If accrual is completed in cohort 4 with 0/3 or 1/6 DLT, the MTD will be considered 
“not reached” and cohort 4 will be expanded into the phase II portion of the trial.   
-If 2 subjects experience DLTs in cohort 0, patients will be accrued in cohort -1, one 
subject at a time, with the subsequent subject only being accrued once the current subject has 
completed the DLT period (transplant day 30). The doses in cohort -1 will be considered the 
MTD if 0/3 or 1/6 subjects experience DLT.  
-If ≥ 2 subjects experience DLT in cohort -1 the study will be interrupted without 
proceeding to phase IIa and the combination of carfilzomib and high dose melphalan will be 
considered too toxic. 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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Table 2 
 
Carfilzomib dose 
 
Day -3 
Day -2 
Day -2,  
after CFZ administration 
Day 0 
 
Cohort -1 
20 mg/m2 
20 mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
Cohort 0 
20 mg/m2 
27 mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
Cohort 1 
27 mg/m2 
27 mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
Cohort 2 
27 mg/m2 
36  mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
Cohort 3 
27 mg/m2 
45 mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
Cohort 4 
27 mg/m2 
56 mg/m2 
Mel 200 mg/m2 
Autologous Cells 
 
 
3.1.1.1 
Definition of DLT 
During phase I of the study, the occurrence of any of the below toxicities during the first 30 days 
after transplantation will be considered dose-limiting toxicities: 
1) Delayed engraftment- Neutrophil engraftment will be defined as the first of three 
consecutive days with absolute neutrophil count >500/mm3. Platelet engraftment will be 
defined as the first of 3 consecutive days of platelets > 20,000/mm3 without platelet 
transfusion in the prior 7 days. Engraftment will be considered delayed (and therefore 
DLT) if the subject has not met criteria for both neutrophil and platelet engraftment by 
day 30 after AHSCT. 
2) Grade 4 toxicity, other than hematological toxicity. 
3) Grade 3 toxicity, other than hematological toxicity, fever, chills, dyspnea, infection, rash, 
fatigue, abdominal pain, diarrhea, dysphagia, oral mucositis, oral pain, flu-like syndrome, 
pain, anorexia, dehydration, glucose intolerance, hypocalcemia, hypokalemia, 
hypomagnesemia, hyponatremia, hypophosphatemia, pain in extremity, headache, 


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insomnia, hypoxia, pneumonitis, dry skin, pruritus, hypertension, hypotension, increase 
in AST, ALT, bilirubin and alkaline phosphatase. 
4)  Acute toxicity of carfilzomib requiring omission of day -2 dose according to section 6.2. 
5) Death from any cause. 
3.1.1.2 
Phase 1 findings 
The phase I was completed and the safety and efficacy data analyzed in October 201337. Fifteen 
subjects were enrolled in 5 cohorts. There was no DLT identified. The most common grade 3 
toxicity was infection (8/15 subjects). Nine out of 14 subjects that were not in complete 
remission at the time of enrolment had improvement in the response category with protocol 
treatment. Since MTD was not reached, the decision was made to precede with phase 2 enrolling 
subjects in the expanded cohort 4 (highest dose cohort). 
6)  
3.1.2 
PHASE IIa 
Once the MTD for the combination of carfilzomib and high dose melphalan with AHSCT is 
found, there will be expansion of the MTD cohort, (or cohort 4 if no MTD is reached), so that 28 
individuals will be treated at the MTD of carfilzomib and high dose melphalan. 
3.1.2.1 
Maintenance Therapy 
Subjects enrolled in the phase IIa component of the study will receive maintenance therapy with 
single agent carfilzomib starting no sooner than day 100 and not later than day 120 after 
transplantation.   
 
-Maintenance will consist of up to 12 cycles of 28 days. Therefore, a new cycle will start 
28 (+/-2) days after initiation of prior cycle. 
 
-Two regimens will be utilized during maintenance therapy. Regimen A will consist of 
carfilzomib 36 mg/m2 on days 1, 8, 15 and regimen B will consist of carfilzomib 36 mg/m2 on 
days 1, 2, 15, 16. 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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- Patients eligible for the maintenance therapy component will be registered to the 
maintenance therapy portion of the study and UAB will randomize the patient to Arm 1 or Arm 2 
in blocks of two to ensure balance. 
3.2 
NUMBER OF CENTERS 
During the Phase I portion of the study, there will be two centers involved in the study: Medical 
University of South Carolina (MUSC) and Memorial Sloan-Kettering Cancer Center (MSKCC). 
Additional sites will be added during the expansion Phase IIa phase. UAB (P.I. Dr. Luciano 
Costa) will be the coordinating center for the study upon approval of amendment 6. Medical 
College of Wisconsin (P.I. Dr. Parameswaran Hari) will be added as participating site after 
approval of amendment 6. 
3.3 
NUMBER OF SUBJECTS 
A minimum of 6 and a maximum of 30 subjects will be accrued in the phase 1 portion of the 
study. Unless even dose in cohort -1 is considered too toxic and no MTD can be found, accrual 
will continue at the MTD (cohort expansion) to reach a total of 28 subjects treated at the MTD 
cohort. 
3.4 
ESTIMATED STUDY DURATION 
The estimated duration of the phase I component of the study is 15 months. This includes 12 
months for accrual and treatment and 3 months for monitoring of adverse events (AEs) and 
disease reassessments for the last subjects accrued. 
The estimated duration of the phase IIa component of the study is 30 months, consisting of 18 
months for accrual and transplant treatment of all subjects and 12 additional months to complete 
maintenance component for all subjects. 
3.5 
TREATMENT SCHEMA 
Patient enrolled during the Phase I portion of the study will only follow procedures related to 
conditioning therapy and autologous HSCT (day -30 screening through day 100 disease 
assessment). Patients enrolled during the Phase IIa portion of the study will follow procedures 
related to conditioning therapy at the MTD, (or cohort 4 if no MTD is reached), and autologous 


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HSCT (day -30 screening through day 100 disease assessment. In addition, for eligible patients, 
single agent carfilzomib maintenance therapy will be administered for a maximum of 12 cycles 
(one cycle equals 28 days). 
 
CONDITIONING THERAPY AND AHSCT 
(day -30 screening through day 100 disease assessment) 
Applicable during Phase I and Phase IIa study activity 
 
Screening – Subjects likely to meet eligibility criteria will be offered participation in the study 
after the investigator verifies UAB CTNMO registration. During the phase I portion, 
investigators should confirm with UAB availability of a cohort slot prior to offering study 
participation.  Subjects will sign informed consent prior to any protocol associated procedure. 
Screening procedures are outlined in Table 7 and will 1) ensure that subject meets all the 
eligibility criteria, 2) obtain disease assessment to allow efficacy measurements, 3) assess 
baseline toxicity, and 4) provide initial biological samples for pharmacodynamic and correlative 
studies. 
Conditioning Treatment- Subjects will receive the appropriate dose of carfilzomib on days -3 
and -2. The Phase I portion of the study was completed and data was reviewed on October 28, 
2013 concluding that the MTD was not reached and subsequent subjects would receive 
Carfilzomib doses outlined in cohort 4, 27 mg/m2 on day -3 and 56 mg/m2 on day -2. 
Carfilzomib will be infused over 30 minutes (±10 minutes) as described in section 6.1.1. On day 
-2, with 60 to 120 minutes of the end of infusion of carfilzomib, subjects will receive 200 mg/m2 
of intravenous melphalan as an intravenous push or a fast infusion, (see section 6.1.2). 
Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines 
and SOPs. 
Infusion of autologous cells- Infusion of autologous hematopoietic stem cells will occur on day 
0 and follow institutional SOP.  
 


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Post AHSCT Follow-up phase – On day 1 following AHSCT, patients will receive either 
pegfilgrastim 6 mg subcutaneously (single dose) or filgrastim at 5 mcg/kg/day subcutaneously 
continuing at least until 2 days of absolute neutrophil count > 500/mm3 as per institutional 
standard of care aiming at faster engraftment. The post-transplant follow up phase of the study 
will last 100 days and will consist of standard post transplantation supportive care and 
monitoring of AEs. For the phase I component of the study, dose-limiting toxicities will be 
captured during the first 30 days after transplantation (DLT period).  
Post AHSCT Disease assessment- Disease assessment will occur at day 100 (+/- 7 days) and 
will consist of interim medical history and physical exam, serum protein electrophoresis, serum 
and urine immunofixation, 24h urine protein electrophoresis, serum free light chains, bone 
marrow aspiration and biopsy, complete blood counts and metabolic panel including uric acid 
phosphorus. Disease response will be categorized according to appendix B. Patients enrolled to 
the Phase I portion of the study will only be followed until the disease assessment visit at day 
100 (+/- 7 days) and resolution of any treatment related toxicities to baseline or until toxicities 
have been deemed irreversible by the investigator.  
 
 
 


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MAINTENANCE THERAPY 
(post day 100 disease assessment through a maximum of twelve 28 day maintenance cycles) 
Applicable only to Phase IIa study activity 
 
Screening for Maintenance Therapy – Patients must undergo day 100 disease assessment and 
be without disease progression in order to continue with maintenance therapy. Patients must be 
registered by the UAB CTNMO prior to starting any maintenance therapy. Maintenance 
registration forms are included in the UAB CTNMO case report form packet. Registration can 
occur any time after day 100 assessments are completed, but subjects must start maintenance 
therapy by day 120 after transplantation. At the time of registration, patients will be randomized 
to Arm 1 of Arm 2. 
Maintenance Therapy- Maintenance regimen A will consist of carfilzomib 36 mg/m2 infused 
over 30 minutes (±10 minutes)  on days 1,8,15. Maintenance regimen B will consist of 
carfilzomib 36 mg/m2 infused over 30 minutes (±10 minutes) on days 1, 2, 15 and 16. Each cycle 
will have 4 week duration. The first four maintenance therapy cycles will be dictated by a 
randomized assignment at time of study registration to maintenance therapy. Patients will either 
be randomized in blocks of two to either maintenance therapy Arm 1= AABB (two cycles of A 
followed by two cycles of B), or maintenance therapy Arm 2= BBAA (two cycles of B followed 
by two cycles of A). For both maintenance therapy arms, a patient preference questionnaire will 
be administered to the patient upon completion of the 4th cycle. The remaining 8 cycles (cycles 
5-12) will be administered according to the regimen schedule preferred by the patient as 
documented on the patient preference questionnaire. 
Maintenance Therapy Disease Assessment- During the maintenance therapy, disease 
assessments will occur at the end of each even cycle and consist of medical history and physical 
exam assessment, serum protein electrophoresis, serum and urine immunofixation, 24h urine 
protein electrophoresis, serum free light chains, complete blood counts and metabolic panel 
including uric acid and phosphorus. Bone marrow aspiration and biopsy will only be performed 
if needed to confirm complete response.  Patients will complete Quality of Life assessments at 
the end of each even cycle. 


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3.6 
PHARMACODYNAMIC AND CORRELATIVE ASSAYS 
For our secondary objectives, we will perform pharmacodynamic assays to measure DNA 
fragmentation in peripheral blood mononuclear cells during the conditioning regimen.  We also 
hypothesize that carfilzomib targets the Fanconi Anemia (FA) /BRCA pathway, and thus, 
enhances chemotherapeutic response of myeloma cells to melphalan.  We will measure 11 genes 
that are involved in FA/BRAC pathway including brca1, brac2, fanca, fancc, fancd2, fance, 
fancf, fancg, fancl, rad51 and rad51c.  The key end-points for our pharmacodynamics and 
mechanistic studies are: 
-Expression of relevant genes of the FA/BRCA pathway in peripheral blood mononuclear 
cells utilizing quantitative RT-PCR; 
-DNA fragmentation in peripheral blood mononuclear cells. 
During the maintenance treatment on the phase IIa we will measure the degree of proteasoma 
inhibition in peripheral blood mononuclear cells during regimen A and regimen B.  Proteasoma 
inhibition samples will only be collected during the first cycle of each maintenance therapy 
regimen. 
Additionally, for our secondary objectives, we will perform correlative assays to evaluate the 
possible association between biological parameters in the cancer cells and the magnitude of 
response to therapy.  We reason that gene expression level in the FA/BRAC pathway and/or the 
unfolded protein response pathway would predict the response to carfilzomib + melphalan 
conditioning.  The key end-points for our correlative studies are: 
-Expression of genes in the FA/BRCA pathway by quantitative RT-PCR (genes that will 
be measured include: NK-kB, Rel/p50 and brca1, brac2, fanca, fancc, fancd2, fance, 
fancf, fancg, fancl, rad51 and rad51c); 
-Expression of genes from the unfolded protein response pathway [genes that will be 
measured include: heat shock protein 90 and x-box binding protein-1 (XBP-1)].  


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Pharmacodynamic assays intend to verify if the hypothesized effects of the study drugs are 
indeed occurring in vivo. Tables 3 and 4 below summarizes the pharmacodynamic correlative 
assays completed for this study. 
 
Table 3 - Pharmacodynamic (PD) and correlative assays (analyzed by MUSC) 
 
PHASE I STUDY ACTIVITY CORRELATIVES 
Assay 
Material 
Time points 
 
PD 
 
 
 
Expression of relevant 
genes in the 
FA/BRCA pathway 
Peripheral blood 
mononuclear cells 
D -3: Prior to CFZ and 1h after CFZ 
infusion completion. 
D-2: Prior to CFZ, 1h, 12h after Mel 
infusion completion (Mel infused 
immediately after CFZ) 
D 0: Immediately prior to infusion of cells 
 
 
DNA fragmentation 
 
Peripheral blood 
mononuclear cells 
 
D -3: Prior to CFZ and 1h after CFZ 
infusion completion. 
D-2: Prior to CFZ, 1h, 12h after Mel 
infusion completion (Mel infused 
immediately after CFZ) 
D 0: Immediately prior to infusion of cells 
 
PHASE I and Phase IIa  STUDY ACTIVITY CORRELATIVES 
 
Please note that only MUSC patients will be participating the in the Phase IIa portion of 
this study. As of April 2014, the MUSC correlative studies are closed to additional 
enrollment. 
Correlatives 
 
 
 
Expression of genes 
in the FA/BRCA 
pathway 
 
Plasma cells from 
bone marrow sample 
Screening 
Day -1 (optional) 
Day 100 assessment 
 
Expression of genes 
in the unfolded 
protein response 
pathway 
 
 
Plasma cells from 
bone marrow sample 
 
Screening 
Day -1 (optional) 
Day 100 assessment 
DNA fragmentation 
Plasma cells from bone  Day -1 (optional) 
marrow sample 
 


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Table 4 Pharmacodynamic (PD) and correlative assays during Phase IIa (analyzed by 
Onyx) 
 
PHASE IIa CORRELATIVE STUDIES 
 
Please note that only MUSC and MSKCC will participate in the Phase IIa Correlative 
Studies.  
 
Assay 
 
Material 
 
Time points 
PD  
(Proteasoma 
inhibition) 
 
Peripheral blood 
mononuclear cells 
 
Regimen A:  
Day 1: pre dose and 1 hour post dose 
Day 2: 24h +/- 1 hour after day 1 dose  
Day 8: pre dose and 1 hour post dose 
 
Regimen B:  
Day 1: pre dose and 1 hour post dose 
Day 2: pre dose and 1 hour post dose 
Day 8: at any time on day 8 
 
 
 
 
All Phase I PD/mechanistic studies and correlative assays will be performed at the laboratory of 
Dr. Yubin Kang, MD. The phase IIa PD proteasoma inhibition assessment will be performed by 
Onyx. Only selected sites -MUSC and MSKCC- will participate in the Phase IIa PD studies. 
Please refer to the 101669 Correlative Study Manual for handling and processing details. 
3.6.1 
TIME POINTS OF SAMPLE COLLECTION 
Please see the Tables 3 and Table 4 (pharmacodynamics and correlative assays) for the time 
points at which samples will be collected. 
3.6.2 
SAMPLE COLLECTION AND SHIPMENT 
For peripheral blood samples collected during the phase I portion of the study, approximately 
8ml of blood will be collected at each time point, (at least 4ml collected in yellow ACD tube and 
at least 4 ml collected in green sodium heparin tube).  For bone marrow samples, a total of 4 ml 
of marrow aspirate will be collected in green sodium heparin. 
 
 


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For samples collected at MSKCC and MUSC,  
the peripheral blood samples were processed within 24 hours of the time of blood collection to 
ensure specimen quality. Samples collected at MSKCC were shipped overnight to MUSC. The 
specific processing and shipping details are outlined within the 101669 correlative studies manual. At 
the time of issue of Amendment 6 all sample collection for correlative studies has been completed. 
Samples will be processed and analyzed by Dr. Yubin Kang (Duke University, Division of 
Hematological Malignanices & Cellular Therapy, 2400 Pratt Street, DUMC 3961, Durham, NC  27710, LAB 
Location: GSRB1, Rm# 4040)” 
.For PD samples (proteasoma inhibition) collected during maintenance therapy. 
Only MUSC and MSKCC will participate in these pharmacodynamic studies during maintenance 
therapy. Samples for pharmacodynamic studies will be obtained only during the first cycle of 
each regimen- A and B (e.g. Cycle 1 and Cycle 3). See Table 4 for schedule of 
pharmacodynamics samples. Up to 10 evaluable patients will participate. If a patient 
discontinues therapy or has a dose reduction prior to completing cycle 3, then the subject will be 
replaced. All proteasoma inhibition samples will be analyzed by Covance. See the 101669 
correlatives manual for details. 
3.6.3 
ASSAYS 
-- Cellular Proteasome Activity Assay: 
Whole peripheral blood will be collected in yellow ACD tube and mononuclear cells will be 
obtained using Histopaque-1077 (Sigma-Aldrich) gradient separation.  Cell lysates will be 
prepared by hypotonic lysis (BD Pharmalyse; BD Pharmingen) and the cell lysates will be mixed 
with 7-Amino-4-methycoumarin (AMC)-conjugated fluorogenic proteasome substract (Boston 
Biochem). The proteasome activities are determined by the initial rate (first 10 min) of AMC 
product formation. 
-- Gene expression measurement by quantitative RT-PCR: 
Genes that will be measured in this protocol include those that are involved in FA/BRCA 
pathway and those in the unfolded protein response pathway.  These genes are: NK-kB, Rel/p50 
and brca1, brac2, fanca, fancc, fancd2, fance, fancf, fancg, fancl, rad51, rad51c; HSP90 and 
XBP-1.  The samples will be peripheral blood mononuclear cells or bone marrow mononuclear 
cells as indicated in Table 3. 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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Total RNA will be isolated from mononuclear cells using the Trizol (Invitrogen) as per 
manufacturer’s instruction. First-strand cDNA will be synthesized with the iScript cDNA 
synthesis kit (Bio-Rad) using 20 µl reaction mixture containing 1 µg total RNA, 4 µl 5x iScript 
reaction mixture, and 1 µl iScript reverse transcriptase. The complete reaction is cycled for 5 min 
at 25 °C, 30 min at 42 °C, and 5 min at 85 °C. The reverse transcription reaction mixture is then 
diluted with nuclease-free water in the ratio 1:10 and used for PCR amplification of genes of 
interest, and β- actin control gene.  Primers will be purchased from Invitrogen.   The primers for 
control gene (β- actin) are -Actin F (ACCTTCTACAATGAGCTGCG) and -Actin R 
(CCTGGATAGCAACGTACATGG).   
Real-time PCR will performed in duplicate using 25 µl reaction mixture that contains 1.0 µl RT 
mixture, 0.2 µM of both primers, and 12.5 µl iQ SYBR Green Supermix (Bio-Rad) to be  run in 
the iCycler real-time detection system (Bio-Rad) with a two-step method. The hot-start enzyme 
is activated (95 °C for 3 min) and cDNA is then amplified for 40 cycles consisting of 
denaturation at 95 °C for 10 s and annealing/extension at 58 °C for 30 s. A melt curve is then 
performed (55 °C for 1 min and then temperature is increased by 0.5 °C every 10 s) to detect the 
formation of primer-derived trimmers and dimmers. Data will be analyzed using the iCycler iQ 
software (Biorad Laboratories, USA) and adjusted against β- actin.  
-- DNA fragmentation assay: 
The DASH assay captures and detects damage-induced low molecular-weight DNA fragments as 
diffuse halos in an agarose microgel. The peripheral blood mononuclear cells will be washed 
with PBS and embedded in low melting agarose. The embedded cells are lysed for 10 min under 
alkaline conditions, and DNA is precipitated and visualized with SYBR Green fluorogenic dye 
(Molecular Probes). Fifty images will be randomly captured per slide, and the logarithmic radius 
of each nucleoid is calculated using the tail-length parameter of the Loats Associates comet 
analysis software.  


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4 
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA   
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study.   
1. Age ≥ 18 years (or age of majority at participating site, whichever is greater) and ≤ 70 years. 
2. Life expectancy ≥ 12 months. 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0–2.  
4. Diagnosis of symptomatic multiple myeloma38, relapsed after initial therapy. 
5. At least minimal response (defined as 25% decrease in the M protein in serum or urine) to 
the most recent treatment regimen. 
6. Evaluable disease prior to the most recent reinduction regimen as defined by at least one of 
the following: 
-Serum monoclonal (M) protein ≥ 0.5 g/dl by protein electrophoresis  
 
 
->200 mg of M protein in the urine on 24 hour electrophoresis   
 
 
- Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal  
 
 
serum immunoglobulin kappa to lambda free light chain ratio 
 
 
- Monoclonal bone marrow plasmacytosis ≥30%  
7. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum 
direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to registration. 
8. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to registration (subjects may be receiving 
red blood cell [RBC] transfusions in accordance with institutional guidelines).  
9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 14 days prior to registration, either 
measured or calculated using a standard formula (eg, Cockcroft and Gault). 
10. Prior storage of at least 2 x 106 CD34+ cells/kg available for autologous transplantation. 
During the phase I component of the study, at least the same amount of cells is required as 
“back up” in the unlikely event of non-engraftment. 
11. Subjects may have had a prior AHSCT for the treatment of MM as long as it was performed 
greater than 12 months from study registration. 
12. Subjects must meet institutional general eligibility criteria for autologous transplantation. 
13. Written informed consent in accordance with federal, local, and institutional guidelines.  
14. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to 
practice contraception.  
15. Male subjects must agree to practice contraception.  
16. Prior therapy with carfilzomib is allowed as long as subject did not experience disease 
progression while on carfilzomib or within 90 days of treatment discontinuation for any 
reason.. 
 


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4.2 
EXCLUSION CRITERIA 
1. Pregnant or lactating females. 
2. Major surgery within 30 days prior to start of treatment. 
3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) 
within 14 days prior to registration. 
4. Known human immunodeficiency virus infection. 
5. Active hepatitis B or C infection. 
6. Unstable angina or myocardial infarction within 4 months prior to registration, NYHA Class 
III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe 
uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence 
of acute ischemia or Grade 3 conduction system abnormalities unless subject has a 
pacemaker. 
7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration. 
8. Non-hematologic malignancy within the past 3 years with the exception of a) adequately 
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in 
situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-
specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to 
impact survival during the duration of the study, such as localized transitional cell carcinoma 
of the bladder or benign tumors of the adrenal or pancreas. 
9. Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to 
registration. 
10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize 
carfilzomib). 
11. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis 
within 14 days prior to registration. 
12. Any other clinically significant medical disease or condition that, in the Investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent.  
4.3 
CRITERIA FOR REGISTRATION FOR MAINTENANCE (PHASE IIa ONLY) 
In order for patients to continue to maintenance therapy within the Phase IIa portion of the study, 
patients must be meet the following eligibility criteria and be registered via the UAB CTNMO. 
1. Adequate graft function consisting of hemoglobin ≥ 10 g/dL (100 g/L), platelets ≥ 
75,000/mm3, absolute neutrophil count  ≥ 1,000/mm3 within 14 days prior to registration. 
2. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum 
direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 10 days prior to registration. 


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3. Creatinine clearance (CrCl) ≥ 40 mL/minute within 10 days prior to registration, either 
measured or calculated using a standard formula (eg, Cockcroft and Gault). 
4. Absence of progressive disease on day 100 (+/- 7 days) disease assessment. 
5. Absence of any exclusion criteria outlined in 4.2 


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5 
SUBJECT ENROLLMENT 
Once a patient is identified as a candidate for the trial the investigator will contact the UAB 
CTNMO registration office (205-975-5387) prior to obtaining informed consent (phase I only). 
This process is intended to verify if a “slot” is available in the current cohort. Registration will be 
completed upon submission of documentation of eligibility to the registration office and issuance 
of a registration confirmation email.  
 
Prior to accepting the registration, the registration office will verify the following:  
 
- IRB approval at the registering institution  
 
- Patient eligibility  
 
- Existence of a signed consent form  
 
- Existence of a signed authorization for use and disclosure of protected health  
 
  information 
- Pretreatment tests and procedures must be completed within the guidelines specified in 
the test schedule, including assessment of baseline symptoms. 
- Study drugs availability on site (for initial site patient only; Local site is responsible for 
assessing drug available for subsequent site enrollments)  
 
Phase IIa Registration Procedures: 
When the Phase IIA portion of the study begins, the following patient registration procedures 
must be followed prior to any start of conditioning therapy.  
Registration will be completed upon submission of documentation of eligibility to the 
registration office and issuance of a registration confirmation email. Prior to accepting the 
registration, the registration office will verify the following:  
 
- IRB approval at the registering institution  
 
- Patient eligibility  
 
- Existence of a signed consent form  
 
- Existence of a signed authorization for use and disclosure of protected health  
 
information 
- Pretreatment tests and procedures must be completed within the guidelines specified in 
the test schedule, including assessment of baseline symptoms. 


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- Study drugs availability on site (for initial site patient only; Local site is responsible for 
assessing drug available for subsequent site enrollments) 
Effective on approval of Amendment 6, the registration office will be transferred to UAB 
CTNMO Phone No: 205- 975-5387, Fax No: 205-975-9875.  
An enrolled patient is expected to undergo a second registration prior to starting any maintenance 
therapy. Registration will be completed upon submission of documentation of eligibility to the 
registration office and issuance of a registration confirmation email. The registration 
confirmation email will include the maintenance arm randomization. Prior to accepting the 
registration, the registration office will verify the following:  
 
- IRB approval at the registering institution  
 
- Patient eligibility  
 
- Existence of a signed consent form  
 
- Existence of a signed authorization for use and disclosure of protected health  
 
information 
- All required procedures will be performed as day 100 (+/-7days) assessment per Table 
7. Registration can occur any time after assessment completed, but subjects must start 
maintenance therapy by day 120 after transplantation. 


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6 
TREATMENT PROCEDURES 
6.1 
DRUG PREPARATION AND ADMINISTRATION   
6.1.1 
CARFILZOMIB  
 
 Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. 
The lyophilized product is reconstituted with Water for Injection to a final carfilzomib 
concentration of 2 mg/mL prior to administration.  The dose will be calculated using the 
subject’s actual BSA at baseline.  Subjects with a BSA > 2.2 m2 will receive a dose based 
upon a 2.2 m2 BSA.   
 At the discretion of the investigator, patients thought to be at particularly high risk for the 
development of TLS, based on high tumor burden,  oral hydration should be given as 
follows, at least 48 hours before Day -3,:  30 mL/kg/day (approximately 6 to 8 cups of liquid 
per day) continuing up to the time of treatment.  Subject compliance must be assessed before 
initiating treatment, which is to be delayed if oral hydration is not adequate.  
 IV hydration will be given immediately prior to carfilzomib.  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 (eg, ≥ 2 L/day).  Subjects should be monitored periodically 
during this period for evidence of fluid overload. 
 If the subject has a dedicated line for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline prior to and after drug administration.     
 Carfilzomib will be given as an IV infusion over approximately 30 minutes (±10 minutes). 
The dose will be administered at a facility capable of managing hypersensitivity reactions.  
Subjects will remain under observation for at least 1 hour following each dose of carfilzomib 
during conditioning therapy. During these observation times, post dose IV hydration 
(between 250 mL and 500 mL normal saline or other appropriate IV fluid formulation) will 
be given.  Subjects should be monitored periodically during this period for evidence of fluid 
overload. 
 During the maintenance component of the study carfilzomib will be administered over 
approximately 30 minutes (±10 minutes). IV hydration with 250 ml of normal saline will be 


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administered prior to carfilzomib. No post carfilzomib hydration nor observation are 
necessary during maintenance. 
6.1.2 
MELPHALAN 
 
 Melphalan is commercially available and supplied as a sterile, freeze-dried powder. Each vial 
contains 50 mg melphalan hydrochloride and the inactive ingredient, povidone 20 
mg.  Reconstitute per manufacturer instructions using the diluent provided.  Further dilution 
and administration per institutional standards. The manufacturer recommends completion of 
administration of melphalan within 60 minutes of reconstitution. 
 The dose (200 mg/m2) will be calculated using the lesser of the subject’s actual (AW) or 
corrected ideal body weight (CIBW). CIBW= IBW + 0.25(AW-IBW). The ideal body weight 
(IBW) is calculated using the formula: Males: IBW = 50 kg + 2.3 kg for each inch over 5 
feet. Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
 Solution Preparation:  Vial/50 mg:  Constitute with 10 ml of the special diluent to yield a 5 
mg/ml melphalan concentration.  May be further diluted per institutional guidelines. 
 Melphalan must be infused intravenously utilizing a central vein catheter and infusion 
completed within one hour of reconstitution.   
 IV hydration will be given immediately after melphalan per institutional guidelines. 
 Intravenous melphalan is commercially available and will not be provided by the sponsor.  
6.2 
DOSE REDUCTIONS/ADJUSTMENTS  
6.2.1 
TRANSPLANT COMPONENT 
Since each subject will only undergo one “cycle” of therapy, the possibility of intra patient dose 
reduction/adjustment for subsequent cycles does not apply. 
Since subjects will receive carfilzomib on days -3 and -2 of treatment, subjects experiencing 
significant immediate toxicity after day -3 dose will have day -2 dose omitted according to Table 
5. 
Table 5 – Adverse events requiring omission of day -2 dose of carfilzomib. 


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Symptom 
Recommended Action regarding 
Carfilzomib 
Allergic reaction/hypersensitivity, grade 
2 or greater 
Omit day -2 dose 
Tumor lysis syndrome (≥ 3 of following: 
≥ 50% increase in creatinine, uric acid, 
or phosphate; ≥ 30% increase in 
potassium; ≥ 20% decrease in calcium; 
or ≥ 2-fold increase in LDH 
Omit day -2 dose 
“First dose effect” of any grade (see 
section 6.3) > Grade 2 
Omit day -2 dose 
Any other non-hematologic immediate  
toxicity assessed as carfilzomib-related 
> Grade 3 
Omit day -2 dose 
 
 
6.2.2 
MAINTENANCE COMPONENT 
During maintenance therapy one level dose reduction will be allowed for carfilzomib related 
toxicity according to Table 6. The reduced dose will consist of carfilzomib 27 mg/m2. Subjects 
requiring further dose reduction will have experimental therapy discontinued. 
Dose reductions during maintenance component will carry forward to all subsequent cycles for 
both regimens A and B.  
Omitted doses will not be replaced. Patients who interrupt therapy due to toxicity will resume 
therapy as outlined in Table 6 receiving any remaining doses on the ongoing cycle. If no 
remaining doses on the current cycle, then treatment will resume after the cycle is completed, 28 
(+/- 2) days from the initiation of the prior cycle. 
Table 6 – Dose adjustments during maintenance therapy 
Hematologic 
toxicity 
CTC 4.0 grade 
Action 


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Thrombocytopenia Grade 3  
Hold therapy until resolution to grade  2, then 
resume at the same dose. If toxicity lasts more 
than 2 weeks, reduce dose. 
 
 
Grade 4 or 
bleeding 
First occurrence - Hold carfilzomib until 
resolution to grade  2 and no bleeding. Resume 
therapy at one level dose reduction. 
Second occurrence- Discontinue therapy 
Anemia 
Grade 3 
Hold therapy until resolution to grade  2, then 
resume at the same dose. If toxicity lasts more 
than 2 weeks, reduce dose. 
 
Grade 4 or 
transfusion 
requirement 
First occurrence - Hold carfilzomib until 
resolution to grade  2. Resume therapy at one 
level dose reduction 
Second occurrence- Discontinue therapy. 
Neutropenia 
Grade 3 
Hold therapy until resolution to grade  2, then 
resume at the same dose.  If toxicity lasts more 
than 2 weeks, reduce dose. 
 
 
 
Grade 4 or grade 
3 with infection 
First occurrence - Hold carfilzomib until 
resolution to grade  2. Resume therapy at one 
level dose reduction 


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6.3 
SAFETY CONSIDERATIONS 
Based upon the experience in the Phase 1 and 2 clinical studies with carfilzomib, the following 
observations are noted:  
 A “first dose effect” has been seen with carfilzomib, which is notable for fever, chills, rigors, 
and/or dyspnea occurring during the evening following the first day of infusion and an 
increase in creatinine on the following day, which may be the clinical sequelae of rapid 
tumor lysis and/or cytokine release.    
 Dexamethasone at least 4 mg PO/IV will be administered prior to all carfilzomib doses.  
Second occurrence- Discontinue therapy. 
Non-hematologic 
toxicity 
CTC 4.0 grade 
Action 
Any 
Grades  2 
No action is required. Investigator is allowed to 
hold study drug for up to two weeks and then 
resume at same dose. On second occurrence, the 
investigator has the option to resume therapy at 
reduced dose. 
 
Grade 3 
Hold therapy until resolution to grade  2, then 
resume at the same dose. If toxicity lasts more 
than 2 weeks, reduce dose. 
 
Grade 4 
First occurrence - Hold carfilzomib until 
resolution to grade  2. Resume therapy at one 
level dose reduction. 
Second occurrence- Discontinue therapy. 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN FOR 
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 Should a “first dose effect” occur after day -3 dose of carfilzomib, 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.  
 Acyclovir, or a similar medication, should be given to all subjects, per institutional 
prophylaxis guidelines, unless contraindicated. 
 CrCl changes are mostly transient, reversible, and non-cumulative. All subjects should be 
well hydrated.  Clinically significant electrolyte abnormalities should be corrected prior to 
dosing with carfilzomib. Renal function must be monitored closely during treatment with 
carfilzomib.  Serum chemistry values, including creatinine, must be obtained and reviewed 
prior to each dose of carfilzomib. Carfilzomib must be held for subjects with a CrCl < 15 
mL/min at any time during study participation. 
 Subjects with active or suspected infection of any kind that required systemic treatment 
should not be dosed with carfilzomib until the infection has resolved and,  if being treated 
with anti-infective, the course of antibiotics has been completed.  
 Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes 
requiring the use of antiemetic or antidiarrheal medications.  Fluid and electrolyte 
replacement should be administered to prevent dehydration. 
 The treatment with melphalan as outlined in this protocol constitutes standard of care. The 
dose of 200mg/m2 of melphalan is myeloablative, therefore subjects are expected to develop 
grade 4 thrombocytopenia requiring transfusion, grade 4 neutropenia with near 100% risk of 
neutropenic fever and anemia requiring transfusion of red blood cells. Subjects will be 
monitored for need of transfusional support and for fever and other complications until 
engraftment.  
 Melphalan at the doses employed in this protocol will cause nausea, vomiting and mucositis 
manifested mostly as oral pain, dysphagia and diarrhea. Subjects will receive antiemetic and 
antidiarheal medications according to institutional guidelines. 


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6.3.1 
GUIDELINES FOR MONITORING, PROPHYLAXIS, AND TREATMENT OF 
TUMOR LYSIS SYNDROME (TLS) 
TLS, which may be associated with multiorgan failure, has been observed in treatment cycles 1 
and 2 in some patients with MM who have been treated with carfilzomib.  
 
The following safety measures are mandatory for all subjects.  In addition, MM subjects with 
high tumor burden (e.g., Durie-Salmon or ISS Stage II/III) or rapidly increasing M-protein or 
light chains or compromised renal function (CrCl < 50 mL/min) should be considered to be at 
particularly high risk. Please see section 6.1.1 for hydration requirements. 
6.3.1.1 
Laboratory Monitoring 
Appropriate chemistries, including creatinine and complete blood counts (CBC) with platelet 
count, should be obtained and reviewed prior to carfilzomib dosing.  Results of laboratory 
studies must be reviewed and deemed acceptable prior to administering the carfilzomib dose.  
Subjects with laboratory abnormalities consistent with lysis of tumor cells (e.g., serum creatinine 
≥ 50% increase, LDH ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 50% increase, 
potassium ≥ 30% increase, calcium ≥ 20% decrease) prior to dosing should not receive the 
scheduled dose.  Subjects with such abnormalities should be re-evaluated again within the next 
24 hours (or sooner, if clinically indicated) and then periodically as clinically indicated.    
6.3.1.2 
 Management of Tumor Lysis Syndrome 
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. 
All cases of TLS must be reported to Onyx as a Serious Adverse Event (SAE) through the 
normal process within 24 hours of the clinical site becoming aware of the event. 
6.4 
CONCOMITANT MEDICATIONS 
Concomitant medication is defined as any prescription or over-the-counter preparation including 
vitamins and supplements.  Concomitant medications should be recorded from 14 days before 


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Day -3 through the end of the subject’s study participation.  Any change in concomitant 
medications must be recorded.   
6.4.1 
REQUIRED CONCOMITANT MEDICATIONS 
Female subjects of child-bearing potential must agree to use dual methods of contraception for 
the duration of the study.  Male subjects must agree to use a barrier method of contraception for 
the duration of the study if sexually active with a female of child-bearing potential. 
Dexamethasone at least 4 mg PO/IV will be administered prior to all carfilzomib doses.  
On Day 1 of AHSCT subjects will receive either single dose of pegfilgrastim at 6mg 
subcutaneously or start filgrastim at 5 mcg/kg/day subcutaneously and continue until ANC is 
greater than 500/mm3 on two consecutive days. 
Subjects should receive antibiotic prophylaxis with ciprofloxacin or other fluoroquinolone during 
the period of neutropenia according to institutional guidelines. In addition, subjects should 
receive acyclovir or similar (famiciclovir, valacyclovir) anti-varicella (anti-herpes) agent 
prophylaxis until day 100 as per institutional guidelines. Subjects receiving maintenance therapy 
in the phase IIa portion of the study will continue acyclovir or similar for the entire duration of 
maintenance. 
6.4.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
Allopurinol (in subjects at risk for TLS due to high tumor burden) is optional and will be 
prescribed at the Investigator’s discretion.  These subjects may receive allopurinol 300 mg PO 
daily on days -3, -2, -1 and 0 (total of 4 days). 
Vitamins and supplements should be recorded on the concomitant medication page.  All 
transfusions and/or blood product related procedures must be recorded on the appropriate form. 
6.4.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with an approved or investigative anticancer therapeutic with activity against 
multiple myeloma is not allowed.  Other investigative agents (e.g., antibiotics or antiemetics) 
should not be used during the study. 


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7 
STUDY TESTS AND OBSERVATIONS 
Table 7 – Study Evaluations: Conditioning Therapy and AHSCT 
 
Screening 
Treatment 
Follow up 
Disease 
assessment 
 
Within 30 
days from 
 registration 
Within 14 
days from 
registration 
Day 
-38 
Day 
-2 
Day 
-1 
Day 
0 
Recovery of 
blood 
counts4, 5 
Twice 
weekly 
until 
day 21 
Day+100 
 (+/- 7 days) 
History and Physical 
X 
 
X 
X 
X 
X 
 
X 
X 
Vitals 
X 
 
X 
X 
X 
X 
 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Complete blood 
counts 
 
X 
X 
X 
X 
X 
X4, 5 
X 
X 
Metabolic panel (Na, 
K, Cr, BUN, Cl, 
Bicarbonate) 
 
X 
X 
X 
X 
X 
 
X 
X 
Calcium, 
Phosphorus, Uric 
acid 
 
X 
X 
X 
X 
X 
 
X 
X 
LFTs (bilirubin, 
AST, ALT, alkaline 
phosphatase) 
 
X 
X 
X 
X 
X 
 
X 
X 
Serum protein 
electrophoresis 
 
X 
 
 
 
 
 
 
X 
24h urine protein 
electrophoresis9 
 
X 
 
 
 
 
 
 
X 
Serum free light 
chains 
 
X 
 
 
 
 
 
 
X 
Serum and urine 
Immunofixation 
 
X 
 
 
 
 
 
 
X 
Bone marrow 
aspiration and 
biopsy1, 2 
X2 
 
 
 
 
 
 
 
X2 
Pharmacodynamics 
sample3  
 
 
X 
X 
 
X 
 
 
 
Adverse Events 
Assessment6 
X 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant 
Medications  
Review7 
 
X 
X 
X 
X 
X 
 
X 
X 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
1- Bone marrow correlative studies will be performed in each of these specimens as described in section 3.6 and table 3. 
During the Phase I portion of the study only MUSC and MSKCC will participate. During the Phase IIa portion of the study, 
up to 4 patients, from MUSC ONLY,, will participate.  The Day -1 bone marrow aspiration and biopsy is optional   As of 
April 2014, the Day -1 bone marrow correlative study completed.   
2 -  Conventional cytogenetics and FISH for myeloma-associated abnormalities are to be performed. The screening bone 
marrow biopsy can be performed after registration and prior to study treatment.  


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3-These studies are only applicable only to Phase I as described in section 3.6 and table 3.Please note that only MUSC and 
MSKCC will participate in these PD samples during the Phase I portion of this study. When the Phase IIa portion of the 
study opens, these Phase IIa patients will not participate in these PD studies. 
4- During the Phase I portion of the study, complete blood counts will be performed daily until the following is achieved: 
a) platelet ≥ 20,000/mm3 for 3 consecutive days without transfusions in the past 7 days and b) neutrophil count ≥ 500/mm3.  
5 - During the Phase IIa portion of the study, complete blood counts will be performed  until the following is achieved: a) 
platelet ≥ 20,000/mm3 without transfusions for 3 consecutive measurements and b) neutrophil count ≥ 500/mm3. 
6-AEs should be assessed using CTCAE v4.0 from date informed consent signed until 30-days post-last dose of study drug 
or initiation of a new anti-cancer therapy, whichever comes first. See Section 9.3. 
7-Concomitant Medications should be assessed 14 days before Day-3 through the end of study participation. 
8- It is recommended that study treatment begin within 7 days after study registration. If an event occurs that prevents the 
patient from beginning Day -3 treatment within 7 days of registration, the investigator must repeat a history and physical, 
CBCD, CMP, Calcium, Phosphorus, Uric acid, LFTs (bilirubin, AST, ALT, alkaline phosphatase) to ensure the patient 
meets the institutional general eligibility criteria for autologous transplantation and laboratory values as outlined within the 
study’s eligibility criteria.  
9- When the total protein <10g/dL, urine protein electrophoresis is not required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 8 – Study Evaluations: Maintenance Therapy (Applicable to Phase IIa Only) 
 
Registration1 
Regimen A cycle 
Regimen B cycle 
At end of 
cycle 4 
Disease 
assessment 
 
End of 
Study8 
 
 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
2 
Day 
15 
Day 
16 
 
At the 
end of 
each even 
cycle 
 
History and Physical 
X 
X 
 
 
X 
 
 
 
 
X3 
X 
Vitals 
X 
X 
 
 
X 
 
 
 
 
X3 
X 
Weight 
X 
X 
 
 
X 
 
 
 
 
X3 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood 
counts 
X 
X 
 
X 
X 
 
X 
 
 
X3 
X 
Metabolic panel 
(Na, K, Cr, BUN, 
Cl, Bicarbonate) 
X 
X 
 
X 
X 
 
X 
 
 
X3 
X 
Calcium, 
Phosphorus, Uric 
acid 
X 
X 
 
X 
X 
 
X 
 
 
X3 
X 
LFTs (bilirubin, 
AST, ALT, alkaline 
phosphatase) 
X 
X 
 
X 
X 
 
X 
 
 
X3 
X 
Serum protein 
electrophoresis 
X 
 
 
 
 
 
 
 
 
X3 
 
24h urine protein 
electrophoresis5 
X 
 
 
 
 
 
 
 
 
X3 
 
Serum free light 
chains 
X 
 
 
 
 
 
 
 
 
X3 
 
Serum and urine 
Immunofixation 
X 
 
 
 
 
 
 
 
 
X3 
 
Bone marrow 
aspiration and 
biopsy 
X 
 
 
 
 
 
 
 
 
X3, 4 
 
Pharmacodynamics 
sample 
 
X2 
X2 
 
X2 
X2 
 
 
 
 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Concomitant 
Medications Review  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Patient completion 
of Preference 
Questionnaire6 
 
 
 
 
 
 
 
 
X 
 
 
Patient completion 
of Quality of Life 
Questionnaires7 
 
 
 
 
 
 
 
 
 
X 
 
1- All required procedures will be performed as day 100 (+/-7days) assessment per Table 7. Registration can occur 
any time after assessment completed, but subjects must start maintenance therapy by day 120 after transplantation. 
2- Only MUSC and MSKCC will participate in these pharmacodynamic studies during maintenance therapy in 
Phase IIa. Samples for pharmacodynamic studies will be obtained only during the first cycle of each regimen- A and 
B (e.g. Cycle 1 and Cycle 3. Note that Regimen A includes a Day 2 collection and Regimen B includes a Day 8 


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collection. See Table 4 for schedule of pharmacodynamics samples. Up to 10 evaluable patients will participate. If a 
patient discontinues therapy or has a dose reduction prior to completing cycle 3, then the subject will be replaced.  
3- Disease assessment procedures may be combined with day 1 assessment of subsequent cycle. 
4- Bone marrow aspiration and biopsy required only to confirm complete response. 
5- When the total protein <10g/dL, the urine protein electrophoresis is not required. 
6- Refer to Appendix C. 
7- Refer to Appendix D and Appendix E.  Quality of Life questionnaires will be administered at the end of each 
even cycle.   
8- End of Study – these assessments are required in the event that the patient discontinues maintenance therapy due 
to early termination (eg. withdraws consent, toxicity, etc.).  
 


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8 
STUDY DISCONTINUATION 
Reasons for study discontinuation may include, but are not limited to: 
- 
≥ 2 subjects experience DLT in cohort -1 as indicated in section 3.1.1. 
- 
Safety concerns 
- 
Request to discontinue the trial by a regulatory or health authority or an IRB 
- 
Manufacturing difficulties/concerns 


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9 
ADVERSE EVENTS 
9.1 
ADVERSE EVENTS DEFINITIONS  
An AE is any untoward medical occurrence in a study subject administered an investigational 
product and that does not necessarily have a causal relationship with this treatment.  
An AE therefore can be any unfavorable and unintended sign (including laboratory findings), 
symptom or disease temporally associated with participation in an investigational study, whether 
or not considered drug-related.  In addition to new events, any increase in the severity or 
frequency of a pre-existing condition that occurs after the subject signs a consent form for 
participation is considered an AE.  This includes any side effect, injury, toxicity, or sensitivity 
reaction.  
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current IB or prescribing information for a marketed compound.  Also, 
reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs.  For example, an event more specific or more severe 
than described in the IB would be considered “unexpected”.    
Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
should be used to describe the event and for assessing the severity of AEs (see Appendix D).  
Any events representing a change in the CTCAE Grade need to be reported on the AE case 
report form.  This includes any change in laboratory values.   
For AEs not adequately addressed in the CTCAE, the severity Table 9 below may be used: 
 
 
 
 
 


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Table 9. Adverse Event Severity 
Severity 
Description 
GRADE 1 – Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
GRADE 2 – Moderate 
Moderate; minimal local or noninvasive 
intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). 
GRADE 3 – Severe 
Severe or medically significant but not life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limited self-care 
ADL. 
GRADE 4 – Life-threatening 
 Life-threatening consequences; urgent intervention 
indicated. 
GRADE 5 – Fatal 
Death related to AE. 
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history. 
9.2 
CAUSALITY 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:   
Yes:  The event is suspected to be related if:  
 there is a clinically plausible time sequence between onset of the AE and administration 
of study treatment; and/or 
 there is a biologically plausible mechanism for the study treatment to cause or contribute 
to the AE; and/or  
 the event responds to withdrawal of the study medication (dechallenge) and/or recurs 
with rechallenge (when clinically feasible); and/or 
 the AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, or 
procedures 
No:  
 the AE is more likely to be explained by the subject’s clinical state, underlying disease, 
concomitant medication, study or non-study procedure; and/or 
 the time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
 the event is unlikely to be related to the investigational product(s) 


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9.3 
ADVERSE EVENTS REPORTING PROCEDURES 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition or 
laboratory finding) with an onset date after the subject signs consent for study participation must 
be promptly documented on the appropriate summary.  Details of the event must include 
severity, relationship to study drug, duration, action taken, and outcome.  Serious adverse events 
(SAEs) will be recorded on the appropriate form. 
All AEs that are considered related to study drug must be followed to resolution or stabilization 
if improvement is not expected.  
AEs should be reported from the time the subject signs consent through 30 days post-last dose of 
study drug or initiation of a new anti-cancer therapy, whichever occurs first.  In addition, the 
Investigator should report any AE that may occur after this time period that is believed to have a 
reasonable possibility of being associated with study drug.  If a subject is registered but 
discontinues the study prior to receiving any study drug, AEs must be reported through the end-
of-study visit.  AEs which completely resolve and then recur should be recorded as a new AE.  
For subjects who complete the end of study visit less than 30 days following their last dose of 
study drug, a follow up of ongoing AEs should be attempted by telephone and documented in the 
subject’s source document.  AEs continuing at 30 days post-last dose should have a comment in 
the source document by the Investigator that the event has stabilized or is not expected to 
improve. 
The Principal Investigator is responsible for evaluating all AEs, obtaining supporting documents, 
and determining that documentation of the event is adequate.  Adverse events will be assigned a 
severity grade using the NCI-CTCAE grading scale v4.0.   
All Grade 3 and 4 adverse events must be recorded as AEs on the CRF.  Grade 1 and 2 adverse 
events should only be recorded if considered clinically significant by the Investigator. 
The Principal Investigator may delegate these duties to Sub-investigators and must ensure that 
these Sub-investigators are qualified to perform these duties under the supervision of the 
Principal Investigator and that they are listed on the FDA Form 1572.   


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9.4 
SERIOUS ADVERSE EVENTS DEFINITIONS 
An SAE is one that meets the following criteria:  
 Death 
 Life threatening experience defined as any adverse experience that places the subject, in the 
view of the Investigator, at immediate risk of death at the time of occurrence; i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of an existing hospitalization (except 
scheduled hospitalizations for non-acute, unrelated causes such as an elective surgery) 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect in the offspring of an exposed subject 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE, when, based upon appropriate medical judgment, 
it jeopardizes the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
Any death occurring within 30 days of the subject receiving study drug, regardless of the subject 
having discontinued from the study must be reported to the Sponsor as an SAE. 
9.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
All SAEs occurring from the time that the subject signs consent for study participation through 
30 days after the last administered dose of study drug will be reported.  All SAEs, regardless of 
relationship to study drug, must be followed to resolution or to stabilization if improvement or 
resolution is not expected. 
If a subject is permanently withdrawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report as well as the appropriate form for Study 
Discontinuation. 
The sponsor is responsible for notifying the appropriate Regulatory Agencies, when required, 
and in accordance with applicable laws and regulations of any Expedited Safety Reports.  
Generally, these are all SAEs that are judged to be unexpected and related to study drug(s), as 
specified in ICH E2B guidelines: Clinical Safety Data Management Data Elements for 
Transmission of Individual Case Safety Reports.   However, certain Regulatory Agencies may 
have additional requirements for expedited safety report submissions. 


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This submission of IND Safety Reports (North America) or Suspected Unexpected Serious 
Adverse Reactions (SUSARS [Europe]) will be cross referenced according to local regulations to 
Onyx Investigational Compound Number (IND, CSA, etc) at the time of submission.  
The Investigator is also responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), in accordance with local regulations, of all SAEs.   
Additionally, the Investigator is responsible for reporting adverse events to Onyx as described 
below: 
Expedited Reporting by Investigator to Onyx 
The Investigator must inform Onyx Drug Safety in writing by Fax at the contact information 
listed below of all Expedited Safety Reports submitted to the relevant Regulatory Agencies.  
These notifications should be performed in parallel to the Regulatory Agency submissions [e.g., 
within 7 calendar days for any Fatal or Life-threatening SUSARs and within 15 calendar days for 
all other SUSARs], but in no case any later than 1 business day from the submission date. This 
must be documented on a FDA 3500A MEDWATCH form.  This form must be completed and 
supplied to Onyx Drug Safety in English and accompanied by the global IST SAE Report Cover 
Page. 
The initial report must be as complete as possible, at a minimum including the serious adverse 
event term(s), patient identifier, date of awareness of the event, an assessment of the causal 
relationship between the event and the investigational product(s), and name of the reporter 
(investigator).  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-up 
FDA 3500A MEDWATCH form and submitted to Onyx Drug Safety in the same timelines as 
outlined above.  The Onyx protocol number (IST-CAR-536) and the institutional protocol 
number should be included on all reports to Onyx Drug Safety.   
All other serious adverse events regardless of drug causality will be reported to Onyx Drug 
Safety on a FDA 3500A Medwatch form no later than 30 days from the time the sponsor-
investigator becomes aware of the SAE.  Onyx reserves the right to review the CRFs or source 
documents in response to any inquiries by regulatory agencies that the sponsor may receive. 


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Onyx Drug Safety and Pharmacovigilance Contact Information: 
Drug Safety Hotline:     650.266.2501 
Drug Safety Fax:           1-805-480-9205 or US Toll Free 1-888-814-8653 
 
With Copy to: UAB CTNMO  
(Reference IST-CAR-536/UAB #XXXX) 
 
Fax: 
 
205-975-9875 
 
Phone:  
205-975-5387 
 
Email:  
 pamdixon@uab.edu 
 
9.6 
PREGNANCY 
If a subject or spouse or partner of a subject becomes pregnant while enrolled in this clinical trial 
or up to three months following administration of carfilzomib, Onyx Drug Safety must be 
notified within 24 hours of the Investigator, designee, or site personnel learning of the pregnancy 
(See Onyx Drug Safety and Pharmacovigilance Contact information above).  If the subject is 
pregnant, carfilzomib must be withheld.   
Subjects, spouses, or partners will be followed through the outcome of the pregnancy.  The 
Investigator will be required to report the results to Onyx Drug Safety. 
All pregnancies are considered a SAE and will require expedite reporting. Investigators will 
follow the outcome of the pregnancy for (spontaneous abortion,(any congenital anomaly detected 
in an aborted fetus is to be documented), stillbirth, neonatal death, or congenital anomaly.. 
 


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10 
STATISTICAL ANALYSIS 
10.1 
STUDY DESIGN 
The study has a phase I/IIa design.  The first phase I portion will be a standard 3+3 dose 
escalation study to include between 9 and 30 patients.  However, it is highly unlikely that 30 
patients will be enrolled (this would occur if dose expansion to 6 patients per level occurred at all 
of dose levels 0 through 4) and expected enrollment is expected to be 18 or fewer.  The phase IIa 
portion of the study will expand the MTD cohort (or cohort 4 if MTD not reached) to enroll a 
total of 28 patients using a single stage design.   Due to the 100 day lag between treatment and 
evaluation, an interim analysis for the primary endpoint is not feasible. 
10.2 
STUDY ENDPOINTS 
10.2.1 
PRIMARY ENDPOINTS 
Phase I – The primary endpoint in phase I is the occurrence of a dose-limiting toxicity as defined 
in section 3.1.1.1. 
Phase IIa – Rate of very good partial response (VGPR) + complete response (CR) in patients 
with relapsed MM treated with the melphalan + MTD of carfilzomib as determined in the phase I 
component of the study. 
10.2.2 
SECONDARY ENDPOINTS 
Phase I and IIa –  Pharmacodynamic effects of this combination at the proposed doses and 
schedule: changes in expression of Fanconi anemia/BRCA DNA repair genes and DNA 
fragmentation.  
Phase IIa – Rate of overall response, defined as CR+VGPR+PR (Appendix B). Rate of PFS 12 
months after AHSCT in the setting of carfilzomib + melphalan conditioning and carfilzomib 
maintenance therapy. Pharmacodynamic effect of  maintenance regimens A and B assessed by 
proteasome inhibition in peripheral blood mononuclear cells. Subject’s preference for regimens 
A and B.  Measurement of proteasome inhibition is described in section 3.6.   
 


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10.2.3 
SAFETY ENDPOINTS 
Both phase I and phase IIa, transplant component – Engraftment kinetics, described by the 
median time for neutrophil and platelet engraftment (as defined in section 3.1.1.1) and the rate of 
engraftment by day 30. Frequency and nature of grades 3 and 4 non-hematologic AEs and SAEs. 
Phase IIa, maintenance component – Frequency and nature of AEs and grades 3 and 4 AEs. 
10.3 
SAMPLE SIZE CONSIDERATIONS 
The phase I sample size is determined based on the occurrence of DLTs at each dose level and 
the expansions.  The minimum number of patients treated would be 6 (with 3 patients at each of 
dose levels 0 and -1) and the maximum would be 30 (with an expansion to 6 patients at each of 
dose levels 0 to 4).  These are both unlikely and it is expected that the number of patients treated 
in the phase I portion will be between 12 and 18.  
Patients will be enrolled in the phase 2 portion of the study to expand the MTD cohort (or cohort 
4 if MTD is not reached) in order to reach 28 patients.  There is little preliminary data to suggest 
a historical control response rate to the proposed treatment regimen.  As a result, we are choosing 
to enroll 28 patients in order to be able to estimate the response rate with sufficient precision.  
More specifically, N=28 provides a half width of <0.20 for the 95% confidence interval for any 
response rate.  This precision will provide sufficient information to determine if the regimen is 
sufficiently promising, in conjunction with the safety information learned in the phase IIa 
portion. 
The phase IIa maintenance portion of the study is included to describe additional endpoints 
including proteasome inhibition in two different regiments of treatment, and patient preference.  
There will be no hypothesis testing performed and so there is no power calculation.  No 
additional patients are enrolled specifically for the objectives addressed by the maintenance 
phase. 
10.4 
INTERIM AND SAFETY ANALYSIS  
 
There is no interim analysis in Phase IIa for futility or efficacy. However, there will be 
continuous monitoring for safety.  A sequential probability ratio test (SPRT) approach will be 


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used.  If there is strong evidence that the rate of grade 4 toxicities is 0.30 or above, as compared 
to a null rate of 0.15, the study will be stopped.  The stopping boundary is based on the 
likelihood ratio comparing the null rate of 0.30 versus the alternative rate of 0.15 using binomial 
likelihoods.  If the ratio favoring a rate of 0.30 (vs. 0.15) ever exceeds 10, then the study will be 
stopped.  A likelihood ratio of 10 is similar to a significance level of 0.05. The stopping criteria 
for this approach are listed in Table 10 below.   
 
Table 10.  Stopping criteria for early stopping due to excessive toxicity.  For example, if four 
of the first six patients experience a grade 4 toxicity, the study will be stopped.  The last 
boundary (9 grade 4 toxicities in 28 patients) would not stop the study (because the maximum N 
is 28); but at the end of the study, the treatment would be deemed to toxic to take to the next 
phase of research.  
Number of Grade 4 
toxicities 
Number of Patients 
Treated 
Observed toxicity 
rate 
Likelihood Ratio 
(favoring 30% 
toxicity rate) 
4 
6 
67% 
10.9 
5 
10 
50% 
12.1 
6 
15 
40% 
11.2 
7 
20 
35% 
10.3 
8 
24 
33% 
11.5 
9 
28 
32% 
12.8 
10.5 
PLANNED METHODS OF ANALYSIS 
The primary objective of the phase I portion of the study is determination of the maximum-
tolerated dose (MTD).  This will be determined based on the algorithmic dose finding approach 
where the highest dose at which 0 or 1 of 6 patients experiences a DLT is designated as the 
MTD.  The properties of this design are shown in Table 11 below where dose is escalated if 
either (a) 0 out of 3 evaluable patients experience a DLT, or (b) 1 out of 6 patients experience a 
DLT.   
 
 
 
 
 
 
 


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Table 11:  Probability of escalation based on true DLT rates ranging from 10% to 60%.  
We assume that DLT rates of 30% and below are acceptable.  For DLT rates that are 40% or 
greater, we have a relatively low chance of escalation, especially when the DLT rate is as high as 
50% or 60%.  
 
 
 
 
 
The primary objective of the phase IIa portion of the study is to estimate the response rate.  This 
will be done by estimating the proportion of patients who experience a response (defined above) 
with its 95% confidence interval. 
The secondary objectives of the study include describing toxicities in both the phase I and IIa 
portions, and describing the pharmacodynamics effects of the treatment in phase I and phase IIa.  
This will be done by tabulating toxicities by type and grade in each phase.  Pharmacodynamic 
measures will be quantified by changes in quantitative measures (e.g. expression) between 
baseline and follow-up.  These will be summarized using graphical displays and summary 
statistics.  PFS will be graphically displayed using Kaplan-Meier curves and 12 month PFS will 
be estimated with its 95% confidence interval. 
For those patients in the maintenance phase of the phase IIa portion of the study, proteasome 
inhibition will be treated as a continuous variable and summarized by treatment arm using 
graphical displays and summary statistics.  Preference for A vs. B and completion rates will be 
estimated by proportions with exact 95% confidence intervals.  Given that the number of patients 
in the maintenance portion of the study is expected to be small (20-22), hypothesis testing will 
not be performed to compare patients who receive A first versus those who receive B first. 
True DLT rate 
Probability of 
escalation 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 


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11 
INVESTIGATIONAL PRODUCT 
11.1 
CARFILZOMIB DESCRIPTION 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-
4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular formula is 
C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an inhibitor of the 
chymotrypsin-like activity of the 20S proteasome which leads to the accumulation of protein 
substrates within the cell and induction of apoptosis.   
11.2 
CARFILZOMIB FORMULATION 
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer 
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).   
11.3 
CARFILZOMIB STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions outlined in 
the separate Pharmacy Manual, in a securely locked area to which access is limited to 
appropriate study personnel. 
11.4 
CARFILZOMIB ACCOUNTABILITY 
Onyx, Inc. and the Investigator will maintain records of each shipment of investigational 
product.  The records will document shipment dates, method of shipment, batch numbers, and 
quantity of vials contained in the shipment.  Upon receipt of the investigational product, the 
designated recipient at the study site will inspect the shipment, verify the number and condition 
of the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection by representatives of UAB, 
Onyx and by regulatory authorities.  
Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must be 
readily available for inspection by representatives of UAB, Onyx and by regulatory authorities.  


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Only sites that cannot destroy unused drug on-site will be required to return their unused supply 
of investigational product. 
This study uses an Onyx-supported Interactive Response Technology System (IRT) for study 
drug ordering. Training will be provided to investigators and their designees at the different sites 
at or prior to study initiation visit. 
11.5 
MELPHALAN DESCRIPTION 
Melphalan (L-phenylamine mustard, L-PAM, L-Sarcolysin) is an alkylating agent coupled to an 
amino acid. The molecular formula is C13H18C12N2O2 and the molecular weight is 305. 
11.6 
 MELPHALAN FORMULATION 
Melphalan is commercially available and supplied as a sterile, freeze-dried powder. Each vial 
contains 50 mg melphalan hydrochloride and the inactive ingredient, povidone 20 
mg.  Reconstitute per manufacturer instructions using the diluent provided.  Further dilution and 
administration may be done per institutional standards. The manufacturer recommends 
completion of administration of melphalan within 60 minutes of reconstitution.  
 
11.7 
MELPHALAN STORAGE 
 The intact packages of melphalan for intravenous administration should be stored at room 
temperature (15 - 30°C) protected from light.  Shelf life surveillance of the intact dosage form is 
ongoing.  
 
11.8 
MELPHALAN SUPPLIER 
Intravenous melphalan is commercially available for purchase by a third party. Its use in the 
clinical setting addressed by this protocol (high dose chemotherapy and autologous 
hematopoietic stem cell transplantation) is standard of care practice.  


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12 
REGULATORY OBLIGATIONS 
12.1 
INFORMED CONSENT 
The investigator will obtain written informed consent from all participating patients or their 
authorized representatives.  Obtaining informed consent must be done according to International 
Conference on Harmonization- Good Clinical Practice Guidelines (ICH GCP). Copies of the 
signed document will be given to the patient and filed in the Investigator’s study file, as well as 
the patient’s medical record if in conformance with the institution’s Standard Operating 
Procedures. 
12.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
Institutional Review Board (IRB) or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB or Ethics Committee.  Before 
the investigational drug is shipped to the Investigator, the Investigator or designee will provide 
Onyx with a copy of the IRB or Ethics Committee approval letter stating that the study protocol 
and any subsequent amendments and informed consent form have been reviewed and approved. 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics Committee 
reapproval throughout the duration of the study.  Copies of the Investigator’s annual report to the 
IRB or Ethics Committee and copies of the IRB or Ethics Committee continuance of approval 
must be provided to Onyx as follows: 
Onyx Inc. 
Regulatory Department 
2100 Powell St. 
Emeryville, CA 94608 
 
 


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With copy to: UAB CTNMO  
Name: Pamela Dixon 
Address: 1824 6th Avenue South; WTI 110C; Birmingham, AL 35294 
Phone No: 205- 975-5387  
Fax No: 205-975-9875   
Email Address: pamdixon@uab.edu  
The Investigator is also responsible for notifying their IRB or Ethics Committee of any 
significant adverse events that are serious and/or unexpected. 
Onyx will provide study sites with any expedited safety reports generated from any ongoing 
studies with carfilzomib, changes to the Investigator’s Brochure, and any other safety 
information which changes the risk/benefit profile of carfilzomib during the conduct of the study, 
to allow him/her to fulfill his/her obligation for timely reporting to the IRB/ECs and other 
Investigators participating in the study. 
Upon completion of the trial, the Investigator must provide the IRB or Ethics Committee and 
Onyx with a summary of the trial’s outcome. 
 
12.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
Participating study sites cannot begin enrollment until an initiation letter has been issued from 
the UAB CTNMO. Each center is required to participate in an initiation conference call. 
Before the start of this study and the shipment of study drug to a participating study site, the 
following documents must be on file at UAB CTNMO. Participating sites will be responsible for 
forwarding the initiation documents toUAB CTNMO.  
All start-up documents can be submitted via electronic mail to pamdixon@uab.edu or via fax at 
(205) 975-9875. Please ensure that the fax cover page clearly identifies the site, study identifier 
and is addressed to ATTN: UAB CTNMO.  
 
 


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These documents are required to be submitted by each participating center:   
1. U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal 
Investigator at the participating center. 
2. The names of any sub-investigators at the participating center must appear on e 
1572.  Investigators must also complete all regulatory documentation as required 
by local regulations. This includes any required human subjects training required 
by the site’s local IRB. 
3. Current curricula vitae and documentation of professional licensure of the 
Principal Investigator and sub-investigators listed on the 1572. 
4. Resumes and human subject protections documentation (e.g. NIH, CITI) for all 
research personnel (e.g. study coordinators, data managers and other research 
personnel).  
5. A signed and dated investigator brochure acceptance form.  
6. Written documentation of IRB approval of protocol (identified by title, protocol 
version and date of approval) for each site. 
7. IRB approved study informed consent and HIPAA consent form. HIPAA consent 
language can be included within the study informed consent. Please note that all 
informed consent forms should be reviewed and approved by the UAB CTNMO 
prior to submission to the site’s designated IRB. 
8. A signed Confidentiality Agreement.  
9. A signed Clinical Trial Agreement for each site.  
10. Laboratory certifications (CAP, CLIAs) and laboratory reference value ranges for 
each laboratory listed on the site’s 1572. 
11. The UAB CTNMO site specific forms as specified in the investigator-initiated 
multicenter manual.  


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12.4 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that medical 
information be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by Onyx, its 
designee, the FDA and/or other applicable regulatory authority.  The access may consist of trial-
related monitoring, audits, IRB or Ethics Committee reviews, and FDA inspections. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health Information, 45 CFR 164.508. 


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13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
13.1 
PROTOCOL AMENDMENTS AND STUDY COMPLETION 
13.1.1 PROTOCOL AMENDMENTS 
No modifications will be made to the protocol without the agreement of the sponsor-investigator. 
Changes that significantly affect the safety of the patients, the scope of the investigation, or the 
scientific quality of the study will require Institutional Review Board approval prior to 
implementation, except where the modification is necessary to eliminate apparent immediate 
hazard to human subjects.  Any departures from the protocol must be fully documented in the 
protocol deviation case report form and the source documentation.  
13.1.2 STUDY COMPLETION 
The following data and materials are required by UAB CTNMO and Onyx before a study can be 
considered complete or terminated: 
1. Copies of protocol amendments and IRB approval/notification, if appropriate. 
2. Copies of the IRB final report, documentation of submission to the IRB.  
3. A summary of the study prepared by the Principal Investigator (Study report, 
manuscript and/or abstract). 
4. All regulatory documents (e.g., updated curriculum vitae for each Principal 
Investigator, updated U.S. FDA Form 1572 for each site). 
13.2 
STUDY DOCUMENTATION AND ARCHIVE 
13.2.1 DATA RECORDING  
The Clinical Research Coordinator and Investigator will be responsible for the recording of all 
data on the Case Report Forms (CRFs).  
The Investigator will provide access to his/her original records to permit a representative from 
the funding or auditing institution(s) to verify the proper transcription of data.  Data submission 
will be electronically via the REDCap database.  


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13.2.2 RECORD RETENTION 
Federal law requires that an Investigator maintain all study records for two years after the 
investigation is discontinued. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
13.3.1 MONITORING 
UAB CTNMO will be responsible for the monitoring of study patient data and records. 
Monitoring will be performed centrally. All monitoring reports will be kept by the UAB 
CTNMO to ensure that all reports are contained in a central study file. The CTNMO manager or 
UAB internal auditor will be responsible for conducting the review of monitoring packets. A 
final monitoring report will be generated and issued to the site and will be kept in the central 
study file by the UAB CTNMO. The UAB CTNMO will be responsible for forwarding the final 
monitoring reports to the UAB Data Safety Monitoring Committee (DSMB) for review. 
13.3.1.1 
Frequency of Reviews 
The each patient at each participating center will have their eligibility criteria reviewed prior to 
enrollment by the UAB CTNMO.  
During the course of the study, each site will be selected for an audit by the UAB Quality 
Assurance Committee approximately once a year. Audit will include 100% of the subjects 
enrolled at the site. In addition to the once yearly QA audit, monitoring for each patient entered 
into this trial will be 100%. Sites are to send source information on each patient to the UAB 
CTNMO office where a shadow chart will be maintained on each subject for this trial.  Source 
will be verified to data entered into the RedCap database.  
13.3.2 PROTOCOL DEVIATIONS AND SAFETY REPORTING 
A Protocol Deviation is any variance from the protocol involving a subject or subjects that is not 
approved by the IRB prior to its initiation or implementation, and occurs when a member of the 
study team departs from the IRB-approved protocol in any way without the investigator first 
obtaining IRB approval. 


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Any protocol deviation or serious adverse event will be reported by the subsite within 10 days of 
notification. Protocol Deviations will be reported by completion of the hard copy Protocol 
Deviation Report form.  Serious Adverse Events will be reported by completion of a MedWatch 
3500A form and hard copy Serious Adverse Event form. For both Protocol Deviations and 
Serious Adverse Events, all required forms and any supporting clinical documentation should be 
submitted to the UAB CTNMO office within 10 days of notification.  
13.3.3 DATA SAFETY MONITORING BOARD 
The University of Alabama Comprehensive Cancer Center Data Safety Monitoring Board will 
have oversight of the protocol. The UAB CCC DSMB will meet at a minimum on a monthly 
basis to discuss hematology related trials.  
In addition, all protocol deviations and SAEs as defined above will be reviewed by the UAB 
CCC DSMB for review during the DSMB monthly meetings. The coordinating center will 
review protocol deviation and SAE events for form completion and provide assistance in 
communicating to the subsite if more information is warranted. The UAB CTNMO will report 
the event report to the UAB CCC DSMB so that the information can be reviewed at the next 
available DSMB meeting. During the DSMB review, the DSMB can make recommendations for 
any further study action.  
 
13.3.4 DATA COLLECTION  
Data collection will be managed by the UAB CTNMO staff via the study database which is 
housed and maintained at the Hollings Cancer Center along with the MUSC datacenter.  The 
majority of study data will be reported by electronic case report forms in the REDCap database. 
A description of the data collected within the REDCap system includes information regarding 
the administration of study drug, adverse events, response assessments, safety evaluations per the 
protocol study calendar and patient relevant and current medical history.   
 
REDCap is a secure, web application designed to support data capture for research studies, 
providing user-friendly web-based case report forms, real-time data entry validation (e.g. for data 
types and range checks), audit trails and a de-identified data export mechanism to common 
statistical packages (SPSS, SAS, Stata, R/S-Plus).   The system was developed by a multi-


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institutional consortium which includes MUSC and was initiated at Vanderbilt University.  The 
database is hosted at the MUSC Datacenter.  The system is protected behind a login and Secure 
Sockets Layer (SSL) encryption. Data collection is customized for each study or clinical trial 
based on a study-specific data dictionary defined by the research team with guidance from the 
SCTR Informatics REDCap administrator at MUSC. 
 
Time sensitive information such as patient registration, serious adverse events reporting, and 
protocol deviation reporting will be collected via completed hard copy form. These forms are 
available from the UAB CTNMO. . Information collected will be reviewed and processed by the 
UAB CTNMO. 
The data will be initially reviewed for quality assurance purposes to identify any discrepancies or 
missing data. The staff of the UAB CTNMO will notify the participating site of any data queries 
and manage the overall data quality of the study. If data received relates to a serious adverse 
event or protocol deviation, the information will be processed for report to the UAB CCC DSMB 
for review. The sponsor- investigator, Luciano Costa, MD and the assigned MUSC statistician, 
Elizabeth Garrett-Mayer, PhD will also have access to study data for quality assurance and 
analysis purposes. During the course of the study, data quality will be monitored by random 
inspection of the completed forms by a designated monitor.  Any problems detected will be 
discussed with the PI. If necessary, re-training of data collectors will be conducted. 
All data should be substantiated by clinical source documents organized within a patient research 
record. ICH Good Clinical Practices are to be followed.  The study will be subject to a yearly 
internal audit via the UAB CCC Quality Assurance Committee at a minimum and audits may 
occur more frequently at the request of the QA Committee.  


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14 
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Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of 
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Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell 
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Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in 
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Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose 
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Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront 
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Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and 
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Knop S, Liebisch P, Wandt H, et al. Bortezomib, IV  cyclophosphamide, and 
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Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologous 
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17. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose 
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Kumar SK, Flinn I, Noga SJ, et al. Bortezomib, dexamethasone, cyclophosphamide 
and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from 
the multicenter EVOLUTION study. Leukemia. 
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Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible 
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Arastu-Kapur S, Shenk K, Parlati F, Bennett MK. Non-Proteasomal Targets of 
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Kirk CJ, Jiang J, Muchamuel T, et al. The Selective Proteasome Inhibitor Carfilzomib 
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Bross PF, Kane R, Farrell AT, et al. Approval summary for bortezomib for injection in 
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Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L, Goy A. Phase 1 Single Agent 
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Carfilzomib (PR-171) in Hematologic Malignancies. ASH Annual Meeting Abstracts. 
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24. 
Jagannath S, Vij R, Stewart K, et al. Final results of PX-171-003-A0, part 1 of an open-
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refractory multiple myeloma (MM). J Clin Oncol. 2009;27(15S):8504. 
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Wang L, Siegel D, Kaufman JL, et al. Updated Results of Bortezomib-Naive Patients 
in PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) 
in Patients with Relapsed or Refractory Myeloma (MM). ASH Annual Meeting Abstracts. 
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Siegel D, Wang L, Orlowski RZ, et al. PX-171-004, An Ongoing Open-Label, Phase 
II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma 
(MM); Updated Results From the Bortezomib-Treated Cohort. ASH Annual Meeting Abstracts. 
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Niesvizky R, Wang L, Orlowski RZ, et al. Phase Ib Multicenter Dose Escalation Study 
of Carfilzomib Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and 
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Badros AZ, Vij R, Martin T, et al. Phase I Study of Carfilzomib in Patients (Pts) with 
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Kropff M, Liebisch P, Knop S, et al. DSMM XI study: dose definition for intravenous 
cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in 
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San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and 
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32. 
Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-
dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial 
S9321. J Clin Oncol. 2006;24(6):929-936. 
33. 
Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral 
blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of 
a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131-3136. 
34. 
Cook G, Liakopoulou E, Pearce R, et al. Factors Influencing the Outcome of a Second 
Autologous Stem Cell Transplant (ASCT) in Relapsed Multiple Myeloma: A Study from the 
British Society of Blood and Marrow Transplantation Registry. Biol Blood Marrow 
Transplant. 2011. 
35. 
Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as 
conditioning regimen before autologous stem cell transplantation in patients with de novo 
multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 
2010;115(1):32-37. 
36. 
Hather GJ, Mackey H. Some notable properties of the standard oncology Phase I 
design. J Biopharm Stat. 2009;19(3):543-555. 
37. 
Costa LJ, Landau H, Venkata JK, et al. Phase 1 Trial Of Carfilzomib + High Dose 
Melphalan Conditioning Regimen Prior To Autologous Hematopoietic Stem Cell 
Transplantation (AHSCT) For Relapsed Multiple Myeloma. Blood. 2013;122(21):3329-3329. 
38. 
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia. 2009;23(1):3-9. 


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APPENDIX A:  NCI-CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the  
National Cancer Institute (NCI) v4.0 
 
Publish Date:  June 14, 2010 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


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APPENDIX B:  RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
 
 
Response category 
Criteria 
Stringent complete  
response (sCR)    
 
• CR as defined below plus all of the following  
• Normal serum FLC ratio   
• Absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence 
Complete response (CR) 
• Negative immunofixation of the serum and 
urine   
• If only the measurable non-bone marrow 
parameter was  FLC,  
normalization of FLC ratio  
• < 5% plasma cells in bone marrow   
• Disappearance of any soft tissue 
plasmacytomas. 
 
Very good partial  
response (VGPR) 
• PR as defined below plus all of the following:  
• Serum and urine M-component detectable by 
immunofixation but not on  
electrophoresis or  
• If at on study, serum measurable, ≥ 90% or 
greater reduction in serum M-  
component   
• Urine M-component <100 mg per 24 hour 
Partial response (PR) 
One of the following: 
• If serum and urine measurable, ≥ 50% 
reduction of serum M-protein and reduction in 
24-hour urinary M-protein by ≥ 90% or to < 200 
mg per 24 hour. 
• If only serum measurable (but urine not), a ≥ 
50% reduction of serum M-protein. 
• If urine measurable (but serum not), a 
reduction in 24-hour urinary M-protein by ≥ 
90% or to < 200 mg per 24 hour. 
• If only the measurable non-bone marrow 
parameter was  FLC, a ≥ 50% decrease in the 
difference between involved and uninvolved 
FLC  
levels  or a 50% decrease in level of involved 
FLC with 50% decrease in ratio  
• If the bone marrow was only measurable 
parameter, ≥ 50% reduction in bone marrow 
plasma cells is required in place of M-protein,  
provided baseline percentage was ≥ 30%  
• In addition to the above criteria, if  a 
plasmacytoma is present at baseline, ≥  
50% reduction in the size of soft tissue 
plasmacytomas is also required. 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 88 of 97 
Stable Disease (SD) 
Not meeting criteria for CR, VGPR, PR or PD 
 
Progressive Disease (PD) 
Increase of 25% from lowest response value in 
any of the following: 
• Serum M-component (absolute increase must 
be > 0.5 g/dL), and/or 
• Urine M-component (absolute increase must 
be > 200mg/24 h), and/or 
• Only in patients without measureable serum 
and urine M-protein levels: the difference 
between involved and uninvolved FLC levels 
(absolute increase must be > 10mg/dL) 
• Only in patients without measureable serum 
and urine M protein levels and without 
measurable disease by FLC levels, bone marrow 
PC percentage (absolute percentage must be 
10%) 
• Definite development of new bone lesions or 
soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft 
tissue plasmacytomas 
• Development of hypercalcemia (corrected 
serum calcium > 11.5 mg/dL) that can be 
attributed solely to the PC proliferative disorder 
 
 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 89 of 97 
APPENDIX C:  PATIENT PREFERENCE QUESTIONNAIRE 
(see next page) 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 90 of 97 
PATIENT PREFERENCE QUESTIONNAIRE 
Version date April 15, 2013 
 
Patient Study ID: 101669- _______________ Date of Completion (MM-DD-YYY): ___________ 
 
To be completed by the patient: 
During your maintenance treatment period, you were given the study drug- carfilzomib in 
two different ways (or regimens). Below is the description of two ways carfilzomib was 
provided to you during the previous cycles. We would like to get your opinion of which 
regimen you liked best. Based on your response, your doctor will complete the remaining 
eight cycles of treatment based on the treatment regimen you like best. Please answer the 
questions below. There are no wrong or right answers.  
 
Regimen A:  
 The study drug carfilzomib was 
given at a dose of 36mg/m2 infused 
over 30 minutes. 
 The days of treatment happened on 
days 1, 8, 15 every 28 days.  
Regimen B: 
 The study drug carfilzomib was given 
at a dose of carfilzomib 36mg/m2 
infused over 30 minutes.  
 The days of treatment happened on 
days 1, 2, 15 and 16 every 28 days. 
Question 1. Please mark beside the statement below that best fits you. (select only one) 
______ I liked Regimen A the best. 
_____ I liked Regimen B the best. 
Question 2: Circle the response below to describe how strongly you liked the regimen 
you chose above. 
 
    5                              4                            3                            2                            1 
I strongly liked this                                   I liked this regimen                                               I liked both  
over the other.                                                 over the other                                          regimens almost equally. 
                                                                                                                                     It was hard for me to choose.   
Question 3: Can you describe why you chose the regimen over the other? 
 
 
 
Signature of the participant: ___________________________ Date completed: __________ 
To be completed by the study personnel: 
Name of study personnel administering form: _______________________________ 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 91 of 97 
APPENDIX D:  QUALITY OF LIFE QUESTIONNAIRE (QLQ-C30) 
(see next page) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 92 of 97 
THE QLQ-C30 VERSION 3.0  
 
PT STUDY NUMBER: 101669 - __ __ __ __ __ - __ __ 
 
DATE COMPLETED (MM/DD/YYY):______________ 
 
WE ARE INTERESTED IN SOME THINGS ABOUT YOU AND YOUR HEALTH. PLEASE ANSWER ALL OF 
THE QUESTIONS YOURSELF BY CIRCLING THE NUMBER THAT BEST APPLIES TO YOU. THERE ARE NO 
“RIGHT” OR “WRONG” ANSWERS. THE INFORMATION THAT YOU PROVIDE WILL REMAIN STRICTLY 
CONFIDENTIAL. 
 
 
 
Not at 
all 
 
A 
little 
 
Quite 
a bit 
 
Very 
Much 
 
1. Do you have any trouble doing strenuous 
activities, like carrying a heavy shopping 
bag or a suitcase? 
 
 
1 
2 
3 
4 
2. Do you have any trouble taking a long 
walk? 
 
 
1 
2 
3 
4 
3. Do you have any trouble take a short walk 
outside of the house? 
 
 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during 
the day? 
 
 
1 
2 
3 
4 
5. Do you need help with eating, dressing, 
washing yourself or using the toilet? 
 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
During the past week: 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
6. Were you limited in doing either your work 
or other daily activities? 
 
 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies 
or other leisure time activities? 
 
 
1 
2 
3 
4 
8. Were you short of breath? 
 
 
1 
2 
3 
4 
9. Have you had pain? 
 
 
1 
2 
3 
4 
10. Did you need rest? 
 
 
 
 
 
 
1 
2 
3 
4 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
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Confidential 
 
November 21, 2014 
 
Page 93 of 97 
During the past week: 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
11. Have you had trouble sleeping? 
 
 
1 
2 
3 
4 
12. Have you felt weak? 
 
 
1 
2 
3 
4 
13. Have you lacked appetite? 
 
 
1 
2 
3 
4 
14. Have you felt nauseated? 
 
 
1 
2 
3 
4 
15. Have you vomited? 
 
 
1 
2 
3 
4 
16. Have you been constipated? 
 
 
1 
2 
3 
4 
17. Have you had diarrhea? 
 
 
1 
2 
3 
4 
18. Were you tired? 
 
 
1 
2 
3 
4 
19. Did pain interfere with you daily activities? 
 
 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on 
things, like reading a newspaper or 
watching television? 
 
 
1 
2 
3 
4 
21. Did you feel tense? 
 
 
1 
2 
3 
4 
22. Did you worry? 
 
 
1 
2 
3 
4 
23. Did you feel irritable? 
 
 
1 
2 
3 
4 
24. Did you feel depressed? 
 
 
1 
2 
3 
4 
25. Have you had difficulty remembering 
things? 
 
 
1 
2 
3 
4 
26. Has your physical condition or medical 
treatment interfered with your family life? 
 
 
1 
2 
3 
4 
27. Has your physical condition or medical 
treatment interfered with your social 
activities? 
 
 
1 
2 
3 
4 
28. Has your physical condition or medical 
treatment caused you financial difficulties? 
 
 
1 
2 
3 
4 
 
 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 94 of 97 
 
FOR THE FOLLOWING QUESTIONS PLEASE CIRCLE THE NUMBER BETWEEN 1 AND 7 THAT BEST 
APPLIES TO YOU 
 
29. How would you rate your overall health during the past week? 
 
1 
Very poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
Very poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 95 of 97 
APPENDIX E:  QUALITY OF LIFE QUESTIONNAIRE (QLQ-MY20) 
(see next page) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE EORTC QLQ-MY20 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 96 of 97 
PT STUDY NUMBER: 101669 - __ __ __ __ __ - __ __ 
 
DATE COMPLETED (MM/DD/YYY):______________ 
 
PATIENTS SOMETIMES REPORT THAT THEY HAVE THE FOLLOWING SYMPTOMS OR PROBLEMS.  
PLEASE INDICATE THE EXTENT TO WHICH YOU HAVE EXPERIENCED THESE SYMPTOMS OR 
PROBLEMS DURING THE PAST WEEK.  PLEASE ANSWER BY CIRCLING THE NUMBER THAT BEST 
APPLIES TO YOU. 
 
 
During the past week: 
 
 
Not at 
all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
31.  Have you had bone aches or pain? 
 
 
1 
2 
3 
4 
32.  Have you had pain in your back? 
 
 
1 
2 
3 
4 
33.  Have you had pain in your hip? 
 
 
1 
2 
3 
4 
34. Have you had pain in your arm or 
shoulder? 
 
 
1 
2 
3 
4 
35. Have you had pain in your chest? 
 
 
1 
2 
3 
4 
36. If you had pain did it increase with activity? 
 
 
1 
2 
3 
4 
37. Did you feel drowsy? 
 
 
1 
2 
3 
4 
38. Did you feel thirsty? 
 
 
1 
2 
3 
4 
39. Have you felt ill? 
 
 
1 
2 
3 
4 
40. Have you had a dry mouth? 
 
 
1 
2 
3 
4 
41. Have you lost any hair? 
 
 
1 
2 
3 
4 
42. Answer this question only if you lost any 
hair:  Were you upset by the loss of your 
hair? 
 
1 
2 
3 
4 
43. Did you have tingling hands or feet? 
 
1 
2 
3 
4 
44. Did you feel restless or agitated? 
 
1 
2 
3 
4 
During the past week: 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
45. Have you had acid indigestion or heartburn? 
 
 
1 
2 
3 
4 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA  
Confidential 
 
November 21, 2014 
 
Page 97 of 97 
46. Have you had burning or sore eyes? 
 
 
1 
2 
3 
4 
47. Have you felt physically less attractive as a 
result of your disease or treatment? 
 
 
1 
2 
3 
4 
48. Have you been thinking about your illness? 
 
 
1 
2 
3 
4 
49. Have you been worried about dying? 
 
 
1 
2 
3 
4 
50. Have you worried about your health in the 
future? 
 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE 
MYELOMA- Statistical Plan 
 
Confidential 
 
November 21, 2014 
 
Page 1 of 5 
1 
STATISTICAL ANALYSIS 
1.1 
STUDY DESIGN 
The study has a phase I/IIa design.  The first phase I portion will be a standard 3+3 dose 
escalation study to include between 9 and 30 patients.  However, it is highly unlikely that 30 
patients will be enrolled (this would occur if dose expansion to 6 patients per level occurred 
at all of dose levels 0 through 4) and expected enrollment is expected to be 18 or fewer.  The 
phase IIa portion of the study will expand the MTD cohort (or cohort 4 if MTD not reached) 
to enroll a total of 28 patients using a single stage design.   Due to the 100 day lag between 
treatment and evaluation, an interim analysis for the primary endpoint is not feasible. 
1.2 
STUDY ENDPOINTS 
1.2.1 
PRIMARY ENDPOINTS 
Phase I – The primary endpoint in phase I is the occurrence of a dose-limiting toxicity as 
defined in section 3.1.1.1. 
Phase IIa – Rate of very good partial response (VGPR) + complete response (CR) in patients 
with relapsed MM treated with the melphalan + MTD of carfilzomib as determined in the 
phase I component of the study. 
1.2.2 
SECONDARY ENDPOINTS 
Phase I and IIa –  Pharmacodynamic effects of this combination at the proposed doses and 
schedule: changes in expression of Fanconi anemia/BRCA DNA repair genes and DNA 
fragmentation.  
Phase IIa – Rate of overall response, defined as CR+VGPR+PR (Appendix B). Rate of PFS 
12 months after AHSCT in the setting of carfilzomib + melphalan conditioning and 
carfilzomib maintenance therapy. Pharmacodynamic effect of  maintenance regimens A and 
B assessed by proteasome inhibition in peripheral blood mononuclear cells. Subject’s 
preference for regimens A and B.  Measurement of proteasome inhibition is described in 
section 3.6.   


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE 
MYELOMA- Statistical Plan 
 
Confidential 
 
November 21, 2014 
 
Page 2 of 5 
 
1.2.3 
SAFETY ENDPOINTS 
Both phase I and phase IIa, transplant component – Engraftment kinetics, described by the 
median time for neutrophil and platelet engraftment (as defined in section 3.1.1.1) and the 
rate of engraftment by day 30. Frequency and nature of grades 3 and 4 non-hematologic AEs 
and SAEs. 
Phase IIa, maintenance component – Frequency and nature of AEs and grades 3 and 4 AEs. 
1.3 
SAMPLE SIZE CONSIDERATIONS 
The phase I sample size is determined based on the occurrence of DLTs at each dose level 
and the expansions.  The minimum number of patients treated would be 6 (with 3 patients at 
each of dose levels 0 and -1) and the maximum would be 30 (with an expansion to 6 patients 
at each of dose levels 0 to 4).  These are both unlikely and it is expected that the number of 
patients treated in the phase I portion will be between 12 and 18.  
Patients will be enrolled in the phase 2 portion of the study to expand the MTD cohort (or 
cohort 4 if MTD is not reached) in order to reach 28 patients.  There is little preliminary data 
to suggest a historical control response rate to the proposed treatment regimen.  As a result, 
we are choosing to enroll 28 patients in order to be able to estimate the response rate with 
sufficient precision.  More specifically, N=28 provides a half width of <0.20 for the 95% 
confidence interval for any response rate.  This precision will provide sufficient information 
to determine if the regimen is sufficiently promising, in conjunction with the safety 
information learned in the phase IIa portion. 
The phase IIa maintenance portion of the study is included to describe additional endpoints 
including proteasome inhibition in two different regiments of treatment, and patient 
preference.  There will be no hypothesis testing performed and so there is no power 
calculation.  No additional patients are enrolled specifically for the objectives addressed by 
the maintenance phase. 
1.4 
INTERIM AND SAFETY ANALYSIS  
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
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Confidential 
 
November 21, 2014 
 
Page 3 of 5 
There is no interim analysis in Phase IIa for futility or efficacy. However, there will be 
continuous monitoring for safety.  A sequential probability ratio test (SPRT) approach will be 
used.  If there is strong evidence that the rate of grade 4 toxicities is 0.30 or above, as 
compared to a null rate of 0.15, the study will be stopped.  The stopping boundary is based 
on the likelihood ratio comparing the null rate of 0.30 versus the alternative rate of 0.15 using 
binomial likelihoods.  If the ratio favoring a rate of 0.30 (vs. 0.15) ever exceeds 10, then the 
study will be stopped.  A likelihood ratio of 10 is similar to a significance level of 0.05. The 
stopping criteria for this approach are listed in Table 10 below.   
 
Table 10.  Stopping criteria for early stopping due to excessive toxicity.  For example, if 
four of the first six patients experience a grade 4 toxicity, the study will be stopped.  The last 
boundary (9 grade 4 toxicities in 28 patients) would not stop the study (because the 
maximum N is 28); but at the end of the study, the treatment would be deemed to toxic to 
take to the next phase of research.  
Number of Grade 4 
toxicities 
Number of Patients 
Treated 
Observed toxicity 
rate 
Likelihood Ratio 
(favoring 30% 
toxicity rate) 
4 
6 
67% 
10.9 
5 
10 
50% 
12.1 
6 
15 
40% 
11.2 
7 
20 
35% 
10.3 
8 
24 
33% 
11.5 
9 
28 
32% 
12.8 
1.5 
PLANNED METHODS OF ANALYSIS 
The primary objective of the phase I portion of the study is determination of the maximum-
tolerated dose (MTD).  This will be determined based on the algorithmic dose finding 
approach where the highest dose at which 0 or 1 of 6 patients experiences a DLT is 
designated as the MTD.  The properties of this design are shown in Table 11 below where 
dose is escalated if either (a) 0 out of 3 evaluable patients experience a DLT, or (b) 1 out of 6 
patients experience a DLT.   
 
 
 
 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE 
MYELOMA- Statistical Plan 
 
Confidential 
 
November 21, 2014 
 
Page 4 of 5 
 
 
 
 
Table 11:  Probability of escalation based on true DLT rates ranging from 10% to 60%.  
We assume that DLT rates of 30% and below are acceptable.  For DLT rates that are 40% or 
greater, we have a relatively low chance of escalation, especially when the DLT rate is as 
high as 50% or 60%.  
 
 
 
 
 
The primary objective of the phase IIa portion of the study is to estimate the response rate.  
This will be done by estimating the proportion of patients who experience a response 
(defined above) with its 95% confidence interval. 
The secondary objectives of the study include describing toxicities in both the phase I and IIa 
portions, and describing the pharmacodynamics effects of the treatment in phase I and phase 
IIa.  This will be done by tabulating toxicities by type and grade in each phase.  
Pharmacodynamic measures will be quantified by changes in quantitative measures (e.g. 
expression) between baseline and follow-up.  These will be summarized using graphical 
displays and summary statistics.  PFS will be graphically displayed using Kaplan-Meier 
curves and 12 month PFS will be estimated with its 95% confidence interval. 
For those patients in the maintenance phase of the phase IIa portion of the study, proteasome 
inhibition will be treated as a continuous variable and summarized by treatment arm using 
graphical displays and summary statistics.  Preference for A vs. B and completion rates will 
be estimated by proportions with exact 95% confidence intervals.  Given that the number of 
patients in the maintenance portion of the study is expected to be small (20-22), hypothesis 
True DLT rate 
Probability of 
escalation 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 


PHASE I/IIa STUDY OF CARFILZOMIB + HIGH DOSE MELPHALAN AS PREPARATIVE REGIMEN 
FOR AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE 
MYELOMA- Statistical Plan 
 
Confidential 
 
November 21, 2014 
 
Page 5 of 5 
testing will not be performed to compare patients who receive A first versus those who 
receive B first.