Conditions: Hematologic Malignancies Relapse Graft-Versus-Host Disease
Keywords: Allogeneic Transplantation Carfilzomib Relapse Graft-Versus-Host Disease Multiple Myeloma Lymphoma Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 53
Healthy volunteers: no

Brief summary:
The investigators hypothesize that adding carfilzomib to standard conditioning regimen for allo-HCT for advanced or high-risk hematologic malignancies will decrease post-transplant relapse and treatment-related mortality by decreasing severe GVHD, leading to overall improvement in transplant outcomes.

Detailed description:

Arms:
arm 1: Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7.

Interventions: intervention 1: Carfilzomib intervention 2: Tacrolimus
Intervention descriptions: intervention 1: Carfilzomib will be administered starting at dose level 1 (20 mg/m2 IV) on day +1, +2, +6 and +7.

Dose escalation will be performed on the day +6 and day +7 doses only in each dose level. Day +1 and day+2 doses will be fixed at 20 mg/m2 IV in all dose levels. intervention 2: Tacrolimus will be administered at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL INFORMATION 
Study Title: 
Investigator-Initiated Trial 
Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and Graft-versus-host Disease 
in Allogeneic Hematopoietic Cell Transplantation for High-risk Hematologic Malignancies 
Institution Name: 
University of Michigan 
Principal Investigator Information: 
Name: 
Attaphol Pawarode, M.D. 
 
 
Address: 
 
 
Phone No: 
 
Fax No: 
 
Email Address: 
 
Co-Investigators: 
 
 
 
 
 
  
Blood and Marrow Transplantation Program 
Divisions of Hematology/Oncology 
Departments of Internal Medicine, Pediatrics and Statistics 
University of Michigan 
Statistician: 
 Professor of Biostatistics, Department of
Statistics University of Michigan 
Research Coordinator: 
 
Data Manager: 
 
Address: 
 
  
NCT02145403
Protocol version date:  08/24/2018 


Contracting  Person: 
Name: 
 
Address: 
 
 
 
Protocol version date:  08/24/2018 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
3 
 
 
 
PROTOCOL  SYNOPSIS 
TITLE: 
Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and Graft-versus- 
host Disease in Allogeneic Hematopoietic Cell Transplantation for High-risk 
Hematologic  Malignancies 
OBJECTIVES: 
Primary Objective: To determine whether the addition of carfilzomib to 
fludarabine-based 
conditioning 
chemotherapy, 
followed 
by 
allogeneic 
hematopoietic cell transplant for hematologic malignancies will decrease 
relapse/progression and severe graft-versus-host disease (GVHD). 
Secondary  Objectives:  To  determine  the  efficacy  of  this  regimen  in  the 
improvement of overall transplant outcomes. 
STUDY DESIGN: 
Phase 1 Dose Finding: 3+3 design, 4 dose levels 
[20, 27, 36, 45 mg/m2] on day +1, +2, +6, +7 
Phase 2 Efficacy Testing: expansion of the optimal dose level 
STUDY  POPULATION: 
Adult patients with hematologic malignancy requiring allogeneic hematopoietic 
cell transplantation 
 
INCLUSION 
CRITERIA: 
 
 
 
 
 
 
 
EXCLUSION 
CRITERIA: 
1. Age: ≥18 and ≤70 years old at the time of transplant admission (<71 years) 
2. A 8/8 or 7/8 HLA–matched donor is available 
3. Hematologic malignancies requiring allogeneic hematopoietic cell 
transplantation 
4. Adequate cardiac [LVEF≥0.4], pulmonary [FEV1, FVC, corrected DLCO ≥ 
50% predicted], hepatic [DB ≤1.5xULN, AST/ALT ≤3xULN] and renal 
function [GFR≥60 mL/min/1.73 m2] and Karnofsky PS ≥70%. 
5. Prior autologous hematopoietic cell transplant (s) allowed 
 
1. Progressive disease 
2. Active central nervous system involvement by malignancy 
3. Active or uncontrolled infection 
4. Life expectancy <6 months 
5. Serious cardiac conditions: congestive heart failure NYHA class III and IV, 
uncontrolled or persistent atrial fibrillation/flutter, history of ventricular 
fibrillation, ventricular tachycardia/torsade de pointes or myocardial 
infarction within the last 6 months 
6. HIV-1/HIV-2 or HTLV-1/HTLV-2 seropositivity 
7. Active hepatitis A, B or C infection 
8. 
History of pulmonary hypertension 
PROCEDURES: 
Allogeneic hematopoietic cell transplantation using standard fludarabine-based 
conditioning regimen and tacrolimus/methotrexate graft-versus-host disease 
[GVHD] prophylaxis 
 
STUDY TREATMENT: 
Adding Carfilzomib to the above regimen on day +1, +2, +6, +7. 
 
PRIMARY ENDPOINT 
Event-free survival at 1 year 
[Event is defined as relapse/progression or grade III-IV acute GVHD or chronic 
GVHD requiring systemic treatment] 
SECONDARY 
ENDPOINTS: 
 
 
STATISTICAL 
METHODS: 
Progression/Relapse-free survival [PFS/RFS], overall survival [OS], regimen- 
related toxicity (RRT), graft failure, treatment-related mortality (TRM), acute 
GVHD and chronic GVHD 
Molecular Correlates: PD [proteasome inhibition], GVHD,cytokines 
Dose finding: a 3+3 dose escalation method 
Chi-square test [categorical variables], t-test [continuous variables] 
Kaplan-Meier model [Survival], Cox-Regression, Competing-Risk Regression 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
4 
 
 
TREATMENT SCHEMA 
Subjects will be admitted to in-patient BMT unit and receive a standard fludarabine-based 
conditioning regimen,,followed by an allo-HCT, with the addition of carfilzomib per the schema: 
 
Carfilzomib will be administered starting at dose level 1 (20 mg/m2  IV) on Day +1, +2, +6 and 
+7, based on the phase 1/2 carfilzomib studies and the previous Dana Farber phase 1 safety 
experience on the addition of a proteasome inhibitor into a fludarabine-based conditioning 
regimen. 
 
Dexamethasone 4 mg will be administered IV prior to each dose of 20 or 27 mg/m2 carfilzomib. 
Dexamethasone 8 mg will be administered IV prior to each dose of 36 or 45 mg/m2 carfilzomib. 
 
Dose escalation of the phase 1 part will follow the standard 3+3 model. 
Dose Level 
Carfilzomib (mg/m2) 
Day +1 
Day +2 
Day +6 
Day +7 
1 
20 
20 
20 
20 
2 
20 
20 
27 
27 
3 
20 
20 
36 
36 
4 
20 
20 
45 
45 
Standard BMT Procedure 
 
Fludarabine and Busulfan [FluBu2 or FluBu4] 
Fludarabine 40 mg/m2/day IV x 4 on day -5 to day -2 
Busulfan 3.2 mg/kg/day IV x 2 on day -5 to day -4 [FluBu2] or 
Busulfan 3.2 mg/kg/day IV x 4 on day -5 to day -2 [FluBu4 
 
Fludarabine and Melphalan (FluMel140 or FluMel180) 
Fludarabine 30 mg/m2/day IV x 4 on day -5 to day -2 
Melphalan 140 mg/m2 IV x 1 on day -1 [FluMel140] or 
Melphalan 180 mg/m2 IV x 1 on day -1 [FluMel180] 
 
Fludarabine, Cyclophosphamide, Rituximab (FCR) 
 
    Rituximab 375 mg/m2/day IV x 4 on days -13, -6, +1 and +8 
              Fludarabine 30 mg/m2/day IV x 3 on day -5 to day -3 
              Cyclophosphamide 750 mg/m2/day IV x 3 on day -5 to day -3 
 
Low-dose total body irradiation (TBI) at 200 cGy x 1 or anti-thymocyte globulin/thymoglobulin 
may be used in transplants using a 7/8 HLA matched donor per institutional guidelines. 
    Ritumximab may be used in patients with CD20+  B cell malignancies per institutional guidelines. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
5 
TABLE OF CONTENTS 
TITLE PAGE 
1 
PROTOCOL  SYNOPSIS 
3 
TREATMENT  SCHEMA 
4 
TABLE OF CONTENTS 
6 
1. 
INTRODUCTION 
1.1 
ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION [HCT] 
1.1.1 
Allogeneic HCT for Hematologic Malignancies 
9 
1.1.2 
Acute Graft-versus-Host Disease (aGVHD) 
9 
1.1.3 
Lymphoid Malignancies and Allogeneic HCT 
9 
1.1.3.1 Non-Hodgkin’s Lymphoma (NHL) and HCT 
9 
1.1.3.2 Hodgkin’s Lymphoma (HL) and HCT                                   10 
1.1.3.3 Multiple myeloma and allo-HCT                                            10 
1.1.4 
Myeloid Malignancies and Allogeneic HCT                                        11 
1.2 
PROTEASOME                                                                                                11 
1.3 
PROTEASOME  INHIBITORS 
1.3.1 
Bortezomib and immunomodulatory effect 
12 
1.3.2 
Bortezomib use after allogeneic HCT 
13 
1.3.3 
Bortezomib and GVHD Prophylaxis 
13 
1.4 
CARFILZOMIB 
1.4.1 
Carfilzomib Preclinical Antitumor Activity  
14 
1.4.2 
Carfilzomib Toxicology Studies 
14 
1.4.3 
Phase 1 Experience with Carfilzomib as a Monotherapy 
14 
1.4.4 
Phase 2 Experience with Carfilzomib as a Monotherapy 
15 
1.4.5 
Experience with Carfilzomib in Combination with Lenalidomide 
17 
1.4.6 
Experience with Carfilzomib in Combination with Chemotherapy 
17 
1.4.7 
Experience with Carfilzomib in Combination with High-dose 
Chemotherapy and Hematopoietic Cell Transplant 
18 
1.4.8 
Dosing Rationale 
19 
1.5 
STUDY RATIONALE 
20 
1.6 
HYPOTHESIS 
21 
2. 
OBJECTIVES 
2.1 
PRIMARY  OBJECTIVE 
21 
2.2 
SECONDARY  OBJECTIVES 
21 
2.3 
PRIMARY  ENDPOINT 
21 
2.4 
SECONDARY  ENDPOINTS 
21 
3. 
EXPERIMENTAL  DESIGN 
3.1 
STUDY DESIGN 
21 
3.2 
NUMBER OF CENTERS 
21 
3.3 
NUMBER OF SUBJECTS 
21 
3.4 
ESTIMATED STUDY DURATION 
21 
3.5 
TREATMENT  PROCEDURE 
3.5.1 
Transplant Schema 
22 
3.5.2 
Standard Conditioning Regimens 
22 
3.5.2.1 Fludarabine and Busulfan 
22 
3.5.2.2 Fludarabine and Melphalan 
22 
3.5.2.3 Fludarabine, Cyclophosphamide and Rituximab (FCR)  
22 
3.5.2.4 Other Chemo-immunologic Agent 
22 
3.5.3 
Hematopoietic Cell Transplantation 
23 
3.5.4 
GVHD Prophylaxis 
23 
3.5.5 
Carfilzomib 
23 
3.5.6 
Filgrastim 
24 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
6 
3.5.7 
Infection  Prophylaxis 
24 
3.5.8 
Allogeneic 
Hematopoietic 
Stem 
Cell 
Mobilization 
and 
Apheresis 
Procedure for Related Donors 
 
 
 
 
 
24 
3.5.8.1 Stem Cell Source 
24 
3.5.8.2 Stem Cell Mobilization and Collection 
24 
3.5.8.3 Donor Lymphocyte Infusion [DLI] 
24 
4. 
SUBJECT  SELECTION 
4.1 
INCLUSION  CRITERIA 
25 
4.2 
EXCLUSION  CRITERIA 
26 
5. 
SUBJECT  ENROLLMENT 
5.1 
REGISTRATION  PROCEDURE 
26 
5.2 
STUDY  DEFINITIONS 
27 
6. 
TREATMENT  PROCEDURE 
6.1 
DRUG PREPARATION AND ADMINISTRATION 
28 
6.1.1 
Study Drug Carfilzomib 
28 
6.1.2 
Standard Transplantation Drugs 
6.1.2.1 
Fludarabine 
29 
6.1.2.2 
Busulfan 
29 
6.1.2.3 
Melphalan 
30 
6.1.2.4      Cyclophosphamide 
 
 
 
 
   31 
6.1.2.5      Rituximab  
 
 
 
 
 
   32 
 
6.1.2.6 
Tacrolimus 
33 
6.1.2.7 
Methotrexate 
33 
6.1.2.8 
Levetiracetam 
34 
6.1.2.9 
Filgastrim 
35 
6.2 
DEFINITION OF DOSE-LIMITING TOXICITY 
36 
6.3 
DOSE WITHHOLD AND RESTART 
36 
 
6.4 
SAFETY  CONSIDERATIONS 
 
 
 
 
 
  36 
6.4.1 
Contraindications 
37 
6.4.2 
Special Warnings and Precautions for Use 
37 
6.4.3 
Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia 
37 
6.4.4 
Pulmonary  Complications 
37 
6.4.5 
Infusion Reactions 
37 
6.4.6 
Tumor Lysis Syndrome 
38 
6.4.6.1 
Guidelines for Monitoring, Prophylaxis, and Treatment of Tumor 
Lysis Syndrome (TLS) 
38 
6.4.6.2 
Hydration and Fluid Monitoring 
38 
6.4.6.3 
Clinical and Laboratory Monitoring 
38 
6.4.6.4 
Management of Tumor Lysis Syndrome 
38 
6.4.7 
Hepatic toxicity and Hepatic Failure 
38 
6.4.8 
Embryo-fetal  Toxicity 
39 
6.5 
CONCOMITANT  MEDICATIONS 
6.5.1 
Required Concomitant Medications 
39 
6.5.2 
Optional and Allowed Concomitant Medications 
39 
6.5.3 
Excluded Concomitant Medications 
39 
7. 
STUDY TESTS AND OBSERVATIONS 
7.1 
REQUIRED  OBSERVATIONS 
39 
7.2 
DEFINITIONS OF END POINTS 
7.2.1 
Safety End Points 
40 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
7 
7.2.2 
Efficacy End Points 
41 
7.3 
CORRELATIVE  STUDIES 
7.3.1 
Pharmacodynamic (PD) Assay 
42 
7.3.2 
Plasma GVHD Cytokine Assay 
43 
8. 
STUDY  DISCONTINUATION 
8.1 
STOPPING RULE FOR EXCESSIVE GRAFT FAILURE 
43 
8.2 
STOPPING RULE FOR EXCESSIVE MORTALITY 
43 
9. 
ADVERSE EVENTS 
9.1 
ADVERSE EVENT REPORTING 
45 
9.2 
DEFINITIONS  OF  ADVERSE  EVENTS  WITH  COMMERCIALLY  AVAILABLE 
AGENTS 
45 
9.3 
DEFINITIONS OF ADVERSE EVENTS WITH INVESTIGATIONAL AGENTS 
45 
9.4 
CAUSALITY 
46 
9.5 
REQUIRED ADVERSE EVENT REPORTING 
46 
9.6 
HEMATOLOGIC  TOXICITY  AND  DEFINITION  OF  PRIMARY  ENGRAFTMENT 
FAILURE 
47 
9.7 
SERIOUS ADVERSE EVENT REPORTING PROCEDURES 
47 
9.8 
DATA SAFETY MONITORING BOARD (DSMB) 
48 
10. 
STATISTICAL  ANALYSIS 
10.1 
STUDY DESIGN 
48 
10.2 
SAMPLE SIZE CONSIDERATIONS 
48 
10.3 
PLANNED METHODS OF ANALYSIS 
49 
10.3.1 Primary and Secondary Outcomes 
49 
10.3.2 Laboratory  Correlates 
49 
10.4 
SAFETY ANALYSIS 
49 
11. 
INVESTIGATIONAL  PRODUCT 
11.1 
CARFILZOMIB  DESCRIPTION 
49 
11.2 
FORMULATION 
49 
11.3 
STORAGE 
49 
11.4 
ACCOUNTABILITY 
50 
12. 
REGULATORY  OBLIGATIONS 
12.1 
INFORMED  CONSENT 
50 
12.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
50 
12.3 
PRE-STUDY  DOCUMENTATION  REQUIREMENTS 
51 
12.4 
SUBJECT  CONFIDENTIALITY 
51 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
51 
13.2 
STUDY DOCUMENTATION AND ARCHIVE 
51 
13.3 
STUDY MONITORING AND DATA COLLECTION 
51 
13.3.1 Subject Safety 
51 
13.3.2 Lack of Efficacy 
52 
14. 
REFERENCES 
53 
15. 
APPENDICES 
APPENDIX A 
66 
APPENDIX B 
67 
APPENDIX C 
81 
APPENDIX D 
86 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
9 
1. INTRODUCTION 
 
1.1 
ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION 
 
1.1.1 
Allogeneic Hematopoietic Cell Transplant for Hematologic Malignancies 
Chemotherapy and novel targeted agents have a curative potential for patients with standard and low- 
risk hematologic malignancies. However, high-risk and advanced relapsed/refractory diseases remain 
incurable with these modalities. Few effective therapies exist for patients with high-risk disease. Since 
immune tolerance to cancer plays a major role in cancer pathogenesis, allogeneic hematopoietic cell 
transplantation (allo-HCT), which is considered the most potent immunotherapy via the graft-versus- 
tumor (GVT) effect, is the only treatment option with a curative potential or the one which may provide a 
prolonged progression-free survival.[1-6] 
 
The major obstacles for the success of allo-HCT are graft-versus-host disease (GVHD) and relapse. 
Myeloablative HCT was first explored >30 years ago but its use resulted in a very high early transplant-
related mortality (TRM) from direct regimen-related toxicities (RRT) and severe acute graft- versus-host 
disease (aGVHD).[7-11] The attempts to improve transplant outcomes and to expand this option to 
ineligible elderly population and to those with comorbidities with the development of reduced-intensity 
HCT resulted in an increase in relapse, despite a decrease in TRM and regimen- related toxicity, and 
thus there was no improvement  in  overall  outcome.[12-16]  Moreover,  acute GVHD rates did not 
decrease but were only delayed in onset.[17] 
 
1.1.2 
Acute Graft-versus-Host Disease (aGVHD) 
Acute GVHD is an allo-immune reaction of donor allo-reactive T-cells against normal host tissues and 
contributes significantly to post-transplant morbidity and mortality [18,19]. It remains a major obstacle of 
success for both myeloablative and reduced-intensity HCTs, with cumulative incidences [CI] of 40- 50% 
for grade II-IV and 10-20% for severe grade III-IV aGVHD in related donor HCTs. The frequency and 
severity of aGVHD is higher in unrelated donor HCTs, with the CIs of 50-60% for grade II-IV and 20% 
for grade III-IV aGVHD.[20-27] In addition to the increased risk of serious  life-threatening infections 
from the use of systemic high-dose steroids and more potent immunosuppressive therapy, most 
aGVHD therapies do not have differential suppressive effects on GVHD and graft versus tumor (GVT) 
and thus obviously have a deleterious effect on the latter. Consequently, the risk of primary disease 
relapse increases. As a result, prevention of severe aGVHD is of critical importance for the success of 
allo-HCT. 
 
Our University of Michigan experience on allo-HCT using a fludarabine and busulfan conditioning in 
patients with acute myeloid leukemia (AML) revealed the CIs of grade II-IV and grade III-IV aGVHD of 
45% and 10% in the related donor HCT setting, and 50% and 10-15% in the unrelated HCT setting, 
respectively. [28,29] 
 
1.1.3 
Lymphoid Malignancies and Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) 
 
1.1.3.1 Non-Hodgkin’s Lymphoma (NHL) and Allo-HCT 
NHL is a heterogeneous group of malignancy of the lymphoid organs.[31] It is the seventh leading site of 
new cancer cases among men and women, accounting for 79,190 new cancer cases and 20,130 
cancer-related deaths in 2012.[32] Effective treatments are very limited for primary refractory or 
advanced chemotherapy-resistant NHLs of any histologic types, and new treatment approaches are 
needed.[33-40] 
 
In addition to anti-lymphoma effect, myeloablative allo-HCT provides an alloimmune donor  T-cell reaction 
against lymphoma (GVL effect).[41-46] Several studies of myeloablative allo-HCT reported a 
significantly low relapse rate compared to that with  HDT/ASCT.[31,36-57]  Unfortunately,  this 
observations  occurred  at  the  expense  of  unacceptably  high  TRM,  particularly  GVHD  and  regimen- 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
10 
 
related toxicity, resulting in similar OS to that from HDT/ASCT.[36,58,59] The degree of tissue injury after 
conditioning regimen correlates the severity of GVHD,[60-62] which has high impact on TRM.[62-64] To 
decrease TRM and expand eligible candidates  for  allo-HSCT,  reduced-intensity HSCT has been 
extensively explored during the past 10 years.[61,65-76] Fludarabine is a potent immunosuppressive agent 
with less toxicity, compared with high-dose cyclophosphamide in myeloablative conditioning, and has 
replaced the latter in fludarabine-based regimens e.g. fludarabine/Busulfan [22] and 
fludarabine/Melphalan.[77] However, the relapse rate increased due to the less intensity of the regimen and 
thus progression-free survival (PFS) and overall survival (OS) did not improve .[31,36-57,58,65-76] . 
 
Allogeneic HSCT for NHLs at University of Michigan 
During 1996-2012, we performed 120 (82 myeloablative and 38 fludarabine-based)  allo-HCTs  on patients 
with relapsed/refractory or advanced diffuse large B cell NHL, which constituted the majority of lymphoma 
patients undergoing allo-HCT at University of Michigan. The 3-yearOS and PFS) were 40% and 38 % for 
myeloablative transplant []Blue] and 18% and 15% only for  fludarabine-based transplant [Green][Figure 1], 
indicating relapse was the major problem after allo-HCT, especially fludarabine-based transplant. These 
results were consistent with the literature. 
 
 
 
 
 
 
 
 
 
 
 
 
1.1.3.2 Hodgkin’s Lymphoma (HL) and Allo-HCT 
Figure 1: Kaplan-Meier 
estimates of overall 
survival and progression 
free survival for DLBCL 
patients undergoing 
myeloablative non- 
fluadarine-based  (n=82; 
Blue) and fludarabine- 
based (n=38; Green) 
allogeneic HCTs at 
University of Michigan. 
[unpublished data] 
Approximately 80% of HL patients are cured with standard chemotherapy with/without radiotherapy and 
those who relapse may still then be salvaged with HDT/ASCT, resulting in durable response in 40-50% of 
relapsed and 25-40% of  primary  refractory  patients,  respectively.[78-81]  Unfortunately, very limited 
effective treatment options are available for patients who relapse after HDT/ASCT. Even though, several 
series reported the existence of graft-versus-HL effect, outcomes of myeloablative allo-HCT have remained 
disappointing due to the unacceptable TRM as high as 43-61%.[46,82-87]. Reduced-intensity allo-HCT has 
been used in patients with relapsed HL after autologous HSCT, but the outcomes are not promising.[76,88-
101]. Most series demonstrated the existence of graft-vs HL effect, but still noted high relapse rate and TRM. 
Novel approach to decrease relapse after allo-HCT is needed to improve outcome of advanced refractory HL 
in this unfortunate young population. 
 
1.1.3.3 Multiple Myeloma and Allo-HCT 
The American Cancer Society has estimated 22,350 new  cases  of  multiple  myeloma  (MM)  in  the 
United States in 2013.[32] MM is a clonal neoplastic proliferation of plasma cells and is considered 
chronic and incurable, with current novel chemo-biologic targeted agents. In the previous conventional 
chemotherapy era, the median overall survival was ~4-5 years for average-risk patients while this has 
been estimated to be much improved to >7 years in the current targeted  therapy  era.[102-108] 
However, outcomes of high-risk or advanced MM therapy remains poor, with a median survival only 
~8-14 months after therapy.[109-113]. 
 
The current standard therapy for MM consists of 3 phases: 1) primary induction therapy 2) 
consolidative high-dose melphalan/ASCT and 3) post-transplant  maintenance  therapy.[114]  Despite 
these  measures,  relapse  or  progression  during  maintenance  therapy  is  inevitable.  Few effective 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
11 
 
treatment options are available for advanced relapsed or refractory MM. In addition, MM with certain 
cytogenetic abnormalities (t(4;14), t(14;16), (14:20), 17p-, 13- by conventional karyotyping, complex 
karyptype and hypodiploidy) and plasma cell leukemia are associated with an extremely poor prognosis, with 
a median survival of 8-14 months post HDT/ASCT.[109-113] Certain novel targeted agents e.g. bortezomib 
have been shown to overcome resistance of some types of high-risk MMs [115,116] but none is proven to be 
curative or to provide meaningful long-term MM control. 
 
The use of myeloablative allo-HCT for advanced MM resulted in very high early TRM up to 50% in the first 6 
months post transplant.[117] However, those who had survived subsequently enjoyed a sustained long-term 
MM control and likely a cure of MM. Attempts have been made to reduce TRM by the use of reduced-
intensity allo-HCT; however, the success was at the expense of increasing MM relapse, thus resulting in no 
improvement of overall outcomes.[6,118-120]. To improve MM control, HDT/ASCT was incorporated prior to 
reduced-intensity allo-HCT (tandem auto-allo HCTs). As expected, auto-allo transplant patients experienced 
increased TRM but a trend towards a better MM control and no definite improvement in the overall 
survival.[5,121-123] 
 
University of Michigan (UM) experience on allo-HCT for high-risk MMs 
Between 2008-2011, UM BMT program enrolled 22 patients  with  high-risk  or  advanced  MM  on  a phase 
2 study using the fluadarabine and busulfan x 4 (FluBu4).[30] TRMs were very low (19% at 1 year), with 
similar rates of GVHD, compared with those reported in the literature.[6,118-120] However, relapse rates 
remained high. There was no improvement in OS [40% 3-year OS and 5% 3-year PFS;, Figure 2], similar to 
those reported in the literature.[6,118-120] 
 
Figure 2: Kaplan-Meier 
estimates of overall 
survival and progression 
free survival for high-risk 
multiple myeloma 
patients undergoing 
fluadarbine-basd allo- 
HCTs at University of 
Michigan [30] 
 
 
1.1.4 
Myeloid Malignancies and Allo-HCT 
Myeloid malignancies constitute the majority of hematologic diseases requiring HCT due to the strong 
evidence of potent graft-versus-tumor effect.[8] In addition, as in the case of lymphoid malignancies, allo-
HCT is the only treatment option, which may offer a curative potential or long-term survival for patients with 
high-risk or advanced relapsed/refractory myeloid malignancies. [1,7-11] One-year relapse-free survival in 
elderly patients with very high-risk AML at UM was ~50% only.[28,29] 
 
1.2 
PROTEASOME 
The proteasome-ubiquitin system is a multi-catalytic 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.[124-128] 
Proteasome activity has an important a role in promoting constitutional activation of survival pathways in 
some cancer cells. In the NF-κB transcription factor pathway, this effect is mediated by 1) the degradation of 
the inhibitory chaperone IκB, thus releasing the active p50/p65 hetero-dimer, in the classic pathway or 2) the 
degradation of the inactive substrates precursor p100 and p105 into the active p50 and p52, respectively, in 
the alternative pathway. The resultant transcription homo- and hetero-dimers translocate into nucleus where 
they bind to NF-κB binding sites of the target genes. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
12 
 
Proteasome inhibition leads to the accumulation of inhibitory IκB within MM cells with relatively increased 
constitutive NF-κB transciption factor expression, resulting in the selective induction of apoptosis in MM 
cells, while sparing most normal cells. The down-regulation of NF-κB transcription factors inhibits 
interleukin-6 (IL-6) production and causes direct apoptosis of MM cells. In addition, this leads to an 
indirect anti-angiogenesis effect, contributing to anti-tumor activity.[126-128] 
 
In addition to its important role in tumor survival, NF-κB transcription factor system is pivotal in T cell 
function.[129-132] NF-κB pathway expression is increased in activated T  cells,  compared  with  the resting 
counterparts. The activation through T-cell receptor/CD3/co-stmulating molecules results in translocation 
of NF-κB transcription factor complex into nucleus, leading to increased Th1 and Th17 cytokine 
signaling and T-cell activation and proliferation.[131-132] Moreover, the activated NF-κB pathway 
promotes antigen-presenting dendritic  cell  function  -  antigen  uptake  through  phagocytosis and the 
response to activating cytokines.[133-134] Lastly, proteasome activity is important in maintaining 
activated B cell survival. BIM, which induces apoptosis of activated B cells, is degraded by 
proteasome. Thus, proteasome inhibition results in increased level of BIM and shortened survival of 
activated B cells.[135] 
 
1.3 
PROTEASOME INHIBITORS 
Bortzomib is a first-generation dipeptide boronic acid which reversibly inhibits the chymotrypsin-like 
(CT-L) activity of the 20s proteasomes of  the  ubiquitin-proteasome  pathway.  Bortezomib  has  anti- 
tumor activity in pre-clinical and clinical settings in various hematologic malignancies especially 
lymphoid cancers.[136-143] Bortezomib is currently used in the therapy  for  MM,  with  a  potential superior 
activity to other targeted agents for high-risk refractory disease. 
 
In addition, a few series reported the safety of its use after allogeneic HCT as either maintenance or 
salvage therapy for relapse.[144-147] Unlike lenalidomide, which was found to increase GVHD, the 
use of bortezomib post-allo-HCT did not appear to do so. Interestingly, some patients with a baseline 
severe refractory chronic GVHD  improved or resolved with bortezomib therapy. This indicated that 
bortezomib might have immunomodulatory property, in addition to anti-tumor effect.[147] 
 
Bortezomib also has anti-tumor activity in other lymphoid malignancies, especially mantle cell 
lymphoma,[148-154] and myeloid malignancies.[155-161] It has been used in combination with other 
chemotherapeutic and/or immuno-biologic agents in phase 2 and 3 trials.[149-153, 156-158] More 
importantly, it has been also incorporated into high-dose melphalan  conditioning  chemotherapy  in 
various fashions.[162-165] These were feasible, without excess toxicities or effects on engraftment or 
other transplant-related events. However, no clear clinical benefits were seen in this approach. 
 
A phase 1 study by Massachusette General Hospital of the addition of bortezomib to a standard 3+7 
induction regimen, idarubicin and cytarabine in 31 patients with very high-risk myeloid malignancies 
(22 patients older than 60 years, 8 had therapy-related or secondary AML/MDS). Bortezomib was 
dosed as standard full cycle scheduling on day1, 4, 8 and 11.[160] The MTD was 1.5 mg/m2, which 
was higher than 1.3 mg /m2 standard dose for lymphoid malignancies in chronic therapy. The CR and 
CRi rates were 61% and 10%, respectively in this high-risk population. 
 
1.3.1 Proteasome Inhibitors and Their Immunomodulatory Effect 
The NF-κB transcription factor system is pivotal in activated T cell function. Activation of membrane 
receptors leads to cytoplasmic proteasome degradation of the inhibiting chaperone, IκB [classical pathway] 
or the precursor NF-κB transcription factors into active NF-κB transcription dimmers [alternative pathway]. 
Activated NF-κB transcription dimers subsequently  translocate  into  nucleus where they bind to NF-κB 
binding sites and initiate target gene transcription.[129-132] NF-κB pathway expression is increased in 
activated T cells, compared with the resting counterparts. The activation through T-cell receptor/CD3/co-
stmulating molecules results in translocation  of  NF-κB  transcription factor complex into nucleus, leading to 
increased Th1 cytokine signaling and T-cell activation and proliferation.[130-132] Moreover, the activated 
NF-κB pathway promotes antigen-presenting dendritic cell function- antigen uptake through phagocytosis 
and the response to activating cytokines. [133-134]


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
13 
 
  Bortezomib has been shown to inhibit T cell and dendritic cell functions via abrogating  NF-κB     
 mediating transcription pathway by inhibition of proteasome degredation. In addition, the inhibition of  
 IL-6 production promotes TGF-β induced regulatory T cell (Treg) differentiation.[131] Of note,Treg  plays  
a pivotal role in modulating GVHD.[60] 
 
Based on the above, bortezomib appears to have immunomodulatory effect toward abrogation  of 
activated alloreactive T-cell and dendritic function, which plays a pivotal role in  pathogenesis  of aGVHD. 
In addition, bortezomib has been shown to inhibit alloreactive B cells through the stimulation of Bim, 
which triggers B-cell apoptosis. Bim signaling is up-regulated in activated B lymphocytes and is 
degraded by proteasome. Moreover, Bim is down-regulated by BAFF, which, in turn, promotes B- cell 
survival and maturation. High BAFF level was detected in patients with chronic GVHD. [135] 
 
1.3.2 Proteasome Inhibitor Use After Allo-HCT 
Unlike lenalidomide, the use of bortezomib post-allo-HCT did not increase GVHD. Some cases with baseline 
severe refractory chronic GVHD improved with bortezomib therapy. This was likely due to its 
immunomodulatory effect through promoting Treg proliferation and differentiation and inhibition of allo- 
reactive antigen presenting dendritic cells and B-cells as stated above.[130-135] 
 
1.3.3 Proteasome Inhibitor and GVHD Prophylaxis 
Based on its immuno-modulatory property against alloreactive T cell and dendritic cells, bortezomib 
was tested in a mouse model for GVHD prevention.[166-167] Bortezomib was administered daily from 
day 0-3 and was able to protect severe acute GVHD in a fully-H2  mismatched  HCTs,  without impairing 
engraftment. For a less severe mismatched setting,  it  protected  100%  of  mice  against GVHD while 
preserving graft-versus-tumor effect. However, when bortezomib  was  given  in  a  later period (day 12-
14), it increased mortality from severe gastrointestinal (GI) GVHD in mice.[167] 
 
Based on this very promising pre-clinical data, Dana Faber Cancer Institute group conducted a phase 
1/2 study of bortezomib GVHD prophylaxis in a very high-risk patient cohort for developing severe 
GVHD.[168] All the 45 patients with advanced hematologic malignancies received a 1 or 2 HLA- 
mismatched unrelated transplant with a standard reduced-intensity fludarabine/busualfan conditioning 
and tacrolimus/methotrexate GVHD prophylaxis. The phase 1 part identified the same standard dose 
of bortezomib for primary MM therapy, 1.3 mg/m2, given at day 1, 4 and 7, as the optimal dose level. 
This was the dose used in the standard schedule [Day 1, 4, 8, 11 of a 3- or 4-week cycle) in chronic 
therapy. The day-11 dose was omitted due to the preclinical data showing  increased  GI  GVHD mortality 
with delay administration in a mouse model. The tacrolimus, methotrexate and bortezomib GVHD 
prophylaxis was well-tolerated, with no grade 3/4 toxicities attributed  to  bortezomib.  The median 
(range) neutrophil and platelet engraftment time were 13 (6-29) and 20 (13-27) days, respectively. The 
engraftment was robust, with  day-30  and  day-100  donor  chimerism  of  97%  and 99%. With the 
median follow-up time of 36 months, cumulative grade II-III and grade III acute GVHD were 22% and 
7% respectively. Of note, there were no grade IV GVHDs occurring and the 1-year cumulative 
incidence of chronic GVHD was 29% only, resulting in a TRM of 9% only in this cohort receiving a 
very high–risk mismatched unrelated transplant. The 1-year PFS and OS were impressive at 60% and 
76% respectively. In summary, the addition of the proteasome inhibitor bortezomib to standard GVHD 
prophylaxis regimen was safe and feasible, with unexpectedly impressive low rates of GVHD and TRM. 
 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
14 
 
1.4 
CARFILZOMIB 
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. When measured against a broad panel of proteases including 
metallo, aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-targeted non-
proteasomal proteases when compared to bortezomib.[169-174] 
 
1.4.1 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-hour exposure to carfilzomib is associated with potent 
cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived cell lines in culture.[169,170,175] 
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 
lines.[169,170,175] 
 
The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice implanted with various 
tumor cell lines. In addition to MM,[175] carfilzomib  has  been  shown  to  have  anti-tumor activity against 
other hematologic malignancies.[176,177] It is synergistic with histone deacetylase inhibitors in tumor 
killings.[178,179] 
 
1.4.2 Carfilzomib Toxicology Studies 
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies, carfilzomib was tested in rats and 
monkeys as two two-week cycles of QDx5 days.[180]. When administered 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  bortezomibA  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 IV push or an IV  infusion.  The  DLTs  of carfilzomib 
in both the rat and monkey 28 day GLP toxicity studies included toxicity to the GI tract, bone marrow, 
pulmonary, and cardiovascular systems. No behavioral or histopathological signs of neurotoxicity were 
observed, and carfilzomib does not cross the blood-brain barrier. 
 
In 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 
tumors [3]. Tolerability was excellent, with no evidence of neurotoxicity, observed even at high doses. This is 
in stark contrast to that observed with bortezomib.[181,182] DLTs included effects on the GI, renal, 
pulmonary, and cardiovascular systems and appeared to related to Cmax effects. Of note, neutropenia was 
not observed; rather, transient neutrophilia was seen following acute dosing. Renal, cardiovascular and GI 
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 achieve 
with bortezomib at its MTD on a less intensive schedule. 
 
1.4.3 
Phase 1 Experience with Carfilzomib As A Monotherapy 
In the Phase 1 PX-171-002 study testing carfilzomib in subjects with relapsed/refractory hematologic 
malignancies,[183,184]36 subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
15 
 
cycle. Subjects with advanced  MM,  NHL,  Waldenström’s  macroglobulinemia,  and  Hodgkin’s Lymphoma 
(HL) were enrolled on the study. 
 
No dose limiting toxicities (DLTs) were observed in the initial 7 cohorts (1.2 to 15 mg/m2 ). At the 20 mg/m2 
dose level, 1/8 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, 1/6 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  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, 3/5 subjectsexperienced an increase in serum creatinine to Grade 2 (including 
the subject with the DLT). This elevation was rapidly reversible and all 3 subjects were re-challenged 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 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. 
 
Of the 36 evaluable patients enrolled in PX-171-002, 20  subjects  had  MM.[183,184]  Four  MM patients 
achieved a partial response (PR), 1/2 at the 15 mg/m2 dose, 1/6 at the 20 mg/m2 dose, and 2/5 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 mononuclear cells [PBMCs] was  
observed  one  hour  after  dosing.  At  27  mg/m2,  ~90%  inhibition  of  proteasome  activity  was 
achieved in PBMCs.[184] The median number of prior therapies for subjects on this trial was 5, 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. 
 
Another phase 1 study of carfilzomib in 29 patients with advanced lymphoid malignancies [MM, WM, NHL 
and HD] who received a more intensive schedule of carfilzomib IV push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15 
and 20 mg/m2 for 5 consecutive days of a 14-day cycle until unacceptable toxicities or progressive disease 
[median=4.8 cycles (range, <1-16)] determined that the 15 mg/m2 dose level was the MTD.[17] Despite 
intensive scheduling, severe AEs were infrequent. Common (>20%) grade 3/4 non-hematologic treatment-
emergent AEs were essentially absent [grade 3/4 dyspnea=6% and grade 
3/4 fatigue=3%]. Grade 3/4 hematologic AEs were also rare, including thrombocytopenia  (7%), anemia, 
febrile neutropenia and neutropenia (3% each). Proteasome inhibition of >75% was detected in  WB  and  
PBMCs  after  a  single  dose  of  carfilzomib  at  dose  levels  of  15  mg/m2  or  higher.  The 
inhibition was increased to >90% after the fifth consecutive day dosing due to accumulative effect with 
repeating dosing.  Anti-tumor activity was observed at doses >11 mg/m2.[17] 
 
1.4.4 
Phase 2 Experience With Carfilzomib As A Monotherapy 
Two phase 2 clinical studies were conducted with carfilzomib in MM patients, PX-171-003-A0 
[186,187](N=46) in relapsed/  refractory  MM  and  PX-171-004  (N=39)  in  relapsed  MM.[188-190]  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 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
16 
 
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 other 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 in serum creatinine that were primarily < Grade 2 and were transient, rapidly reversible, 
and non-cumulative. A very low rate of severe treatment-emergent peripheral neuropathy, 1 case (2.2%) 
with pre-existing Grade 2 neuropathy progressing to Grade 3,  was observed in PX-171-003-A0 despite the 
fact that 87% of patients had Grade 1/2 neuropathy upon study  entry.[186,187] 
 
The response rate in PX-171-003-A0 was 16.7% 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 
(100%), lenalidomide (91%) and thalidomide (91%). The best overall response rate was 16.7% (95% CI, 7.0-
31.4) months, with the duration of response (DOR) of 7.2 (CI, 1.9-not estimated) months. The clinical benefit 
response rate was 23.8% (95% CI, 12.1-39.5) months, with the DOR of 13.8 (95% CI, 4.8-16.6) months. The 
median time to progression on the PX-171-003-A0 study was 3.5 (95% CI, 2.4-6.7) months (mean follow up 
of 7.6 months).[186,187] 
 
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 and may form the basis for an accelerated approval NDA filing by the end of 
2010. This dosing schedule has been well tolerated.[183,184]   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 3.4% 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 12.4% new onset or 
worsening of pre-exisiting Grade 1/2 peripheral  neuropathy  (77%  had  pre- exisitng Grade 1/2  peripheral 
neuropathy) and 1.1% Grade 3 event reported on PX-171-003- A1.[186,187] 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. Grade 3/4 thromobocytopenia rate was 29% 
and grade 3/4 neutropenia rate was 11%.[186,187] 
 
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). [188,189] The median TTP was 7.6 and 5.3 
months in these two groups, respectively. Thus, carfilzomib can induce very high levels of response in 
patients who have not previously been treated with bortezomib[190] and, even in bortezomib-treated 
patients,[191] 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 toxicity (e.g., bone marrow, severe fatigue, or 
neuropathy) have not been observed. 
 
In these phase 2 studies, prolonged carfilzomib exposure at higher doses was associated with low incidence 
of new onset severe peripheral neuropathy or worsening of pre-existing peripheral neuropathy.[192,193] 
Carfilzomib was found to be safe in MM patients with renal  insufficiency, including those requiring 
hemodialysis.[194] In addtion, pooled safety data from phase 1/2 and phase 2 studies of single agent 
carfilzomib confirmed safety and low rates of grade 3/4 treatment-emergent AEs [195-197].  


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
17 
   Lastly,  unfavorable  cytogenetic  characteristics  in  MM  patients  had  no  impact  on response to    
  carfilzomib.[198-200] 
 
1.4.5 
Experience With Carfilzomib In Combination With Lenalidomide [201-203] 
PX-171-006 is a phase 1b study in patients with relapsed MM in which carfilzomib is administered in 
combination with lenalidomide (Revlimid®) and dexamethasone.[201,202] 
 
Patients with MM who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was 
administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m2 on days 1, 2, 8, 9, 15, and 16; 
Lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly.[201,202] 
 
The maximum per protocol doses of carfilzomib (27mg/m2) with lenalidomide 25 mg and low dose 
dexamethasone were used. 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 3 study PX- 171-
009. 
 
Forty patients enrolled in 6 cohorts.[201,202] Prior treatment included bortezomib (75%) and 
lenalidomide (70%); 20% and 36% were refractory overall. The MTD was not identified, and the highest 
dose combination tested was recommended for the phase II study. The most common toxicities of any 
grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included 
neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 
neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. 
The overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median 
duration of response and PFS were 11.8 and 10.2 months, respectively. Importantly, lenalidomide-
associated neutropenia and thrombocytopenia did not appear to be exacerbated by 
concurrent treatment with carfilzomib, even up to 27mg/m2. 
 
The phase 2 dose expansion at the maximum planned dose (MPD), focusing on the 52 patients enrolled in 
the MPD cohort.[203] Median follow-up was 24.4 months. In the MPD cohort, overall response rate 
(ORR) was 76.9% with median time to response of 0.95 month (range 0.5-4.6) and duration of 
response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% 
in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients w i t h  median DOR of 
22.1 and 10.8 months, respectively. A median of 9.5 (range 1-45) carfilzomib cycles were started with 
7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse 
events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia 
(19.2%), and anemia (19.2%). CRd at  the  MPD  was  well  tolerated  with  robust, rapid, and durable 
responses. 
 
1.4.6 Experience With Carfilzomib In Combination with Chemotherapy 
Carfilzomib has recently been shown to be safe and effective for the use in combination with conventional 
chemotherapy, including cyclophosphamide, melphalan and rituximab.[204-207] 
 
Reeder et al [204] conducted a phase I/II trial of a combination of Cyclophosphamide, Carfilzomib, 
Thalidomide and Dexamethasone (CYCLONE) in patients with newly-diagnosed MM. [carfilzomib IV Days 
1,2 8,9,15,16, cyclophosphamide 300 mg/m2  PO Days 1,8,15, thalidomide 100 mg PO Days 1- 
28 and dexamethasone 40 mg PO Days 1, 8, 15, 22. No DLTs were observed in the initial phase I/II 
regimen, with patients nearly fully accrued to the Phase 2 at 27mg/m2 and expansion MTD (36mg/m2). 
Ninety percent completed at least 4 cycles. Grade 3/4 toxicities occurring in >5% were uncommon 
(hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%).  There  were  no  cardiac events 
seen in greater than 5% of patients. All patients advancing to ASCT successfully collected stem cells. The 1-
year PFS was 90% and 1-year OS was 98%. Thus, the 4 drug CYCLONE regimen is highly efficacious at 
the dosing level of carfilzomib IV 20/27-36 mg/m2  in newly diagnosed myeloma. 
 
Toxicities are manageable, with minimal cardiac or pulmonary toxicity. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
18 
 
A Phase 2 Study  with  prolonged  administration  of  Carfilzomib,  Cyclophosphamide  and Dexamethasone 
(CCd) for newly-diagnosed elderly MM (median age 71 years; 28% of patients >75 years).[205]   The   
regimen   included   oral   cyclophosphamide   (300   mg/m2    on   days   1,8,15),   oral 
dexamethasone (40 mg on days 1, 8, 15, 22) and IV carfilzomib (20 mg/m2 on days 1, 2, and 36 
mg/m2 on days 8, 9, 15, 16, cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, 16, cycles 2-9) every 28 days 
for 9 cycles, followed by maintenance with IV carfilzomib (36 mg/m2 on days 1, 2, 15, 16) every 28 days until 
progression or intolerance. After 9 induction cycles, 96% of patients achieved at least PR, 76% VGPR, 64% 
CR/nCR, including 24% sCR. The 1-year PFS was 86% and the 1-year OS was 87%. G3/4 non-hematologic 
AEs were infections (7%), cardiac (5%), constitutional (4%), renal (4%) and GI complications (2%). Overall, 
the CCd regimen was well tolerated. After a median duration of maintenance of 6 months, the PR rate was 
100%, including 68% CR/nCR. The most frequent toxicity (all grades) during maintenance was fever (G1/2 
in 24%, G3 in 8%), not associated with chills, rigors, dyspnea and/or creatinine increase. There was only 1 
(4%) G3 neutropenia. Thus, The CCd regimen is highly effective, (>nCR 64% and sCR24). It is well 
tolerated with limited grade 3-4 AEs. 
 
A phase 1/2 study of a combination of Carfilzomib, Melphalan and  Prednisone  (CMP)  in  elderly patients 
(median age, 72 years) with newly diagnosed MM revealed the safety and efficacy  of combined carfilzomib 
and chemotherapy in the elderly population.[206] Carfilzomib was started at 20mg/m2, then escalated to 
45mg/m2, in 42-day cycles on D1,2,8,9,22,23,29,30 for 9 cycles. Melphalan 9mg/m2  and prednisone 
60mg/m2 were given PO D1–4. The phase I part identified an MTD of 36mg/m2 in this combination. In Phase 
2 expansion, 44 additional patients  received  CMP  at 36mg/m2 carfilzomib. CMP was well tolerated. Overall 
response rate was 89.5% including 56% ≥ very good partial response. The 2-year OS was 87%, and the 
median EFS was 22 months.  Thus, carfilzomib 36mg/m2/melphalan/prednisone regimen is tolerable and 
effective in elderly patients. 
 
Lastly, carfilzomib was reported to be safe in the use  in  combination  with  rituximab  and dexamethasone 
(CaRD) in patients with Waldenstrom’s macroglobulinemia.[207] 
 
1.4.7. Experience With Carfilzomib In Combination with High-dose Chemotherapy And 
Hematopoietic Cell Transplant. 
Costa et al has conducted a phase 1 study of combination of carfilzomib and standard high-dose melphalan 
conditioning, followed by autologous blood stem cell transplant in MM patients.[208] Treatment consisted of 
two doses of carfilzomib administered IV over 30 minutes on days -3 and -2. 
The day -2 dose was administered one hour prior to administration of myeloabaltive high-dose melphalan 
200 mg/m2. Carfilzomib dose consisted of 20 (day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 mg/m2  (cohort 1), 
27/36 mg/m2  (cohort 2), 27/45 mg/m2  (cohort 3) and 27/56 mg/m2 (cohort 4). All 
subjects received pegfilgrastim 6 mg subcutaneously on day +1. At the time of reporting, enrolment of cohort 
4 (27/56 mg/m2 ) was ongoing. Twelve subjects were accrued in cohorts 0-3 with no DLT being identified. 
Median age was 56 (range 45-68) years. Median number of prior lines of therapy was 3 
(range 2-6) and 5 subjects had previously received HDT/ASCT. There was no acute toxicity associated with 
carfilzomib infusion. Median CD34+ dose infused was 4.15 x 106/kg (range 2.21-9.34). Neutrophil 
engraftment occurred at a median of 11 days (range 8-15) and platelet engraftment at a 
median of 17.5 days (range 11-24). There were no non-hematologic grade  4  toxicities.  The  most frequent 
grade 3 toxicity was infection in 7/12 subjects consisting  of  1  episode  of  pneumonia,  1 episode of 
bacteremia, 1 episode of urinary  tract  infection  and  4  episodes  of  febrile  neutropenia. Other grade 3 
toxicities were rash (n=2), hypertension (n=1),  hypophosphatemia  (n=1)  and hypocalcemia (n=1). At the 
time of reporting, nine subjects, from cohorts 0, 1 and 2 reached day +100 response assessment and the 
cumulative responses were PR in 3/9, VGPR in 3/9 and CR in 3/9 subjects. Pharmacodynamic studies in 
peripheral blood mononuclear cells revealed that carfilzomib. Thus, transplant conditioning with combined 
carfilzomib and standard high-dose melphalan is well tolerated, without impaired engraftment. 
 
 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
19 
 
1.4.8        Dosing 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 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. 
 
In multiple preclinical studies, the tolerability of carfilzomib in rats has been shown to be significantly higher 
when administered as a 30 min 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 min 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 min was gastrointestinal bleeding. The reduced toxicity seen with 
dosing by infusion may reflect the reduced Cmax  of carfilzomib vs 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’ infusion. 27mg/m2 of carfilzomib (bolus administration over 2- 10’) 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’). A review of the tolerability of 36 mg/m2 carfilzomib in 
these patients indicates that this regimen was very well tolerated with only one DLT (fatigue) and an overall 
adverse event profile similar to that seen with the 27mg/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  carfilzomib,  the  Phase  1b  portion  of  this  
study  was  reopened,  and  a  separate  arm  for multiple myeloma was added. 
 
In the PX-171-007 trial, more recently 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 does 
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; the lower doses were 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  
20/56mg/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  have received 
20/56mg/m2 and are tolerating it. Patients with advanced, refractory MM being treated at 36mg/m2 and 
45mg/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 ≥36mg/m2 carfilzomib are now administering the drug as 
a 30-minute infusion. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
20 
 
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 adjustment.[195]. 
 
1.5 STUDY RATIONALE 
 
We are conducting a phase 1/2 study of fludarabine-based allo-HCT with the addition of carfilzomib in 
patients with hematologic malignancy. 
 
The rationale for this strategy includes: 
 
1. No effective therapies are available for high-risk or advanced relapsed/refractory hematologic 
malignancies. Current combination chemotherapy, chemo-immunotherapy or chemo-biologic 
targeted therapies can only provide short-term disease control, with inevitable subsequent relapse 
and refractoriness. 
 
2. The use of conventional myeloablative allo-HCT resulted in poor outcomes due to high immediate 
treatment-related mortality (TRM) including regimen-related toxicities (RRT) and acute graft-
versus- host disease (aGVHD). The attempts to decrease TRM by use of reduced-intensity 
conditioning, in turn, have resulted in higher relapse rates, despite decreased TRM, thus there 
was no improvement in overall outcome. In addition, despite a delay in onset, aGVHD 
incidence has remained high and has continued to be a major obstacle for transplant 
success. GVHD therapy with high-dose steroid and more aggressive immunosuppressive agents 
abrogate graft-versus-tumor effect and increase relapse. At UM, the incidence of grade II-IV 
aGVHD was ~45% while 1-year PFS was ~20-30% only for high-risk lymphoid malignancies 
and it was ~50% for high-risk myeloid malignancies, emphasizing the need of measure to 
decrease relapse and GVHD. 
 
3. Proteasome-ubiquitin degradation system has a pivotal role in maintaining survival signaling in 
malignant cells. Inhibition of proteasome function results in down-regulation of the NF-κB 
signaling pathway and selective apoptosis of malignant cells with constitutive over-expression of 
this pathway. The NF-κB signaling pathway also mediates inflammatory and immune response 
by promoting activated T and dendritic cell function and survival. In addition, proteasome 
degradation system, independent of the NF-κB axis, promotes activated B cell survival. 
 
4. Bortezomib, a reversible first-generation proteasome inhibitor, has anti-tumor activity in 
hematologic malignancies, especially lymphoid diseases. Moreover, it has  been  shown  by  
Dana Farber group to decrease acute GVHD and relapse in a mouse model and in high-risk 
HLA- mismatched unrelated allo-HCTs for high-risk hematologic malignancies when 
incorporated into the conditioning  regimen. 
 
5. Carfilzomib, an irreversible and more potent second-generation proteozome inhibitor, has been 
shown to overcome bortezomib resistance, with significantly less off-target toxicities, especially 
myelosuppression and neuropathy, compared with bortezomib. Pooled safety data from phase 1 
and 1/2 studies reported <20% incidences of grade 3/4 myelosuppression and GI toxicities. In 
addition, carfilzomib has been used safely when combined with other highly myelosuppressive 
agents in their full dosage. Lastly, carfilzomib, like bortezomib, may potentially prevent aGVHD 
through proteasome and non-proteasome mechanisms, while preserving GVL effect. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
21 
 
1.6 
HYPOTHESIS 
Based on the above rationale, we hypothesize that adding carfilzomib to standard fludarabine-based 
conditioning regimen for allo-HCT for advanced or high-risk hematologic malignancies will decrease post-
transplant relapse and TRM by decreasing severe GVHD, leading to overall improvement in transplant  
outcomes. 
 
2. 
OBJECTIVES 
 
2.1 
PRIMARY  OBJECTIVE 
To determine whether the addition of carfilzomib to fludarabine-based conditioning, followed by allogeneic 
hematopoietic cell transplant for hematologic malignancies  will  decrease relapse/progression and severe 
GVHD. 
 
2.2 
SECONDARY  OBJECTIVES 
To determine the efficacy of this regimen in the improvement of overall transplant outcomes. 
 
2.3 
PRIMARY  ENDPOINT 
 
Event-free survival at 1 year after transplant. 
 
Event  is  defined  as  relapse/progression  or  grade  III-IV  acute  GVHD  or  chronic  GVHD  requiring 
systemic treatment. 
 
2.4 
SECONDARY  ENDPOINTS 
Progression/Relapse-free  survival 
Overall survival 
Regimen related toxicity (RRT), 
Graft failure, Treatment-related mortality (TRM) 
Cumulative incidence of acute GVHD 
Cumulative incidence of chronic GVHD 
Molecular Correlates:   Pharmacodymanics: Proteasome inhibition 
GVHD cytokines 
 
 
3. 
EXPERIMENTAL  DESIGN 
 
3.1 
Study Design 
This study is a phase 1/2 study. The phase 1 part consists of 4 dose levels [Table 2]. Subjects will be 
enrolled on the first dose level 1, following a standard 3+3 dose escalation rule until the optimal or 
maximal tolerated dose (MTD) [0/3 or 1/6 subject developing dose-limited toxicities (DLT)] is identified. 
 
The phase 2 part is an extension of the optimal dose level which is identified from the phase 1 part. 
 
3.2 
NUMBER OF CENTERS 
The University of Michigan only. 
 
3.3 
NUMBER OF SUBJECTS 
A total of 55 subjects will be accrued. 
 
3.4 
ESTIMATED STUDY DURATION 
2 years of accrual 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
22 
 
3.5 
TREATMENT  PROCEDURE 
 
3.5.1 
TRANSPLANT  SCHEMA 
Subjects will be admitted to in-patient BMT unit and receive a standard fludarabine-based conditioning 
chemotherapy regimen, followed by an allo-HCT, with the addition of carfilzomib per the schema: 
 
 
 
 
3.5.2 STANDARD CONDITIONING REGIMENS 
Either standard FluBu or FluMel regimen will be used, following Institutional Guidelines for blood and marrow 
transplant (BMT) Procedure. 
 
3.5.2.1             Fludarabine and Busulfan (FluBu2 or FluBu4) 
Fludarabine 40 mg/m2/day IV x 4 on day -5 to day -2  
 
Busulfan 3.2 mg/kg/day IV x 2 on day -5 to day -4 [FluBu2] or 
Busulfan 3.2 mg/kg/day IV x 4 on day -5 to day -2 [FluBu4] 
 
Standard anticonvulsant prophylaxis [e.g. Levetiracetam (Keppra®) 1,000 mg PO/IV bid] will be started on 
day -6 until 24 hours after the last dose of busulfan and busulfan pharmacokinetic study may be performed, 
following Institutional Guidelines for BMT Procedure for investigational conditioning  regimens. Busulfan 
pharmacokinetic study is recommended for the FluBU4 regimen. 
 
3.5.2.2 
Fludarabine and Melphalan (FluMel140 or FluMel180) 
Fludarabine 30 mg/m2/day IV x 4 on day -5 to day -2 
Melphalan 140 mg/m2 IV x 1 on day -1 [FluMel140] or 
Melphalan 180 mg/m2 IV x 1 on day -1 [FluMel180] 
 
3.5.2.3 
  Fludarabine, Cyclophosphamide and Rituximab (FCR) 
 
   Rituximab 375 mg/m2/day IV x 4 on days -13, -6, +1 and +8 
             Fludarabine 30 mg/m2/day IV x 3 on day -5 to day -3 
             Cyclophosphamide 750 mg/m2/day IV x 3 on day -5 to day -3 
 
Low-dose total body irradiation (TBI) at 200 cGy x 1 or anti-thymocyte globulin/thymoglobulin may be used 
for a transplant using a 7/8 HLA matched donor. 
 
  3.5.2.4              Other Chemo-immunologic Agent 
Ritumximab [Monoclonal anti-CD20, Rituxan®] may be used for CD20+  B cell malignancies [R-  FluBu4, R-
FluMel180], following Institutional Guidelines for BMT Procedure for B-cell malignancies. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
23 
Commercially available fludarabine, busulfan, melphalan, cyclophosphamide and rituximab will be 
used following standard Institutional Guidelines for BMT Procedure. 
 
3.5.3 
HEMATOPOIETIC  CELL  TRANSPLANTATION 
 
Hematopoietic cell transplant will occur on day 0. If there are >2 days of transplant, day 0 will be adjusted 
accordingly e.g [day 0a and 0b] for a subject undergoing 2 days of transplant. 
 
3.5.4 GVHD  PROPHYLAXIS 
 
A standard combination of tacrolimus (FK506) and low-dose (mini) methotrexate will be used following 
Institutional Guidelines for BMT Procedure. 
 
- 
Tacrolimus will be administered by continuous IV infusion or by mouth, starting on day -
3, with a targeted serum trough level following Institutional Guidelines for BMT procedure. 
Tacrolimus will be tapered off by day 180 if no clinically significant GVHD develops, following 
Institutional Guidelines for BMT Procedure. Cyclosporine may be used as a substitute for tacrolimus 
at the investigator’s discretion. 
 
- 
Methotrexate at 5 mg/m2/day IV will be administered on day +1, +3, +6 and +11 
following standard BMT protocol or Institutional Guidelines for BMT Procedure. 
 
- 
Leucovorin may be administered after each dose of mini-methotrexate, following 
Institutional Guidelines for BMT Procedure for methotrexate GVHD prophylaxis. 
 
- Commercially available tacrolimus, methotrexate and leucovorin (if any) will be used. 
 
- 
For a subject who cannot continue to receive tacrolimus and cyclosporine due to a serious 
complication e.g. posterior reversible leukoencephalopthy syndrome (PRES) or thrombotic 
microangiopathy, an alternative GVHD prophylaxis regimen may be used at the investigator’s 
discretion or per Institutional Guidelines for BMT Procedure. 
 
3.5.5 
CARFILZOMIB 
 
- Only carfilzimib from the study supply will be used. 
 
- Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2  IV) on Day 
+1, +2, +6 and +7 (Table 1), based on the phase 1/2 carfilzomib studies and the previous Dana 
Farber phase 1 safety experience on the addition of a proteasome inhibitor into a fludarabine-based 
conditioning  regimen. 
 
- Carfilzomib will be admisnistered after methotrexate on day +1 and +6. 
 
- 
Dexamethasone 4 mg IV will be administered 30-60 minutes prior to each dose of 20 and 
27 mg/m2 carfilzomib. Dexamethasone 8 mg IV will be administered prior to each dose of 36 
and 45 mg/m2 carfilzomib. In any case, subsequent doses of pre-medication dexamethasone 
may be increased as clinically indicated at the investigator’s discretion. 
 
- Subjects will be observed closely during carfilzomib treatment. 
 
- Dose escalation of the phase 1 part will follow the standard 3+3 design as previously stated 
(Table 1). 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
24 
Table 1: DOSE ESCALATION SCHEDULE 
Dose Level 
Carfilzomib (mg/m2) 
Day +1 
Day +2 
Day +6 
Day +7 
1 
20 
20 
20 
20 
2 
20 
20 
27 
27 
3 
20 
20 
36 
36 
4 
20 
20 
45 
45 
 
3.5.6 
FILGRASTIM [Granulocyte-stimulating colony factor (G-CSF), NEUPOGEN®] 
Filgrastim will be administered starting on day +1 at 5 µg/kg/day per the previous Dana Farber study, until 
ANC >2,500/µL for 2 consecutive days or ANC >5,000/µL x 1 or following Institutional Guidelines for BMT 
Procedure. After day +14, filgrastim dose may be increased up to 10 µg/kg/day and/or sargramostim [GM-
CSF, Leukine®] may be added at  investigator’s  discretion  per  Institional Guidelines for BMT Procedure. 
 
3.5.7 
INFECTION  PROPHYLAXIS 
Infection prophylaxis will follow Institutional Guidelines for BMT Procedure. The exception is that an “azole” 
anti-fungal prophylaxis other than fluconazole (e.g.voriconazole or posaconazole), if indicated, will be started 
after the last dose of carfilzomib or on/after day +8. 
 
3.5.8 
ALLOGENEIC 
HEMATOPOIETIC 
STEM 
CELL 
MOBILIZATION 
AND 
APHERESIS 
PROCEDURE FOR RELATED DONORS 
 
3.5.8.1 
STEM CELL SOURCE 
 
Peripheral blood stem cells (PBSC) will be the preferred choice of stem cell source. 
Bone marrow stem cells may be used; cord blood is not allowed. 
3.5.8.2 
STEM CELL MOBILIZATION AND COLLECTION 
 
For related donors, PBSC mobilization and collection will follow the Institutional Guidelines for BMT 
Procedure. The apheresis procedure shall begin on day 0 of transplant, with a goal of collecting 3.0 to 
8.0 x 106 CD34+ cells/kg, based on the recipient’s body weight following Institutional Guidelines for 
BMT Procedure. For bone marrow stem cells, the recommended cell dose is ≥ 2.0 x 108 mononuclear 
cells/kg recipient weight. 
 
For related donors, fresh PBSC and bone marrow stem cells should be infused into the patient on the 
same day of collection or following Institutional Guidelines for BMT Procedure. 
 
For unrelated donors, fresh PBSC and bone marrow stem cells should be infused into the patient 
within 48 hours of collection. Further delay of stem cell infusion is at investigator’s discretion but this 
must not beyond 72 hours of collection or following Institutional Guidelines for BMT Procedure. 
 
3.5.8.3 
Donor Lymphocyte Infusion (DLI) 
 
The use of DLI is not mandated by this protocol, even in the setting of  diminished  T  cell  donor chimerism 
or relapse. In such circumstances, DLI may be considered at Investigator’s discretion or following 
Institutional Guidelines for BMT Proceudure. Patients will be considered “off protocol therapy” at the 
time of DLI infusion. Patients who receive a DLI will still be  followed  for  study endpoints. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
25 
 
3 
SUBJECT  SELECTION 
 
4.1 
INCLUSION  CRITERIA 
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. 
 
4.1.1 
Disease-related: meeting one of the following diagnosis 
 
1. Lymphoid malignancies requiring allogeneic hematopoietic cell transplantation 
1.1 
Multiple Myeloma including primary or secondary plasma cell leukemia and secondary 
amyloidosis 
 
1.2 
Lymphomas and related chronic lymphoid proliferative disorders: Hodgkin’s lymphoma, 
Non-Hodgkin’s lymphoma of any types (B-cell, T-cell, Null/NK-cell type), chronic lymphocytic leukemia 
(CLL), pro-lymphocytic leukemia (PLL), hairy-cell leukemia, large granular lymphocytic leukemia 
1.3 
Waldenstrom’s macroglobulinemia / lymphoplasmacytic lymphoma 
1.4 
Acute lymphoblastic leukemia (ALL) of any types 
 
2. Myeloid malignancies requiring allogeneic hematopoietic cell transplantation 
2.1 
Acute  myeloid  leukemia  (AML)  and  acute  leukemia  of  mixed  or  undetermined  or 
ambiguous lineage 
2.2 
Myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD) [chronic myeloid 
leukemia  [CML],   primary  myelofibrosis,  post-polycythemic/post-thrombocythemic  myelofibrosis], chronic 
myelomonocytic leukemia [CMMoL] and acute blastic transformation of these conditions. 
 
3. Pathology review by the study institution is required. 
4. Prior high-dose chemotherapy and autologous HCT(s) is (are) allowed. 
5. Disease status:  Stable disease or better at the time of enrollement. 
 
4.1.2 
Demographic 
1. Age: ≥18 and ≤70 years old at the time of transplant (<71 years at transplant admission) 
2. Life expectancy ≥ 6 months after transplant 
3. An 8/8 or 7/8 HLA–matched non-syngeneic donor is available and eligible to donate  
 
hematopoietic stem cells following Institutional Guidelines for BMT Procedure. High 
 
resolution HLA typing is required at HLA-A, -B, -C and –DR alleles. 
4. Karnofsky Performance Stuatus ≥70% [APPENDIX A] 
 
4.1.3 
Laboratory 
1. Cardiac: Left ventricular ejection fraction (LVEF) ≥0.4 by MUGA or echocardiogram 
2. Pulmonary: FEV1, FVC and DLCO (corrected for hemoglobin) ≥ 50% predicted 
3. Hepatic function: Serum AST/ALT ≤ 3 times the upper limit of normal (ULN) and serum direct 
bilirubin (DB) ≤ 1.5 times ULN within 14 days prior to admission 
Renal: Serum creatinine ≤1.2 mg/dL or serum creatinine >1.2 mg/dL and an estimated glomerular 
filtration rate (GFR) >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal 
Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x 
(age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black). 
 
4.1.4 
Ethical 
1. Written informed consent in accordance with federal, local, and institutional guidelines. 
2. Females of child-bearing potential must agree to ongoing pregnancy testing and to practice 
contraception as directed. 
3. Male subjects must agree to practice contraception as directed. 


 
 
 
Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
26 
 
4.2 
EXCLUSION CRITERIA 
 
4.2.1 
Disease-related 
1. Progressive disease [APPENDIX B] at the time of enrollement 
2. Active central nervous system involvement by malignancy 
 
4.2.2 
Concurrent Conditions 
1. Non compliance to medications or medical instructions 
2. Lack of appropriate caregivers 
3. Life expectancy <6 months 
4. Pregnant or lactating females 
5. Uncontrolled infection requiring active treatment (systemic antibiotics, anti-virals, or anti-fungals) 
within 14 days 
6. HIV-1/HIV-2 or HTLV-1/HTLV-2 seropositivity 
7. Active hepatitis A, B or C infection  * Hepatitis A serology is not required for normal liver function. 
8. Unstable angina or myocardial infarction within 6 months prior to randomization, NYHA Class III or 
IV heart failure, uncontrolled angina, history of severe coronary artery disease, uncontrolled or 
persistent atrial fibrillation/flutter, history of ventricular fibrillation, ventricular tachycardia/torsade   
de pointes, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 
conduction system abnormalities unless subject has a pacemaker 
9. History of pulmonary hypertension 
10. Uncontrolled hypertension or uncontrolled diabetes mellitus 
11. 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 (PSA) 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 
12. Known history of allergy to Captisol®  (a cyclodextrin derivative used to solubilize carfilzomib) 
13. Contraindication to any of the required concomitant drugs or supportive treatments, including 
hypersensitivity to all available anti-microbial drugs or intolerance to IV hydration due to pre- 
existing pulmonary or cardiac impairment 
14. Subjects with pleural effusion requiring thoracentesis or ascites requiring paracentesis within 14 
days prior to admission 
15. Uncontrolled psychiatric condition 
16. Any other clinically significant medical or psychiatric disease or condition that, in the Investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed consent 
5. 
SUBJECT  ENROLLMENT 
5.1 
REGISTRATION/ENROLLMENT   PROCEDURES 
This study will be conducted at the University of Michigan. Once a patient is deemed eligible for the 
protocol, a signed IRB-approved informed consent must be obtained form patients prior to the initiation 
of treatment with carfilzomib. Patient’s data and eligibility criteria will be recorded at entry of the 
study. All screening evaluations will be completed as part of the standard workup for allogeneic 
transplant. Enrollment must be performed prior the initiation of treatment with carfilzomib.


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
27 
 
This study is a phase 1/2 study. The phase 1 part consists of 4 dose levels [Table 1]. Subjects will be 
enrolled on the first dose level 1, following a standard 3+3 dose escalation rule until the optimal or 
maximal tolerated dose (MTD) [0/3 or 1/6 subject developing dose-limited toxicities (DLT)] is identified. 
 
The phase 2 part is an extension of the optimal dose level which is identified from the phase 1 part 
and a total of 35 patients will be needed on this dose level [See 10.2]. 
 
5.2 
STUDY DEFINITIONS 
 
5.2.1 
Screening: A subject will be considered to be in the “Screening” period from  the time 
he/she signs consent until the date the subject is determined as either “eligible” or “ineligible” (screen 
failure) by PI or a Co-I. Patients may be consented to this study based on disease status and other 
criteria at the time of consent, but later removed from the study prior to admission and initiation of 
transplant conditioning regimen if the change of disease status makes the subject “ineligible”. In the 
event that his occurs, the subject will be replaced. 
 
5.2.2 
Enrolled: A subject will be considered to be “Enrolled” onto the study once  they have 
signed consent AND have successfully met all screening criteria, as documented by the 
inclusion/exclusion document, AND the eligibility criteria has been reviewed and accepted by the PI or 
a co-I. The date of enrollment will be documented as the date that the PI or a co-I has reviewed and 
approved the subject’s eligibility. Enrollment must be performed prior the initiation of treatment with 
carfilzomib 
 
5.2.3 
Treatment Period: The “Treatment Period” is defined as the first day through the last 
day of treatment with carfilzomib [Day +1 to +7]. 
 
The assessment and reporting period for adverse events (AE) related to the study drug 
(carfilzomib) will start from day +1 at the time of carfilzomib administration through day +100. 
 
5.2.4 
Follow Up Period: The “Follow Up period” is defined as the first day a subject is no 
longer receiving carfilzomib (day +8) through at least 1- y e a r  post-transplant (primary efficacy 
endpoint) 
 
However, subjects will be followed further for 3 years  on  secondary  efficacy  endpoints  (relapse, GVHD, 
infections, late toxicities and survival). Data not concerning endpoints collected through other BMT 
clinical research studies may be used for analysis. 
 
5.2.5 
On Study: The “On Study period” starts from the day that a subject signs the protocol 
consent document and subsequently meets the protocol eligibility criteria (“Enrolled”), completes the 
study drug on day +1, +2, +6 and day +7 and ends on day +100 or prior to day 100 if one of the 
following event occurs earlier: 
 
1. Death 
2. Lost to follow-up 
3. Withdrawal of consent 
4. Entry on to a competing trial 
5. Relapse and its treatment or development of new malignancy and its treatment 
6. Grade III-IV acute GVHD and its treatment 
7. Unacceptable or dose limiting toxicity or complication 
 
After day +100, the patient will be considered “Off Study/Off Protocol.” But they will be followed for the 
primary and secondary endpoints off study/off protocol until 3 year as  mentioned  in  “Follow  Up Peroid”. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
28 
5.2.6  
Off Treatment: The “Off Treatment” period starts after a patient has completed the study 
drug on day +7 or prior to day+7 if one of the listed event in 5.2.5 occurs earlier, and ends a day +100. 
 
Subjects who take part in this study will be followed for adverse events (AEs) directly related to the 
study drug (carfilzomib) through day 100. 
 
Adverse events occurring after the “Off Treatment” period (day+100) will  not  be  reported  unless related 
(probably or definitely) to the study drug (carfilzomib). 
 
5.2.7 
Evaluable: Subjects who have received all the 4 doses of carfilzomib will be considered 
“evaluable” for endpoint analysis. The number of subjects who are considered not  “evaluble”  for endpoint 
analysis will be monitored closely. Additional subjects will be replaced. 
 
6.          TREATMENT PROCEDURE 
 
6.1       DRUG PREPARATION AND ADMINISTRATION 
 
6.1.1     STUDY DRUG: CARLFILZOMIB 
 
6.1.1.1 
CARFILZOMIB  DESCRIPTION 
Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical 
name 
is 
(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. 
 
6.1.1.2 
FORMULATION 
Carfilzomib for Injection will be provided as a white to off-white lyophilized cake or 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-b-cyclodextrin (SBE-b-CD, Captisol®). 
 
6.1.1.3 
STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC and in the original package to protect 
from light under the conditions outlined in the separate Pharmacy Manual, in a securely locked area to 
which access is limited to appropriate study personnel. 
 
6.1.1.4 
DOSING AND ADMINISTRATION 
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 2.0 mg/mL prior 
to administration. 
For a standard dosing of carfilzomib, the dose will be calculated using the subject’s “actual” body 
surface area (BSA) at baseline. Subjects with a BSA >2.2 m2 will receive a dose based upon a 2.2 m2  
BSA. 
 
Carfilzomib will be administered as an IV infusion over 30 minutes


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
29 
 
 
. 
6.1.1.5 
PRE-MEDICATION 
Dexamethasone 4 mg IV will be administered 30-60 minutes prior to each dose of 20 and 27 mg/m2 
carfilzomib. Dexamethasone 8 mg IV will be administered prior to each dose of 36 and 45 mg/m2 
carfilzomib. In any case, subsequent doses of pre-medication dexamethasone may be increased as 
clinically indicated at the investigator’s discretion. 
 
6.1.1.6 
HYDRATION 
 
Per standard BMT procedure, subjects will receive adequate maintenance IV hydration, starting on 
the admission day, continuously through conditioning chemotherapy course, stem cell infusion 
(transplant), the first dose of carfilzomib on day +1 of transplant until the last dose of carfilzomib on 
day +6, following Institutional Guidelines for blood and marrow transplant procedure. 
Pre and post dose IV hydration (between 250 mL and 500 mL normal saline or other appropriate IV 
fluid formulation) will be given for subjects, for any reasons, NOT receiving maintenance  IV  fluid hydration 
on days of IV carfilzomib administration. 
 
6.1.2 
STANDARD  TRANSPLANTATION  DRUGS 
 
6.1.2.1 FLUDARABINE (FLUDARA®, FAMP) 
Formulation: The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O- 
phosphono-D-arabinofuranosyl). The molecular formula of  fludarabine  phosphate  is  C10H13FN5O7P (MW 
365.2). A fluorinated nucleotide analog of the anti-viral agent vidarabine 9-D- arabinofuranosyladenine 
(ara-A) that is relatively resistant to deamination by adenosine deaminase. 
 
Availability: FLUDARA® for injection contains fludarabine phosphate. Each vial of sterile lyophilized 
solid cake contains 50 mg of the active ingredient fludarabine phosphate, 50 mg of mannitol, and 
sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Reconstitution with 
2 mL of Sterile Water for Injection USP results in a solution containing 25 mg/mL  of  fludarabine phosphate 
intended for intravenous administration. 
 
Fludarabine is available as a 25mg/ml solution for injection and as powder for injection (Fludara). 
Both products are stored in the refrigerator (2° to 8° C / 36° to 46° F). Reconstituted Fludarabine IV is 
chemically and physically stable at room temperature or 48 hours if refrigerated. In addition, 
reconstituted fludarabine (IV) contains no antimicrobial preservative and thus care must be taken to 
ensure that there is sterility of the prepared solutions. Prepared solutions should be discarded 8 hours 
after initial use. Reconstituted powder vials are stable for 16 days at room temperature or refrigerated. 
Solutions diluted in 0.9%NaCl or Dextrose in Water are stable for 48 hours at room temperature or the 
refrigerator. However, as stated above, reconstituted and diluted solution do not contain antimicrobial 
preservative and should be used within 8 hours. 
 
Administration: The recommended dose of fludarabine in a non-transplant setting is 25 mg/m2 
administered intravenously over a period of approximately 30 minutes daily for 5 consecutive days per 
cycle. Dosing for standard allogeneic stem cell transplant conditioning regimen is 120-160 mg/m2 in a 
total course. 
 
Potential and Expected Toxicities: Fludarabine can  cause diarrhea, nausea, vomiting, and skin rash. 
Fludarabine can temporarily lower the number of white blood cells, which help defend the body against 
infection and other diseases in your blood. This can increase your  chance  of  getting  an infection. It can 
also lower the number of platelets, which are 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
30 
necessary for proper blood clotting, resulting in easy bruising and excessive bleeding from wounds. 
Less common side effects are aching muscles, general feeling of discomfort or illness, headache and 
loss of appetite. Rare side effects include cough or hoarseness, fever or chills, loss of vision, lower 
back or side pain, painful or difficult urination. Rarely, fludarabine can cause a temporary loss of hair 
in some people. 
 
6.1.2.2 BUSULFAN  (BUSULFEX®) 
Formulation: Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, 
dimethanesulfonate with a molecular formula of CH3SO2O(CH2)4OSO2CH3  and a molecular weight of 
 246 g/mole. The pharmacokinetics of IV busulfan was studied in 59 patients participating in a prospective    
trial    of    a    busulfan-cyclophosphamide    preparatory    regimen    prior    to    allogeneic  hematopoietic 
progenitor stem cell transplantation. Patients received 0.8mg/kg busulfan IV every six hours, for a total of 16 
doses over four days. Fifty-five of fifty-nine patients (93%) administered IV busulfan maintained AUC values 
below the target value (<1500 µM•min). Busulfan pharmacokinetics showed consistency between dose 9 
and dose 13 as demonstrated by reproducibility of steady state Cmax and a low coefficient of variation for 
this parameter. In a pharmacokinetic study of IV busulfan in 24 pediatric patients, the population 
pharmacokinetic (PPK) estimates of busulfan for clearance (CL) and volume of distribution (V) were 
determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr/20 kg (3.37 ml/min/kg; 
interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%). IV busulfan daily 
infusion of 3.2 mg/kg has been tested in multiple studies and considered to be equal in terms of toxicity and 
efficacy. Thus most centers use every 24h dosing. 
 
Availability: IV busulfan (Busulfex®) is supplied as a clear, colorless, sterile solution in 10-mL single- 
use glass vials each containing 60 mg of busulfan at a concentration of 6 mg/mL for intravenous use. 
IV busulfan is packaged in a tray pack of 8 vials. Unopened vials of Busulfex must be stored under 
refrigerated conditions between 2°-8°C (36°-46°F). 
 
Administration: IV busulfan must be diluted prior to use with either NS or D5W. The diluent quantity 
should be 10 times the volume of Busulfex, so that the final concentration of busulfan is approximately 
0.5 mg/mL. Infusion pumps should be used to  administer  the  diluted  busulfan  solution.  DO  NOT infuse 
concomitantly with another intravenous solution of unknown compatibility. Warning:  Rapid infusion of IV 
busulfan has not been tested and is not recommended. Follow the institutional guidelines for more 
detailed preparation and administration procedures of busulfan. 
 
Potential and Expected Toxicities: For BMT setting, busulfan can cause nausea and vomiting, 
myelosuppression/ablation, seizures, diarrhea, impotence, sterility, generalized skin pigmentation, 
scarring of the heart muscle and lungs, testicular atrophy, cataracts and the development of a new 
cancer. 
 
Toxicities reported in non-transplant setting as more than 10%  incidence  are:  Tachycardia, hypertension, 
edema, thrombosis, chest pain, vasodilation, hypotension, insomnia, fever, anxiety, headache, chills, 
pain, dizziness, depression, confusion, rash, pruritus, alopecia, hypomagnesemia, hyperglycemia, 
hypokalemia,  hypocalcemia,  hypophosphatemia,  nausea,  mucositis/stomatitis, vomiting, anorexia, 
diarrhea, abdominal pain, dyspepsia, constipation, xerostomia, rectal disorder, abdominal fullness, 
myelosuppression, neutropenia, thrombocytopenia, lymphopenia, anemia, hyperbilirubinemia, ALT 
increase,  veno-occlusive disease, jaundice,  injection  site  inflammation, injection site pain, weakness,  
back  pain,  myalgia,  arthralgia,  creatinine  increased,  oliguria,  rhinitis, lung disorder, cough, epistaxis, 
dyspnea, pneumonia, hiccup, pharyngitis, infection, allergic reaction. Toxicities with expected incidences 
of  1%  to  10%  are:  Arrhythmia,  cardiomegaly,  atrial  fibrillation, ECG abnormality, heart block, heart 
failure, pericardial effusion, tamponade, ventricular extrasystoles, hypervolemia, lethargy, hallucinations, 
agitation, delirium, encephalopathy, seizure,  somnolence, 
cerebral hemorrhage, vesicular rash, 
vesiculobullous rash,  skin  discoloration,  maculopapular  rash, acne, exfoliative dermatitis, erythema 
nodosum, hyponatremia, ileus, weight gain, hematemesis, pancreatitis, prothrombin time increase, 
hepatomegaly, hematuria, dysuria, hemorrhagic cystitis, BUN increase, asthma, alveolar hemorrhage, 
hyperventilation, hemoptysis, pleural effusion, sinusitis, atelectasis,  hypoxia. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
31 
 
6.1.2.3 MELPHALAN  [ALKERAN®] 
Formulation: Chemistry: Melphalan (L-phenylanine mustard) is a bifunctional alkylating agent. It 
forms covalent linkages with susceptible cellular proteins. IV administration of melphalan revealed 
rapid elimination 
from plasma with terminal half-life of 1.8 hours. 13% is excreted in the urine. It is 
rapidly distributed in total body water and eliminated in a biphasic manner. IP administration of 20-30 
mg/M2 revealed a peak concentration in the peritoneal cavity of 6.4 ± 2.4 µg/ml and half-life of 85 ± 
30 minutes. The peak plasma concentration was 1.22 µg/ml, and half-life was 86 ± 31 minutes. It 
induces formation of DNA interstrand and DNA protein cross-links. 
 
Availability: The drug is available as an injectable kit. This kit contains an ampule of 100 mg (equivalent) 
melphalan, a 1 ml ampule of acid- alcohol diluent (containing 0.047 ml 37% HCl, q.s. to 1 ml with alcohol) 
and a 9 ml ampule of final duluent containing dipotassium phosphate, 108 mg propylene glycol 5.4 ml sterile 
water for injection q.s. 9.0 ml. This kit should be stored at room temperature and projected from light. 
 
Adminstration: The 100 mg injectable formulation is put into solution initially with the addition of 1 m acid- 
alcohol diluent. When dissolution is complete, the 9 ml final diluent is added. This final solution has a pH of > 
7 and should be used promptly. According to the manufacturer (8.5% hydrolysis 24 hours after mixing) a 
further dilution in D5W is also reportedly stable for 24 hours. 
 
Potential and Expected Toxicities: Human Toxicology: Melphalan's major systemic toxicity is bone 
marrow depression with secondary anemia, leukopenia and thrombocytopenia, usually occurring within three 
to five weeks of the onset of therapy and lasting four to eight weeks. These effects are exacerbated by prior 
chemotherapy or radiotherapy. Other adverse reactins include nausea, vomiting, diarrhea, stomatitis, 
esophagitis, colitis, increases in liver function and kidney function tests, renal/bladder necrosis, pulmonary 
fibrosis, respiratory distress, peripheral neuropathy, paresthesia, alopecia, fever and hypersensitivity 
including edema, rash and anaphylaxis. At high doses, supraventricular arrhythmias, including atrial 
fibrillation, may occur. The occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator  combination  chemotherapy. 
 
 
6.1.2.3 
CYCLOPHOSPHAMIDE [CYTOXAN®] 
Formulation: Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active 
compounds. The initial product is 4-hydroxycyclophosphamide (4- HC) which is in equilibrium with 
aldophosphamide which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent in vitro 
than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those produced by 
mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug. Cyclophosphamide is well absorbed orally with a 
bioavailability greater than 75%. The plasma half-life ranges from 4.1 to 16 hours after IV administration and 
1.3 to 6.8 hours after oral administration. 
 
Availability: Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium bicarbonate/100 mg 
cyclophosphamide and the lyophilized powder for injection contains 75 mg mannitol/100 mg 
cyclophosphamide. Storage at or below 25oC (77oF) is recommended. The product will withstand brief 
exposures to temperatures up to 30oC (86oF).  
 
Administration: Cyclophosphamide for Injection: Reconstitute with Sterile Water or Bacteriostatic Water for 
Injection (paraben preserved only) to a concentration of 20 mg/mL. Solutions reconstituted with preservative 
should be used within 24 hours if stored at room temperature or within 6 days if stored under refrigeration. If 
administered as undiluted drug at the 20 mg/mL concentration, reconstitute with NS only to avoid a 
hypotonic solution. Cyclophosphamide may be further diluted in dextrose or saline containing solutions for IV 
use


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
31 
Potential and Expected Toxicities: Common immediate toxicities related to the use in a conditioning 
chemotherapy include anorexia, nausea & vomiting (acute and delayed), bone marrow suppression 
(leukopenia, thrombocytopenia, anemia), hemorrhagic cystitis, alopecia, immune suppression, abdominal 
discomfort and diarrhea. Potential delayed toxicity is gonadal dysfunction. 
 
6.1.2.5  RITUXIMAB (RITUXAN®)  
Formulation: Rituximab is a genetically engineered chimeric murine/human monoclonal antibody, which 
binds specifically to the antigen CD20 (human B lymphocyte restricted differentiation antigen, Bp35) located 
on the surface of pre B and mature B lymphocytes of both normal and malignant cells. The antibody is an 
IgG kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human 
constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light 
chains of 213 amino acids and has an approximate molecular weight of 145 kD. It is produced in mammalian 
cell (Chinese Hamster Ovary) culture. CD20 regulates an early step(s) in the activation process for cell cycle 
initiation and differentiation, and possibly functions as a calcium ion channel. Rituximab binds to the CD20 
antigen on B lymphocytes and recruits immune effector functions to mediate B-cell lysis. Possible 
mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cell mediated 
cytotoxicity. The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.  
 
Availability: Rituximab is a sterile, clear, colorless, preservative free liquid concentrate for intravenous 
administration. Rituximab is supplied at a concentration of 10 mg/ml in either 100 mg (10 ml) or 500 mg (50 
ml) single use vials. The product contains 9.0 mg/ml sodium chloride, 7.35 mg/ml sodium citrate dihydrate, 
0.7 mg/ml polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5. Store refrigerated at 
temperatures of 2-8°C (36-46°F). Protect from direct sunlight.  
 
Administration: Dilute to a final concentration of 1 to 4 mg/ml in saline or dextrose containing solutions. 
Rituximab solutions for infusion may be stored at 2-8°C (36-46°F) for 24 hours and have been shown to be 
stable for an additional 24 hours at room temperature. DO NOT ADMINISTER AS AN INTRAVENOUS 
PUSH OR BOLUS. Premedication consisting of acetaminophen and diphenhydramine should be 
administered prior to each infusion. Since transient hypotension may occur during Rituximab infusions, 
consider withholding antihypertensive medications 12 hours prior to infusion.  
 
For each course of Rituximab after premedication with acetaminophen and diphenhydramine, the first 
infusion should be started at 0.5 mg/kg/hr, maximum 50MG/HR for 30 minutes. The rate may be increased 
by 0.5 mg/kg/hr, maximum 50MG/HR increments every 30 minutes up to a maximum rate of 400MG/HR, as 
tolerated by the patient.  
 
If infusion related events occur at any time during the infusion the rate should be slowed or the infusion 
stopped until resolution occurs. Additional diphenhydramine may need to be given or other medications to 
treat the events occurring. The patient may be re-challenged after resolution of the event with the rate at 
50% of the rate at which the infusion was running when the event occurred. 
 
Potential and Expected Toxicities: Single doses of up to 500 mg/m2 and weekly x 4 doses of 375 mg/m2 
have been administered without dose limiting toxicity. Adverse events are most common during the initial 
antibody infusion and usually consist of grade 1 or 2 fever (73%), asthenia (16%) chills (38%) nausea (19%), 
vomiting (11%), rash (14%) and tumor site pain (3%). Hematologic toxicity is usually mild and reversible. 
Rituximab has caused severe infusion reactions including urticaria, hypotension, angioedema, hypoxia, or 
bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events, transient decreases in the WBC 
or platelet count (patients with high levels of circulating tumor cells or bone marrow involvement), tumor lysis 
syndrome (patients with high numbers of circulating malignant lymphocytes or high tumor burden, bulky 
lesions), hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and death, other viral 
reactivations (JC virus,  cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West 
Nile virus, and hepatitis C virus), mucocutaneous reactions (paraneoplastic pemphigus, Stevens-Johnson 
syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis), bowel 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
32 
obstruction and perforation, serious cardiovascular events e.g. cardiac arrhythmia (reported in rheumatoid 
arthritis patients), renal toxicity including acute renal failure requiring dialysis. 
 
 
6.1.2.6   TACROLIMUS (FK506, PROGRAF®) 
Formulation: Tacrolimus, previously known as FK506, is  the  active  ingredient  in  Prograf®. Tacrolimus 
is a macrolide immunosuppressant produced  by  Stretocyces  Tsukubaensis.  Tacrolimus has an empirical 
formulation of C44H69NO12-H2O and a formula weight of 822.05. Tacrolimus appears as white crystals or 
crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol 
and chloroform.  Tacrolimus inhibits  T-lymphocyte  activation,  although  the exact mechanism of action is 
not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A 
complex of tacrolimus-FKBP-12,  calcium,  calmodulin,  and calcineurin is then formed and the phosphatase 
activity  of  calcineurin  inhibited.  This effect  may prevent the dephosphorylation and translocation of nuclear 
factor of activated  T-cells  (NF-AT),  a nuclear component thought to initiate gene transcription for the 
formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-
lymphocyte activation (i.e., immunosuppression). 
 
Availability: Prograf is available for oral administration as capsules (tacrolimus capsules) containing the 
equivalent of 1mg or 5mg of anhydrous tacrolimus. Inactive ingredients include lactose, hydroxypropyl 
methylcellulose, croscarmellose sodium, and magnesium stearate. The 1 mg capsule shell contains gelatin 
and titanium dioxide, and the 5-mg capsule shell  contains  gelatine,  titanium dioxide, and ferric oxide. 
Prograf® is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5mg 
anhydrous tacrolimus in 1 ml for administration by IV infusion only. Each mL contains polyoxyl 60 
hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v. Prograf injection must 
be diluted with 0.9% sodium chloride injection or 5% dextrose injection before use. 
 
Administration: Tacrolimus is administered as a continuous infusion. Oral preparation will be 
administered on empty stomach every 12 hours. 
 
Potential and Expected Toxicities: Possible side effects of tacrolimus include: depressed kidney function, 
high blood sugar, high blood potassium, skin rash, headache, nausea, vomiting.  Less common side effects 
are loss of appetite, sleep disturbances, vivid dreams, hallucinations, high blood pressure, seizure, 
decreased level of consciousness, anemia, agitation, tremors, irritability,  slurred speech,  tingling  in  the  
hands  and  feet,  pain  in  the  palms  and  soles  of  the  feet,  weakness, and abnormal blood cell levels. 
All of these side effects are reversible by reducing the dose or discontinuing the drug. Rare fatal cases of 
severe allergic reactions have been reported in patients receiving cyclosporine and it is possible that similar 
reactions could also occur in patients receiving tacrolimus.  
 
  6.1.2.7  METHOTREXATE  [TREXALL®] 
 
Formulation: Methotrexate (formerly amethopterin) is an antimetabolite. Methotrexate  inhibits dihydrofolic 
acid reductase. Dihydrofolates must be reduced to  tetrahydrofolates  by  this  enzyme before they can be 
utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, 
methotrexate interferes with  DNA  synthesis,  repair,  and  cellular replication. Actively proliferating tissues 
such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary 
bladder are in general more sensitive to this effect of methotrexate. Refer to the FDA-approved package 
insert for more information. Renal excretion is the primary route of elimination and is dependent upon dosage 
and route of administration. With intravenous administration, 80% to 90% of the administered dose is 
excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less 
of the administered dose. Methotrexate elimination is reduced in patients with impaired renal function, 
ascites, or pleural effusions. After intravenous administration, the initial volume of distribution is 
approximately 0.18l/kg (18% of body weight) and steady state volume of distribution is approximately 0.4 to 
0.8 l/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
33 
cell membranes by means of a single carrier-mediated active transport process. At serum concentrations 
greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular 
concentrations can be achieved. Methotrexate in serum is  approximately  50%  protein bound. Laboratory 
studies demonstrate that it may be displaced from plasma albumin by various compounds including 
sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. 
 
Availability: Each 20 mg and 1 g vial of lyophilized powder contains methotrexate sodium equivalent to 20 
mg and 1 g methotrexate respectively. Store at controlled room temperature, 20°C-25°C (68°C- 77°C); 
excursions permitted to 15°C-30°C (59°F-86°F). Protect from light. 
 
Potential Drug Interactions: Methotrexate is partially bound to serum albumin, and toxicity may be 
increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and 
sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug 
should be carefully monitored. Oral antibiotics such as  tetracycline, chloramphenicol, and nonabsorbable 
broad-spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the 
enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. 
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate 
with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose 
methotrexate. Use of methotrexate with  penicillins  should  be carefully  monitored. 
 
Potential and Expected Toxicities: The most frequently reported adverse reactions associated with 
methotrexate use as GVHD prophylaxis include ulcerative stomatitis, leucopenia and suppressed 
hematopoiesis, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, 
undue fatigue, chills, and fever, dizziness and  decreased  resistance  to  infection. Methotrexate may be  
associated  with  increased  rates  of  pulmonary  complications  after transplantation. The risk of infections 
is due to the suppression of hematopoiesis after transplantation. 
 
6.1.2.8   LEVETIRACETAM  (KEPPRA®) 
Formulation: Levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its 
molecular formula is C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated 
to existing antiepileptic drugs (AEDs). Levetiracetam is  a  white  to  off-white  crystalline powder with a faint 
odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 
g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in 
acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL 
solvent.) 
 
Availability: Keppra is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (orange), 
and 1000 mg (white) tablets and as a clear, colorless, grape-flavored liquid (100 mg/mL) for oral 
administration. Keppra (levetiracetam) 500 mg/5 mL injection is  a  clear,  colorless,  sterile solution. It is 
supplied in single-use 5 mL vials. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
 
Administraion: Keppra injection is for intravenous use only and  must  be  diluted  prior  to administration. 
Keppra injection (500 mg/5 mL) should be diluted in 100 mL of a compatible diluent (NS, Lactated Ringer’s 
injection or D5W) and administered intravenously as a 15-minute IV infusion. 
 
Potential and Expected Toxicities: Toxicities reported in more than 1% in adults are asthenia, headache, 
infection, pain, anorexia, somnolence, dizziness, nervousness, anorexia vertigo, amnesia, anxiety, hostility, 
paresthesia, emotional lability, pharingitis, rhinitis, increased cough, sinusitis, diplopia. 
 
  6.1.2.9  FILGRASTIM  (r-metHuG-CSF,  NEUPOGEN®) 
 
Formulation: Filgrastim, (recombinant human granulocyte-colony stimulating factor, r-metHuG- 
CSF), is a protein produced by E. coli into which has been inserted the human granulocyte colony- 
stimulating factor gene.  Filgrastim differs from the natural protein in that the N-terminal amino acid is a 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
34 
methionine and it is not o- glycosylated. G-CSF functions as a hematopoietic growth hormone; it increases 
the proliferation, differentiation, maturation and release of precursor cells into mature blood cells of the 
neutrophil lineage. G-CSF has demonstrated in vitro  effects  on  mature  neutrophils, including an increased 
expression of chemotactic receptors, enhanced phagocytosis and intracellular killing of certain organisms, 
as well as enhanced killing of target cells that are bound by antibodies. 
 
Approximately 6,400 patients in U.S. and international based trials have participated in clinical trials of 
filgrastim to date, and the worldwide commercial populations receiving filgrastim totaled approximately 
190,000. The drug has been found to be well tolerated at dosages up to 69 µg/kg/day given IV or SC, with 
no toxic effects attributable to filgrastim. A maximum tolerated dose has not yet  been determined. 
 
Availability: Recombinant G-CSF, filgrastim, NEUPOGEN®, is supplied as a clear, colorless preservative-
free liquid for parenteral administration. Single use vials contain filgrastim 300 µg/ml in a preservative-free 
solution with 0.59 mg/ml acetate, 50 mg/ml  sorbitol,  0.004%  Tween®  80,  0.035 mg/ml sodium, and water 
for injection, USP, pH 4.0 to make 1 ml filgrastim Neupogen® is commercially available in 2 vial sizes: 300 
µcg/1 ml and 480 µg/1.6 ml. Dilution: If required, filgrastim may be diluted in 5% dextrose.  Filgrastim diluted 
to concentrations between 5 and 15 µg/ml should be protected from adsorption to plastic materials by 
addition of albumin (Human) to a final concentration of 2 mg/ml. When diluted in 5% dextrose or 5%  
dextrose  plus  albumin  (Human), filgrastim is compatible with glass bottles, PVC and polyolefin IV bags, 
and polypropylene syringes. Dilution of filgrastim to a final concentration of less than 5 µg/ml is not 
recommended at any time. Do not dilute with saline at any time; product may precipitate. Storage and 
Stability: Filgrastim should be stored in the refrigerator at 2 - 8°C (36 - 46°F). Avoidshaking. Prior to 
injection, filgrastim may be allowed to reach room temperature for a maximum of 24 ho urs.  Any vial left at 
room temperature for greater than 24 hours should be discarded. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration, whenever solution and 
container permit; if particulates or discoloration are observed, the container should not be used. 
 
Administration:   Filgrastim is administered as a single daily injection by SC bolus injection, by short 
IV infusion (15 - 30 minutes), or by continuous SC or continuous IV infusion. 
 
Potential and Expected Toxicities: The most frequently reported adverse effect was medullary bone 
pain, occurring in 20 - 25% of patients in Phase II and III trials. When bone pain was reported it often 
preceded a rise in the circulating neutrophil count; it occurred more frequently in patients treated with 20 - 
100 µg/kg/day of intravenously administered filgrastim and less often in lower subcutaneous doses. The pain 
was generally mild to moderate in severity, and usually controlled with non-narcotic analgesics such as 
acetaminophen. Other side effects include transient but reversible increases of alkaline phosphatase, lactate 
dehydrogenase and uric acid levels. These occurred in 27 - 58% of patients, without clinical  sequelae  
observed.  Elevations of  leukocyte  alkaline  phosphatase  levels have also been noted but the significance 
is not yet known. Less frequently reported adverse events related to filgrastim administration include 
subclinical splenomegaly, exacerbation of pre-existing skin rashes, alopecia, and thrombocytopenia, and  
cutaneous  vasculitis.  Rarely, allergic-type  reactions have occurred. Since the commercial introduction of 
filgrastim there have been reports (<1 in 4,000 patients) of symptoms suggestive of an allergic-type reaction, 
but in which an immune component has not been demonstrated. These have generally been characterized 
by systemic symptoms involving at least two body systems, most often skin (rash, urticaria, edema), 
respiratory (wheezing, dypsnea), and cardiovascular (hypotension,  tachycardia).   Some  reactions  occurred  
on  initial  exposure. Reactions tended to occur within the first thirty minutes after administration and 
appeared to occur more frequently in those patients who received filgrastim intravenously. Rapid resolution 
of symptoms occurred in most cases after administration of standard supportive care, and symptoms 
recurred in more than half the patients when rechallenged. 
 
6.2 
DEFINITION OF DOSE-LIMITING TOXICITY 
Subjects will be evaluated for toxicity according to the Common Terminology Criteria for Adverse 
Events (CTCAE) of the National Cancer Institute (NCI) version 4.0 [Appendix D] 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
35 
DLTs are defined as any of the below treatment emergent toxicities, with attribution to carfilzomib, 
which occur within day +28. 
 
NON-HEMATOLOGIC 
• 
≥ Any Grade 3 toxicity (excluding nausea, vomiting, diarrhea) 
• 
≥ Grade 3 nausea, vomiting, or diarrhea, despite maximal antiemetic/antidiarrheal therapy 
• 
≥ Grade 4 fatigue lasting for ≥ 7 days 
• 
≥ Grade 2 neuropathy with pain 
EXCEPTIONS 
The following adverse events are NOT considered DLTs. 
• 
Any grade hematologic adverse events which are fully expected after conditioning chemotherapy 
• 
Fever < 38.5 °C plus all the followings 
• 
No evidence of infection e.g. positive culture and 
• 
No unstable vital signs at the discretion of the investigator or the attending physician.  
• 
Any grade alopecia 
• 
Any grade hyperglycemia attributed to dexamethasone 
6.3 
DOSE WITHHOLD AND RESTART 
If a DLT occurs before day +7, the remaining dose(s) of carfilzomib will NOT be administered. 
The remaining doses may be re-initiated at the investigator’s discretion if the event is assessed not to 
be a true DLT. However, carfilzomib will NOT be administered after day +7. 
 
6.4 
SAFETY  CONSIDERATIONS 
Based upon the experience in the Phase 1 and 2 clinical studies with carfilzomib, the followings are 
recommended: 
 
• 
Dexamethasone 4 or 8 mg IV (See 3.5.5) will be administered prior to each dose of carfilzomib. If 
treatment-related fever, rigors, chills, and/or dyspnea are observed with a 4 mg dexamethasone, an 8 
mg dose IV may be administered prior to subsequent doses after resolution of the symptoms and no 
document infection is identified. 
 
• 
In patients with high tumor burden, a “first dose effect”, 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 next day, may be the clinical sequelae of  rapid  tumor  lysis  and/or  cytokine release. Treatment 
with high-dose glucocorticoids (e.g. methylprednisolone 50–100 mg IV) is recommended. In addition, 
intravenous fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be available for 
immediate use and instituted, as medically indicated. However, patients who are eligible for this study 
generally do not have high tumor burden at the time of carfilzomib administrations. 
• 
Acyclovir or similar, which is used for standard infectious transplant prophylaxis, should be given per 
institutional prophylaxis guidelines. 
• 
Renal function or creatinine clearance (CrCl) changes are mostly transient, reversible, and non- 
cumulative. All subjects should be well hydrated during carfilzomib administrations. Clinically significant 
electrolyte abnormalities should be promptly 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. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
36 
• 
Subjects with documented infection should not be dosed with carfilzomib until the infection has been 
controlled with appropriate treatment. Low-grade fever alone (<38.5 C) without unstable vital signs or 
documented infection occurs frequently during transplant admission due to various non- infectious 
etiologies, and should not the sole reason to hold carfilzomib. 
• 
Carfilzomib administration can cause nausea, vomiting, diarrhea, or constipation sometimes requiring 
the use of antiemetics or antidiarrheals. Fluid and electrolyte replacement should be administered to 
prevent dehydration. 
6.4.1 CONTRAINDICATIONS 
 
Besides allergy to carfilzomib, there are no known contraindications for carfilzomib. 
 
6.4.2 SPECIAL WARNINGS AND PRECAUTIONS FOR USE 
The warnings and precautions in this section are based on the analysis of safety data from Phase 1 and 2 
clinical studies submitted as part of the initial FDA NDA submission for monotherapy treatment of multiple 
myeloma patients who have received at least 2 prior therapies, including bortezomib and 
an immunomodulatory agent. 
 
6.4.3 CARDIAC ARREST, CONGESTIVE HEART FAILURE, MYOCARDIALISCHEMIA 
Death due to cardiac arrest has occurred within a day of carfilzomib administration. New onset or worsening 
of pre-existing congestive  heart  failure  with  decreased  left  ventricular  function  or myocardial ischemia 
has occurred following administration of carfilzomib. Cardiac failure events (eg, cardiac failure congestive, 
pulmonary edema, ejection fraction decreased) were reported in  7%  of patients. Monitor for cardiac 
complications and manage promptly. Unless otherwise specified in the individual protocol, withhold 
carfilzomib for Grade 3 or 4 cardiac events until recovery and consider whether to restart carfilzomib based 
on a benefit/risk assessment. Patients with NYHAClass III and IV heart failure, myocardial infarction in the 
preceding  6  months,  and  conduction  abnormalities uncontrolled by medications were not eligible for the 
clinical trials. These patients may be at greater risk for cardiac complications. 
 
6.4.4 PULMONARY  COMPLICATIONS 
Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with carfilzomib and was 
Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. 
Unless otherwise specified in the individual protocol, withhold carfilzomib for pulmonary hypertension until 
resolved or returned to baseline and consider whether to restart carfilzomib based on a benefit/risk 
assessment. Dyspnea was reported in  35%  of  patients  enrolled  in  clinical  trials. Grade 3 dyspnea 
occurred in 5% of patients; no Grade4 eventsoccurred, and 1death (Grade 5) was reported. Monitor and 
manage dyspnea immediately. Unless otherwise specified in the individual protocol, interrupt carfilzomib 
until symptoms have resolved or returned to baseline. 
 
6.4.5 INFUSION  REACTIONS 
Infusion reactions in clinical trials were characterized by a spectrum of systemic symptoms including fever, 
chills, arthralgia, myalgia, facial flushing, facial edema, vomiting,  weakness,  shortness  of breath, 
hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 
24 hours after administration of carfilzomib. Administer dexamethasone prior to carfilzomib to reduce the 
incidence and severity of infusion reactions. Inform patients of the risk and symptoms and to contact 
physician if symptoms of an infusion reaction occur. 
 
6.4.6 TUMOR LYSIS SYNDROME [TLS] 
Tumor lysis syndrome occurred following carfilzomib administration in <1% of patients. Patients with multiple 
myeloma and a high tumor burden are at greater risk for TLS. Prior to receiving carfilzomib, patients must be 
well hydrated. Patients should be monitored for evidence of TLS during carfilzomib treatment, and manage 
promptly. Carfilzomib is to be on hold until TLS is resolved. 
 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
37 
6.4.6.1 
GUIDELINES  FOR  MONITORING,  PROPHYLAXIS,  AND  TREATMENT  OF  TUMOR 
LYSIS SYNDROME (TLS) 
TLS, which may be associated with multi-organ failure, has been observed in some patients with high tumor 
burden who have been treated with carfilzomib. This is not expected in typical patients undergoing 
allogeneic HCT. In addition, transplant subjects routinely receive IV hydration during conditioning 
chemotherapy and stem cell infusion. 
 
For few subjects who are at high risk of developing TLS, standard TLS prevention measures must be 
followed including adequate hydration and initiation of allopurinol or alternative, per the institutional 
guidelines. 
 
6.4.6.2 
Hydration and Fluid Monitoring 
Subjects should receive adequate IV hydration during  conditioning  chemotherapy  until  at  least  24 hours 
after the last dose of carfilzomib per standard institutional guidelines for TLS. For few exceptional  subjects  
who  achieve  adequate  oral  fluid  intake  and  do  not  receive  maintenance  IV 
hydration during carfilzomib administrations [day +1 to +7], a bolus of 250–500 mL of IV normal saline (or 
other appropriate IV fluid formulation) must be given before AND after each dose. 
 
6.4.6.3 
Clinical and Laboratory Monitoring 
Symptoms and signs that may be indicative of TLS, such as fevers, chills/rigors, dyspnea, nausea, vomiting, 
muscle tetany, weakness, or cramping, seizures, and decreased urine output. Appropriate chemistries, 
including creatinine, and complete blood counts (CBC) with platelet count are routinely performed and 
reviewed daily in transplant setting. 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 and appropriate management for TLS must be initiated per institutional 
guidelines. 
 
6.4.6.4 
Management of Tumor Lysis Syndrome 
Management of TLS should be performed appropriately or per the institutional guidelines. All cases of TLS 
must be reported to Amgen as a Serious Adverse Event (SAE) through the normal process within 24 hours 
of the clinical site becoming aware of the event. 
 
6.4.7 HEPATIC TOXICITY AND HEPATIC FAILURE 
Cases of hepatic failure, including fatal cases, have been reported (<1%). Carfilzomib can cause elevations 
of serum transaminases and bilirubin. Unless otherwise specified in the individual protocol, withhold 
carfilzomib in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver 
abnormalities until resolved or returned to baseline. After resolution, consider if restarting carfilzomib is 
appropriate. However, carfilzomib will NOT be administered after day +7. 
 
6.4.8 EMBRYO-FETAL  TOXICITY 
Carfilzomib can cause fetal harm when administered to a pregnant woman based on its mechanism of action 
and findings in animals. There are no adequate and well-controlled studies in pregnant women using 
carfilzomib. Carfilzomib caused embryo-fetal toxicity  in  pregnant  rabbits  at  doses  that  were lower than in 
patients receiving the recommended dose. 
 
In general, it is extremely rare for female subjects receiving conditioning chemotherapy to conceive in the 
first 2-4 weeks after transplant. However, all male and female subjects and their partners must use dual 
barrier methods of contraception in the first 8 weeks after transplant when having sexual intercourse. 
 
6.5 
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 transplant (day 0) 
through the end of the subject’s study participation. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
38 
6.5.1 
REQUIRED  CONCOMITANT  MEDICATIONS 
Dexamethasone 4 or 8 mg IV (See 3.5.5) will be administered prior to each dose of carfilzomib. If 
treatment-related fever, rigors, chills, and/or dyspnea are observed with a 4 mg dexamethasone, an 8 
mg dose IV may be administered prior to subsequent doses after resolution of the symptoms and no 
document infection is identified. 
 
Subjects should receive antibiotic prophylaxis, which are already part of routine standard infectious 
prophylaxis in an allogeneic stem cell  transplant  setting.  The  carfilzomib-specific  infectious prophylaxis 
includes ciprofloxacin or levofloxacin or similar and acyclovir or similar (famiciclovir, valacyclovir). Other 
transplant-specific fungal, PCP and encapsulated bacteria prophylaxis follows institutional  guidelines.  
 
6.5.2.    OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
Allogeneic   transplantation   procedure   will   follow   standard   allogeneic   transplant   
protocol   per institutional BMT guidelines including the use of 
1. 
Granulocyte- and Granulocyte-Macrophage Colony-Stimulating Factors [G-CSF, GM-CSF] 
2. 
Blood products 
3. 
Concomitant   supportive   medications   e.g.   anti-emetics,   anti-diarrheal,   ursodiol   
(Actigall), narcotic pain medication, parenteral nutrition 
4. 
Allopurinol or rasburicase is allowed. 
5. 
Vitamins and supplements are allowed and at the Investigator’s discretion. 
6 
Other  supportive  medications  e.g.  bisphosphonates  and  erythropoietic  agents  are  
generally not used during transplant admission but are allowed if indicated subsequently. 
 
6.5.3 
EXCLUDED  CONCOMITANT  MEDICATIONS 
Concurrent therapy with other approved or investigative anticancer agents in the first 28 days 
is NOT allowed. Disease-specific maintenance therapy with  targeted  agents  e.g.  tyrosine  
kinase  inhibitors may be used after day 28 at Investigator’s discretion 
 
7. 
STUDY TESTS AND OBSERVATIONS 
 
7.1 
REQUIRED OBSERVATIONS (TABLE 2) 
Per standard BMT practice,  subjects will  be followed closely during a transplant admission,  
which typically lasts for 3-4 weeks and will be followed in outpatient BMT clinic after discharge 
per institutional guidelines and as clinically indicated. The required BMT Clinic visits  for  
history  and physical examination and tests are shown in Table 2. 
 
After 1 year, subjects will be followed in clinic for history and physical examination, with 
appropriate tests and investigations per institutional guidelines or at Investigator’s  discretion  
for  relapse  and GVHD until 3 years post transplant. 
 
First clinical GVHD or relapse (before or after 1 year) requires a complete workup per 
Table 2.  
 
 
 
 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
39 
Table 2: REQUIRED OBSERVATIONS 
 
Baseline 
 
Days Post-Transplant 
 
3, 8, 14 
 
30 
 
60 
 
100 
 
180 
 
270 
 
365 
First 
Clinical 
GVHD or 
Relapse 
 
+/- 7 
days 
+/-14 
days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
Within 7 
days 
Blood for PD study 
day -6, 0 
day 3 
 
 
 
 
 
 
 
Blood for GVHD markers 
day -6, 0 
day 3,8,14 
 
 
 
 
 
 
 
History and physical 
exam, Karnofsky 
1 week prior 
to admission 
 
X 
X 
X 
X 
X 
X 
X 
CBC, chemistry, LFTs,      
* Direct Bilirubin 
 
X 
X 
X 
X 
X 
X 
X 
Blood for Chimerism 
 
X 
 
X 
X 
 
X 
X 
** BM examination 
Per 
Institutional 
Guidelines 
 
 
 
X 
 
 
 
 
*** Disease Staging 
 
X 
 
X 
X 
X 
X 
X 
 
 
 * Direct Bilirubin is required at Basline. For subsequent timepoints, Direct Bilirubin is required only if Total 
Bilirubin (part of LFTs) is abnormal at that timepoint. 
 
** Bone marrow specimens will be submitted for investigations following standard procedure or  
institutional guidelines for BMT procedure.  Other special disease specific testings e.g. cytogeneitcs, 
FISH and molecular investigations are sent as indicated. 
 
*** Disease restaging tests follow disease-specific institutional guidelines or at the Investigator’s 
discretion. If disease restaging is not indicated at any time point per institutional guidelines, disease status is 
recorded at the investigator’s discretion. 
 
Correlative pharmacodynamic study on peripheral blood mononuclear cells (PBMC) on day -6, 0 and 
+3 and GVHD markers on day -6, 0, +3, +8, +14 and +30 are secondary endpoints, thus failure to 
acquire specimens will not be considered a protocol violation. 
 
Required observations performed outside of  the  recommended  window  for  emerging  clinical indications 
may be accepted at the PI’s discretion for the closest associated follow up and not considered a deviation. 
 
7.2 
DEFINITIONS OF END POINTS 
 
7.2.1 
SAFTY END POINTS 
 
7.2.1.1 
DOSE-LIMITED TOXICITIES [DLTs] 
See Section 6.2. 
 
7.2.1.2 
GRAFT FAILURE 
 
Primary graft failure will be defined as the inability to achieve an ANC >500/uL AND a platelet 
count >20,000/uL, without transfusion support and without other causes, e.g. viral infection or 
medication, within 35 days post transplant. 
 
Secondary graft failure will be defined as the inability to maintain an ANC >500/uL and a platelet 
count >20,000/uL, without transfusion support and without other causes, e.g. viral infection or 
medication, after initial neutrophil AND platelet engraftments. 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
40 
 
Neutrophil engraftment day will be defined as the first day of the 3 consecutive days  of achieving 
ANC >500/uL 
 
Platelet engraftment day will be defined as the first day of the 2 consecutive days of achieving 
platelet count >20,000/uL, without transfusion support 
 
7.2.1.3 
REGIMEN-RELATED TOXICITY [RRT] 
An RTT is defined as an adverse event (AE) that occurs within 37 days after transplant or 30 days 
after the last dose of carfilzomib (day +7), and is considered to be a direct consequence and a related 
event as a result of the combination of conditioning chemotherapy, GVHD prophylaxis regimen and 
carfilzomib. 
 
7.2.1.4 
TREATMENT-RELATED  MORTALITY  [TRM] 
TRM is defined as any death due to the transplant procedure, including death attributable directly to 
carfilzomib therapy. Death due to, but not limited to, the following events are considered a TRM: RRT, 
GVHD, infection and other transplant specific complications 
 
7.2.2 
EFFICACY END POINTS 
 
7.2.2.1 
EVENT 
“Event” is defined as the occurrence of “Relapse/Progression” or “Grade III-IV acute GVHD” or 
“Chronic GVHD requiring systemic treatment”. 
7.2.2.2 
RELAPSE / PROGRESSION 
See Appendix B for disease-specific definitions of Response Criteria, including relapse/progression. 
 
Patholigical confirmation of relapse is preferred. However, clinical diagnosis alone is allowed at the 
investigator’s discretion if the manifestation is deemed unlikely to be an alternative diagnosis. 
 
Progression is applied for disease not in complete remission or complete response at transplant. 
 
7.2.2.3 
GVHD 
 
7.2.2.3.1 
Acute GVHD 
Pathological  diagnosis  of  acute  GVHD  is  preferred.  Clinical  diagnosis  alone  is  allowed  at  the 
investigator’s clinical judgment or following Institutional Guidelines for diagnosis of acute GVHD. 
 
See Appendix C for Acute GVHD Assessment Guidelines. Acute GVHD onset may be beyond day 
+100. Grading of acute GVHD severity is mandatory and is the maximal grade that eventually occurs. 
 
Only grade III-IV acute GVHD is defined as part of the “Event” in this study. However, the onset of 
Grade III-IV aGVHD is defined as the first day of acute GVHD onset of any grade. 
 
7.2.2.3.2 
Chronic GVHD 
Diagnosis of chronic GVHD is mainly based on clinical evaluation. A biopsy is at the investigator’s 
discretion. See Appendix C for Chronic GVHD Assessment Guidelines. 
 
7.2.2.4 
EVENT-FREE SURVIVAL [EFS] 
 
7.2.2.4.1 
EFS is defined as the period from day 0 to the “onset” day of the first “Event”. 
 
7.2.24.2 Day 0 is the day of stem cell infusion (transplant) or the “LAST” day of stem cell infusion [Day 
0B, Day 0C etc; in this case, Day 0A is the first day] if there are >2 days of stem cell infusion 
(transplant). 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
41 
 
7.2.2.4.3 
Event  is  defined  as  relapse/progression  or  clinical  grade  III-IV  acute  GVHD  or  chronic 
GVHD requiring systemic treatment. 
 
7.2.2.4.4 
The onset of “clinical Grade III-IV acute GVHD” is defined as the first day of any grade 
acute GVHD manifestation leading to the maximal clinical Grade III-IV aGVHD. Pathological  dianosis  
of  acute  GVHD  is  preferred  but  not  mandatory.  Clinical  diagnosis  of  acute GVHD at the 
investigator’s discretion, after appropriate exclusion of other causes, is sufficient. 
 
7.2.2.4.5 
The  onset  of  “chronic  GVHD”  is  defined  as  the  first  day  of  initial  chronic  GVHD 
manifestation leading to subsequent systemic therapy. 
 
Non-systemic  or  non-absorbable  topical immunosuppressive  medications,  which  are  not  considered 
systemic therapy, include 
 
1. 
Topical preparation of immunosuppressive agents for skin, ocular and oral mucosa 
2. 
Oral beclomethasone and oral budesonide for GI GVHD 
3. 
Other immunosuppsive topical preparation which is not absorbed systemically. 
 
Clinical  diagnosis  of  chronic  GVHD  at  investigator’s  discretion,  after  appropriate  exclusion  of  other 
causes, is sufficient [Appendix C]. Pathological diagnosis may be required as indicated. 
 
7.2.4.4.6 
The onset of Relapse/Progression is defined as the day of pathological diagnosis or, in 
case of no pathology confirmation, the day of first clinical manifestation of relapse/progression. 
 
7.2.2.5 
PROGRESSION-FREE SURVIVAL [PFS] 
PFS is defined as the period from day 0 to the day of the first Progression /Relapse [see 7.2.2.2]. 
 
7.2.2.6 
OVERALL SURVIVAL [OS] 
OS is defined as the period from day 0 to the day of death from any cause. 
 
7.3 
CORRELATIVE  STUDIES 
 
We will obtain 6 heparinized (green top) blood samples (approximately 42 mL total) from each patient 
during the course of the study for pharmacodynamic and GVHD marker studies. [Table 3] Samples [a 7 
mL extra draw each] will be collected coincidently with routine daily blood draws on the patients 
during transplant admission. All samples will be processed, frozen, and banked. 
 
Correlative  pharmacodynamic  and  GVHD  markers  study  on  day  -6,  0,  +3,  +8,  +14  and  +30  are 
secondary endpoints, thus failure to acquire specimens will not be considered a protocol violation. 
 
7.3.1 Pharmacodynamic (PD) Assay 
A  PD  assay  measuring  the  inhibition  of  proteasome  chymotrypsin-like  activity  in  peripheral  blood 
mononuclear cells [PBMNs] will be used. 
 
Peripheral blood will be collected in heparinized green top tubes prior to conditioning chemotherapy 
(day-6), prior to transplant (day 0) and after the first two doses of carfilzomib (day +3) when there 
remain an adequate number of PBMCs. 
 
PBMCs  will  be  isolated  and  frozen  for  PD  assay  of  proteazome  inhibition  according  to  the 
manufacturer’s protocol and samples and standards will be run in duplicate. 
 
Samples  will  be  batched  and  run  simultaneously  in  order  to  maximize  efficiency  and  enhance 
comparison of samples 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
42 
7.3.2 Plasma GVHD Cytokine Assay 
Peripheral blood will be collected in heparinized green top tubes prior to conditioning chemotherapy 
(day-6), prior to transplant (day 0) and after two and four doses of carfilzomib (day +3, +8, +14 and 
+30). 
 
We will use commercially available ELISA kits to measure GVHD cytokine levels. 
 
In each case, assays will be performed according to the manufacturer’s protocol and  samples and 
standards will be run in duplicate. 
 
Samples  will  be  batched  and  run  simultaneously  in  order  to  maximize  efficiency  and  enhance 
comparison of samples.  
 
8. 
  STUDY  DISCONTINUATION 
 
8.1 
STOPPING RULE FOR EXCESSIVE GRAFT FAILURE 
Stopping rules  for excessive graft  failure will apply to all subjects entered on  study.  Engraftment failure 
will be defined as the inability to achieve an ANC ≥500/uL and a platelet count ≥20,000/uL, without 
transfusion support, within 35 days post transplant. We consider engraftment failure in more than 10% of 
subjects to be unacceptable. Once 10 subjects have been enrolled and followed for 35 days, we will 
continually monitor the rate of EF35 and stop if we have strong evidence that the actual rate of EF35 is 
above 10%. Subjects who have not engrafted and die within 35 days of transplant will be considered to have 
graft failure and contribute to the number of events of EF35. The official stopping rules are displayed in Table 
3 and are the number of events that would produce a 95% confidence interval of which lower bound exceeds 
our upper limit of 10%. If AE35 equals or exceeds the numbers in Table 3, enrollment will be halted and the 
protocol will be re-evaluated and either closed or modified and re-approved before re-opening. 
 
8.2 
STOPPING RULE FOR EXCESSIVE MORTALITY 
Stopping rules for excessive mortality will apply to all subjects entered on study.  We  consider   all- cause 
mortality in more than 30% of all subjects within 100 days of transplant (ACM100) to be unacceptable. Once 
10 subjects have been enrolled and followed for 100 days, we will continually monitor the rate of ACM100 
and stop if we have strong evidence that the actual rate of ACM100 is above 30%. The official stopping rules 
are displayed in Table 3 and are the number of events that would produce a 95% confidence interval of 
which lower bound exceeds our upper limit of 30%. If ACM100 equals or exceeds the numbers below, 
enrollment will be halted and the protocol will be re- evaluated and either closed or modified and re-
approved before re-opening. 
 
Although this stopping rule requires 100 days of follow-up for each subject, we will not halt accrual to wait for 
full follow-up of previously-enrolled subjects. For example, we will enroll the 11th subject as soon as they are 
eligible, regardless of whether the first 10 subjects have all been followed for 100 days. With a projected 
enrollment of just over 1 subject per month, we would expect to enroll the 11th and 12th subjects before the 
10th subject is fully followed for ACM100.  As  a  result,  there  is  a possibility of enrolling one or two 
additional subjects on this study before we discover the stopping rule has been met. 
 
Table 3: STOPPING RULES FOR EXCESS GRAFT FAILURE AND MORTALITY 
 
Number of Enrolled Subjects 
Number of Subjects with EF 
Within 35 Days 
Number of Subjects with ACM 
Within 100 Days 
10 
4 
7 
15 
5 
9 
20 
6 
11 
25 
7 
13 
30 
8 
15 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
43
 
9. 
ADVERSE EVENTS 
 
9.1 
ADVERSE EVENT REPORTING 
 
Adverse events occurring following study  registration,  during  standard  conditioning  chemotherapy, 
stem cell infusion until prior to carfilzomib administration, will not be reported. Study-related therapy does 
not begin until initiation of cafilzomib administration. Adverse events will be reported through day 
100, directly related to the study drug (carfilzomib) as mentioned in section 5.2.6 previously. Following day 
100, patients will still be followed for relapse, GVHD and survival data only.  
 
9.2 
DEFINITIONS OF ADVERSE EVENTS WITH COMMERCIALLY AVAILABLE AGENTS 
 
This trial utilizes commercially available agents for transplant therapy for patients with hematological 
malignancies. Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases, an agent obtained commercially may be used for indications not 
included in the package label. In this case, the agent is still considered to be  a commercial agent and the 
procedures described below should be followed. 
 
An adverse event (AE) is any untoward medical occurrence  in  a  patient  or  clinical  investigation 
subject whether or not it may have a causal relationship with this  treatment.  An  AE  includes 
significant exacerbation of any baseline medical condition including, but not limited to, the disease 
under study. Reporting requirements may include the following considerations: 1) the characteristics 
of the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
 
Expected events are those that have been previously identified as resulting from administration of the 
agent. For commercially available agents, an adverse event is considered unexpected, for reporting 
purposes only, when either the type of event or the severity of the event is not listed in: 
 
The current NCI Agent-Specific Adverse Event List (provided in the Drug Information Section of this 
protocol); or the drug package insert (for treatments with commercially available agents). 
 
Except where otherwise specified, Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 
will be used to grade adverse events in this study. 
 
9.3 
DEFINITIONS OF ADVERSE EVENTS WITH INVESTIGATIONAL AGENTS 
As previously stated, 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 with investigational agents, therefore, can be any unfavorable and unintended sign (including 
laboratory finding), symptom or disease temporally associated with participation in an investigational 
study, whether or not considered drug-related.  In addition to new events, any increase in the severity 
or frequency of a pre-existing condition that occurs after the subject signs 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 investigator’s brochure (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”.  
As in the case of commercially available agents, 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. 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 4 below may be used: 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
44
 
Table 4 
 
 
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. 
 
9.4 
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 event is suspected to be not related if: 
- 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). 
 
9.5 
REQUIRED ADVERSE EVENT REPORTING 
Therapy for hematological malignancies, with or without stem cell transplantation, is associated with 
significant toxicity. These toxicities are generally viewed as an anticipated consequence of therapy 
rather than an adverse event. To summarize, any grades 1 or 2 toxicities and any “expected” 
hematologic grade  3 or 4  toxicities will not be reported  to the IRB nor to the  FDA, as these  are 
expected in patients undergoing stem cell transplantation for hematological malignancies.  
 
DLTs and grade 3, 4 and 5 non-hematologic toxicity events  with  a  possible,  probable  or  definite 
relation to the commercial agent will be reported to the IRB and the FDA. In addition, high rate of 
engraftment failure or excessive mortality will trigger a stopping rule (section 8). Only adverse events, 
directly related to the study drug (carfilzomib) will be reported through day 100, as mentioned in section 
5.2.6 previously. 
 
Severity 
 
intervention/therapy  required. 
 
 
 
 
 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
45
9.6 
HEMATOLOGIC TOXICITY AND DEFINITION OF PRIMARY ENGRAFTMENT FAILURE 
 
For hematologic toxicity purposes, neutrophil recovery will be evaluated in all study subjects. 
Neutrophil toxicity will be graded by a modification of the Autologous Bone Marrow Transplant Studies 
Supplementary Toxicity Criteria. The occurrence of any grade 3-5 neutrophil toxicity will be reported 
as an adverse event within 7 days of its occurrence. Neutrophil toxicity will be  evaluated  post transplant 
using the following criteria: 
 
Grade 3:   Neutrophils< 500/uL for 35 – 56 days post therapy. 
Grade 4:   Neutrophils< 500/uL for > 56 days post therapy. 
Grade 5:   Death due to infection associated with neutrophil count < 500/uL. 
 
The failure to achieve a neutrophil count >500/uL within 35 days of the stem cell infusion will be 
defined as primary engraftment failure, and reported as an adverse event and counted in the stopping 
rules for Engraftment Failure (section 8). 
 
9.7 
SERIOUS ADVERSE EVENT REPORTING PROCEDURES 
 
All serious adverse events (SAE) which require reporting must be reported immediately (i.e. within 24 
hours) to the Principal Investigator or a designee, followed by written documentation to the IRB from 
the Principal Investigator (including the PI’s or designee’s medical summary of the SAE) within 7 days 
of the Investigator’s knowledge of occurrence. The Clinical Trials Office (CTO) staff will coordinate 
the reporting process between the investigator and the IRBMED and between the investigator and the 
FDA within the applicable regulatory reporting regulations. Copies of all correspondence and reporting 
documents will be maintained in a regulatory file held by the CTO. 
 
Patients removed from study due to graft failure or other reasons will continue to be observed for 
adverse events for an additional 30 days. Deaths due to primary graft failure will be reported as a SAE 
regardless of when the patient was removed from study. Other significant events or deaths related to 
causes other than graft failure occurring after the 30- d a y  observation period will be considered 
not related to the study drug and will therefore not be reported. 
 
In addition to complying with all applicable regulatory reporting laws and regulations, Sponsors and 
Investigators are  requested to immediately  (within  24 hours) notify  Amgen GlobalSafety of all serious 
adverse events/experiences (SAEs) prior to or at the same time they are reported to either an IRB or 
a regulatory authority. 
 
Amgen Global Saftey: 
• 
Hotline: Amgen Safety 800-77-AMGEN (800-772-6436) 
• 
Safety Fax: 1-888-814-8653 
• 
Secure connection email: svc-ags-in-us@amgen.com  
  
See Appendix E for Amgen specific Policy on Adverse Reaction Reporting Procedure.  
 
9.8 
DATA SAFETY MONITORING BOARD (DSMB) 
 
A Data and Safety Monitoring Committee (DSMC) consisting of protocol investigators and the data 
managers involved in the conduct of the trial will meet monthly to review the conduct and activity 
of the trial.  A written summary will be made at each meeting and signed by the Principal Investigator 
(or a co-investigator designated by the principal investigator, if necessary) and the data manager 
responsible for the study. 
 
During the course of these meetings, the investigators will discuss issues relating to (a) enrollment 
activity, (b) safety and adverse event reporting, (c) protocol violations or deviations  by  individual 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
46
subjects, (d) data entry and completeness. A determination will be made at each meeting to continue 
the trial without modification, modify the trial, or terminate the trial based the attainment of stopping 
rule criteria. 
 
Reports of these DSMC meetings will be kept on file in the Cancer Center Clinical Trials office (CTO). 
The data manager assigned to the trial will be responsible for maintenance of these records. These 
Data and Safety Monitoring Reports and any other pertinent documents will be submitted to  the 
University of Michigan Comprehensive Cancer Center Data and Safety Monitoring Board (DSMB) for 
review on a monthly basis unless specified more frequently by a DSMB ruling. 
 
10. 
STATISTICAL  ANALYSIS 
 
10.1 
STUDY DESIGN 
Subjects will be enrolled on the first dose level 1 of phase 1 part (Table 2), following a standard 3+3 
dose escalation. For any  given  dose level, if none  of the 3 subjects has developed a  DLT, dose 
escalation will follow. If a DLT occurs in any dose level, the cohort will be expanded to 6. Further dose 
escalation will be made only if DLTs occur in <2 out of 6 subjects. If >2 of 6 develop DLTs, dose de- 
escalation will be made to the previous level. The optimal or maximal tolerated dose (MTD) is the 
dose level in which 0 of 3 or 1 of 6 subjects develops DLTs. 
 
Table 1: DOSE ESCALATION SCHEDULE 
Dose Level 
Carfilzomib (mg/m2) 
Day +1 
Day +2 
Day +6 
Day +7 
1 
20 
20 
20 
20 
2 
20 
20 
27 
27 
3 
20 
20 
36 
36 
4 
20 
20 
45 
45 
 
After MTD or the optimal dose level is identified, a total of 35 subjects are needed on this dose level. 
[See 10.2]. 
 
10.2 
SAMPLE SIZE CONSIDERATIONS 
Based on the University of Michigan experience on fludarabine-based related donor allo-HCT, the event-
free survival at 1 year was 15% [unpublished data]. Event is defined as relapse/progression, grade 
III-IV acute GVHD or chronic GVHD requiring systemic therapy. 
 
We expect that adding carfilzomib to a standard regimen will increase EFS at 1 year from 15% to 35% 
and 35 subjects need to be evaluated for primary efficacy endpoint, with α error of 0.05 and statistical 
power of 80%. Thus, we will enroll 37 patients in the optimal dose used in the phase II part, assuming 
2 patients will not be evaluable for endpoint analysis.  
 
N = Number required 
p0   = Historical probability of event within 1 year 
= (1-0.15) = 
0.85 
p1  = Desired probability of event within 1 year 
= (1-0.35) = 
0.65 
Zα   = 1.96 for 5% significance level 
Zβ   = 0.84 for 80% power 
For phase 1 part, up to 18 additional subjects may be needed for possibility of 6 subjects per 
cohort. Thus, we plan to enroll a maximum 55 patients (18 max Phase I, 37 Phase II). 
 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
47
 
10.3 
PLANNED METHODS OF ANALYSIS 
 
10.3.1 PRIMARY AND SECONDARY OUTCOMES 
OS  and  PFS  will  be  modeled  using  the  Kaplan-Meier  method.  TRM,  relapse  and  GVHD  will  
be estimated with the cumulative incidence. 
 
10.3.2 LABORATORY  CORRELATES 
The association of the values and percentage change of each NFκB and GVHD biomarker with the 
primary and secondary outcomes will be estimated with Cox regression (for OS and PFS) and 
competing risks regression (TRM, relapse, and GVHD). 
 
10.4     SAFETY ANALYSIS 
Subjects will be followed closely for AEs and SAEs, the details of which including incidences, relationship, 
severity, etc, will be reported to IRB and Amgen Global Saftey within required intervals. Once 10 patients 
have been followed for 35 days, graft failure rate will be determined for excess graft failure [section 8.1].  
Once they have been followed for 100 days, all- cause-mortality will be determined for excess all-cause-
mortality [section 8.2]. 
 
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  inhibiton 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 
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-b-cyclodextrin (SBE-b-CD, Captisol®). 
 
11.3 
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. See INSTRUCTIONS FOR  STORAGE AND USE OF LYOPHILIZED 
CARFILZOMIB FOR INJECTION, for Investigator Sponsored Trials (IST's), 19 February 2013, 
Version 3.0. 
 
11.4 
ACCOUNTABILITY 
Amgen 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 Amgen Inc. 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 Amgen Inc. and by regulatory authorities. 
 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
48
Only sites that cannot destroy unused drug on-site will be required to return their unused supply of 
investigational product. 
 
12. 
REGULATORY  OBLIGATIONS 
 
12.1 
INFORMED  CONSENT 
 
Informed consent shall be obtained prior to an enrollment of a subject into the study. 
 
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 Amgen Inc.  
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 re- 
approval 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 Amgen Inc. as follows: 
 
Amgen Inc.. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
 
The Investigator is also responsible for notifying their IRB or Ethics  Committee  of  any  significant 
adverse events that are serious and/or unexpected. The Sponsor-Investigator is also required to notify the 
FDA in writing of any SAE that is both unexpected and related to the study drug, within 15 days of 
knowledge of the event, and within 7 days of a death related to the study drug. 
 
All safety information will be provided to investigator initiated study PI/institution in the 
Investigator Brochure (IB). Updates to the IB will be sent to the PI/institution in a timely manner 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 Amgen Inc. 
with a summary of the trial’s outcome. 
 
12.3 
PRE-STUDY  DOCUMENTATION  REQUIREMENTS 
Informed consent, eligibility checklist and registration forms shall be obtained before subjects can receive 
any study treatments, including conditioning chemotherapy. 
 
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 Amgen Inc., 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 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
49
Identifiable Health Information, 45 CFR 164.508. 
 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Shall any evidence of safety concerns or lack of efficacy arises, study enrollment will be on hold 
Investigation and assessment will be performed for a determination to amend or terminate the study. 
 
13.2 
STUDY DOCUMENTATION AND ARCHIVE 
Required study documentation and archive will be maintained by institutional Clinical Trial Office and 
Amgen Inc. 
 
13.3 
STUDY MONITORING AND DATA COLLECTION 
 
13.3.1 Subject Safety 
A Data and Safety Monitoring Committee (DSMC) consisting of protocol investigators and the data 
managers involved in the conduct of the trial will meet monthly to review the conduct and activity of the 
trial.  A written summary will be made at each meeting and signed by the Principal Investigator (or a co-
investigator designated by the principal investigator, if necessary) and the data manager responsible for 
the study. 
 
During the course of these meetings, the investigators will discuss issues relating to (a) enrollment activity, 
(b) safety and adverse event reporting, (c) protocol violations or deviations  by  individual subjects, (d) 
data entry and completeness. A determination will be made at each meeting to continue the trial without 
modification, modify the trial, or terminate the trial based on the attainment of stopping rule criteria. 
 
Reports of these DSMC meetings will be kept on file in the Cancer Center Clinical Trials office (CTO). The data 
manager assigned to the trial will be responsible for maintenance of these records. These Data and Safety 
Monitoring Reports and any other pertinent documents will be submitted to  the University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Board (DSMB) for review on a monthly basis unless 
specified more frequently by a DSMB ruling. 
 
 
13.3.2 Lack of Efficacy 
Subjects will be followed closely for AEs and SAEs, which will be reported to IRB and Amgen Inc. and 
required interval. Once 20-25 subjects have been followed for 100 days, we will perform an interim 
analysis to evaluate whether the projected primary endpoint will be potentially achieved or, in contrast, 
relapse and/or GVHD increase(s). 
 
 
14. 
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189. Siegel D, Wang L, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti V, Alsina M, Jakubowiak AJ, 
Jagannath D, McDonagh KT, Belch A, Bahlis NJ, Shustik C, Le MH, Kunkel L, Bennett MK, 
Kauffman M, Vij R, and The Multiple Myeloma Research Consortium (MMRC) 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. 
Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 303. 
190. Ravi Vij, Michael Wang, Jonathan L. Kaufman, Sagar Lonial, Andrzej J. Jakubowiak, A. Keith 
Stewart, Vishal Kukreti, Sundar Jagannath, Kevin T. McDonagh, Melissa Alsina, Nizar J. Bahlis, 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
62
Frederic J. Reu, Nashat Y. Gabrail, Andrew Belch, Jeffrey V. Matous, Peter Lee, Peter Rosen, 
Michael Sebag, David H. Vesole, Lori A. Kunkel, Sandra M. Wear, Alvin F. Wong, Robert Z. 
Orlowski, and David S. Siegel. An open-label, single-arm, phase 2 (PX-171-004) study of single- 
agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma 
Blood 2012 119:5661-5670. 
191. Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, 
Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single- 
agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been 
previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. 
192. Ravi  Vij,  Jonathan  L.  Kaufman,  Andrzej  J  Jakubowiak,  A.  Keith  Stewart,  Sundar  Jagannath, 
Vishal Kukreti, Kevin T. McDonagh, Melissa Alsina, Nizar J Bahlis, Andrew Belch, Frederic J. 
Reu, Nashat Y Gabrail, Jeffrey Matous, David H. Vesole, Robert Z. Orlowski, Mai H. Le, Peter 
Lee,  Michael  Wang,  and  The  MMRC.  Carfilzomib:  High  Single  Agent  Response  Rate  with 
Minimal Neuropathy Even In High-Risk Patients.  ASH Annual Meeting Abstracts 2010 116:1938. 
193.Thomas  Martin,  Seema  B.  Singhal,  Ravi  Vij,  Michael  Wang,  A.  Keith  Stewart,  Sundar 
Jagannath, Sagar Lonial, Andrzej J Jakubowiak, Vishal Kukreti, Nizar J Bahlis, Melissa Alsina, 
Asher A. Chanan-Khan, George Somlo, Francis Buadi, Frederic J. Reu, Jeffrey A. Zonder, Kevin 
Song, Edward A. Stadtmauer, Alvin F. Wong, Marcy Vallone, Yu-Lin Chang, Michael Kauffman, 
Robert Z. Orlowski, and David Samuel diCapua Siegel. Baseline Peripheral Neuropathy Does   
Not  Impact  the  Efficacy  and  Tolerability  of  the  Novel  Proteasome  Inhibitor  Carfilzomib  (CFZ): 
Results  of  a  Subset  Analysis  of  a  Phase  2  Trial  In  Patients  with  Relapsed  and  Refractory 
Multiple Myeloma (R/R MM).  ASH Annual Meeting Abstracts 2010 116:3031. 
194. Badros AZ, Vij R, Martin T, Zonder JA, Woo T, Wang, Lee S, Wong A, and Niesvizky R. Phase I 
Study of Carfilzomib in Patients (Pts) with Relapsed and Refractory Multiple Myeloma (MM) and 
Varying Degrees of Renal Insufficiency.Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 
3877. 
195. Seema B. Singhal, David Samuel diCapua Siegel, Thomas Martin, Ravi  Vij,  Michael  Wang, Andrzej 
J Jakubowiak, Sagar Lonial, Vishal Kukreti, Jeffrey A. Zonder, Alvin F. Wong, Leanne McCulloch, 
Michael Kauffman, Ashraf Z. Badros, Ruben Niesvizky, Robert Z. Orlowski, A. Keith Stewart, and 
Sundar Jagannath. Pooled Safety Analysis From Phase (Ph) 1 and 2 Studies of Carfilzomib 
(CFZ) In Patients with Relapsed and/or Refractory  Multiple  Myeloma  (MM)  ASH Annual Meeting 
Abstracts 2010 116. 
196. Seema Singhal, David S. Siegel, Thomas Martin, Ravi Vij, Luhua Wang, Andrzej J Jakubowiak, 
Sagar Lonial, Vishal Kukreti, Jeffrey A. Zonder, Alvin F. Wong, Leanne McCulloch, Ashraf Z. 
Badros, Ruben Niesvizky, Robert Z. Orlowski, A. Keith Stewart, Debbi Kotlovker, and Sundar 
Jagannath. Integrated Safety From Phase 2 Studies of Monotherapy Carfilzomib in Patients with 
Relapsed and Refractory Multiple Myeloma (MM): An Updated Analysis ASH Annual Meeting 
Abstracts 2011 118:1876 . 
197. Seema Singhal, David S. Siegel, Thomas Martin, Ravi Vij, Luhua Wang, Andrzej J Jakubowiak, 
Sagar Lonial, Vishal Kukreti, Jeffrey A. Zonder, Alvin F. Wong, Leanne McCulloch, Ashraf Z. 
Badros, Ruben Niesvizky, Robert Z. Orlowski, A. Keith Stewart, Debbi Kotlovker, and Sundar 
Jagannath. Integrated Safety From Phase 2 Studies of Monotherapy Carfilzomib in Patients with 
Relapsed and Refractory Multiple Myeloma (MM): An Updated Analysis ASH Annual Meeting 
Abstracts 2011 118:1876 . 
198. Andrzej J Jakubowiak, David S. Siegel, Seema Singhal, Thomas Martin, Sagar Lonial, Vishal 
Kukreti, Nizar Bahlis, Asher Alban Chanan-Khan, Melissa Alsina,  George  Somlo,  Francis  K Buadi, 
Frederic J. Reu, Kevin W. Song, Lori Kunkel, Sandra M. Wear, Alvin F. Wong, Robert Z. 
Orlowski, A. Keith Stewart, Sundar Jagannath, and Luhua Wang. Unfavorable Cytogenetic 
Characteristics Do Not Adversely Impact Response Rates in Patients with Relapsed and/or 
Refractory Multiple Myeloma Treated with Single-Agent Carfilzomib on the 003 (A1) Study. ASH 
Annual Meeting Abstracts 2011 118:1875. 
199. Andrzej J Jakubowiak, David S. Siegel, Seema Singhal, Thomas Martin, Sagar Lonial, Vishal 
Kukreti, Nizar Bahlis, Asher Alban Chanan-Khan, Melissa Alsina,  George  Somlo,  Francis  K Buadi, 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
63
Frederic J. Reu, Kevin W. Song, Lori Kunkel, Sandra M. Wear, Alvin F. Wong, Robert Z. Orlowski, 
A. Keith Stewart, Sundar Jagannath, and Luhua Wang. Unfavorable Cytogenetic Characteristics 
Do Not Adversely Impact Response Rates in Patients with Relapsed and/or Refractory Multiple 
Myeloma Treated with Single-Agent Carfilzomib on the 003 (A1) Study. ASH Annual Meeting 
Abstracts 2011 118:1875. 
200. Andrzej J Jakubowiak, Thomas Martin, Seema B. Singhal, Michael Wang, Ravi Vij, Sundar 
Jagannath, Sagar Lonial, Vishal Kukreti, Francis Buadi, Lauren Bray, Marcy Vallone, Michael 
Kauffman, Robert Z. Orlowski, David Samuel diCapua Siegel, and The MMRC. Responses and 
Survival Are Not Affected by Cytogenetics In Patients with Relapsed and Refractory Multiple Myeloma 
(R/R MM) Treated with Single-Agent Carfilzomib. ASH Annual Meeting Abstracts 2010 116:1942 . 
201. Niesvizky R, Martin TG 3rd, Bensinger WI, Alsina M, Siegel DS, Kunkel LA, Wong AF, Lee S, 
Orlowski RZ, Wang M. Phase Ib dose-escalation study (PX-171-006)  of  carfilzomib, lenalidomide, 
and low-dose dexamethasone in relapsed or progressive multiple myeloma. Clin Cancer Res. 
2013 Apr 15;19(8):2248-56. 
202. Michael Wang, Thomas Martin, William Bensinger, Melissa Alsina,  David  Samuel  DiCapua Siegel, 
Edward Kavalerchik, Ruben Niesvizky. Final results from the phase Ib/II study (PX-171-006) of carfilzomib, 
lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma. J 
Clin Oncol 31, 2013 (suppl; abstr 8529) 
203. Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E,  Huang  M, Orlowski RZ, 
Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide and low-dose 
dexamethasone in relapsed or progressive  multiple  myeloma. Blood. 2013 Sep 6. Blood. 2013 Oct 
31;122(18):3122-8. 
204. Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, et al. A Phase I/II Trial Of 
Cyclophosphamide, Carfilzomib, Thalidomide  and  Dexamethasone  (CYCLONE)  In Patients With 
Newly Diagnosed Multiple Myeloma: Final Results Of MTD Expansion Cohort. Blood 2013 122:3179 
[ABSTRACT] 
205. Cerrato C, Petrucci MT, Genuardi M, Gentilini F, Conticello C, Oliva S, et al. A Phase II Study 
With Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)  For  Newly Diagnosed Multiple 
Myeloma Blood 2013 122:685 [ABSTRACT] 
206. Kolb B, Hulin C, Caillot D, Benboubker L, Tiab M, Touzeau C, et al. Carfilzomib PLUS Melphalan 
and Prednisone (CMP) Is A Promising Combination Therapy For The Treatment Of Elderly Patients 
With NEWLY  Diagnosed  Multiple  Myeloma:  Results  Of  A  PHASE  I/II Trial In 68 CASES.  Blood 
2013 122:1933 [ABSTRACT] 
207. Tripsas CK, Meid K, Cropper SJ, Mostyn P, Warren D, Paba-Prada CE, et al. Carfilzomib, 
Rituximab and Dexamethasone (CaRD) Is Highly  Active  and  Offers  a Neuropathy Sparing  
Approach For Proteasome-Inhibitor Based Therapy In  Waldenstrom’s Macroglobulinemia. Blood 
2013 122:757 [ABSTRACT] 
208. Landau H, Venkata JK, Kang Y, Koehne G, Chung DJ, Lendvai N, 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 122:3329 [ABSTRACT] 


Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation 
 
 
 
 
 
64 
 
 
15. 
APPENDICES 
 
 
APPENDIX A 
 
KARNOFSKY PERFORMANCE SCALE 
 
Scale % Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity, minor symptoms of disease 
80 
Normal activity with effort, some signs of symptoms of disease 
70 
Cares for self (consistent with age), unable to carry on normal activity or do active 
work/school/play 
60 
Requires occasional assistance (beyond age-appropriate care), but is able to care 
for  most of their needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled, requires special caer and assistance 
30 
Severely disabled, hospitalization is indicated although death is not imminent 
20 
Hospitalization is necessary, very sick, active support treatment is necessary 
10 
Moribund, fatal processes progressing rapidly 


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65
 
 
APPENDIX B 
 
TABLE A. RECOMMENDED RESPONSE DEFINITIONAFTER TREATMENT FOR CLL 
 
Parameter 
Complete 
Response 
Partial Response 
Progressive 
Disease 
Stable Disease 
*Lymphadenopathy 
None above1.0 
cm 
Decrease > 50% 
from baseline 
Increase 
>50% over 
baseline 
Change -49% 
to +49% 
from baseline 
Liver and/or spleen 
size 
Normal size 
Decrease > 50% 
from baseline 
Increase 
>50% over 
baseline 
Change -49% to 
+49% 
from baseline 
Constitutional 
symptoms 
None 
Any 
Any 
Any 
Leukocyte Count 
> 1500/mm3 
<1500/mm3  AND 
> 50% 
improvement from 
pre-CloBu2 
baseline 
Any 
Any 
Circulating B 
Normal 
Decrease of > 50% 
Increase > 
Change  -49% 
lymphocytes 
from  pre-CloBu2 
50% 
to +49%from 
baseline 
overpre- 
pre-CloBu2 
CloBu2 
baseline 
baseline 
Platelet count 
> 100,000/mm3 
(untransfused) 
<100,000/mm3 
AND 
Increase >50% 
from pre-CloBu2 
baseline 
Decrease 
>50% 
from pre- 
CloBu2 
baseline 
<100,000/mm3 
AND 
Change  -49% 
to +49%from 
pre-CloBu2 
baseline 
Hemoglobin 
> 11.0 g/dL 
<11.0 g/dL AND 
Decrease of 
<11.0 g/dL 
(untransfused) 
Increase of > 2 
>2 g/dL 
AND 
g/dL over pre- 
from pre- 
Change -1.9 
CloBu2baseline 
CloBu2 
g/dL to -1.9 
baseline 
g/dLfrom pre- 
CloBu2 
baseline 
Marrow 
Normocellular, 
AND 
< 30% 
lymphocytes, 
AND no B- 
lymphoid 
nodules 
Hypocellular, OR 
B-lymphoid 
nodules, OR 
Decrease of 
lymphocytes > 
50% from baseline 
BUT remaining > 
30% involvement , 
Or  not done 
Increase of 
lymphcytes 
>30% from 
baseline 
No change of 
marrow 
infiltratefrom 
baseline 
Modified from Eichhorst B and Hallek M. Revision of the guidelines for diagnosis and therapy of chronic 
lymphocytic leukemia (CLL). Best Practice & Research Clinical Haematology 2007;20:469-477. 
 
* Sum of the product of the diameters of multiple lymph nodes 


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66 
 
 
TABLE B. RECOMMENDED RESPONSE CRITERIA FOR LYMPHOMA (including PET CT) 
 
 
 
 
 
 
 
 
 
 
 
p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma.J of Clin Oncol 2007;25(5):579-586. 
Recommended for use with Diffuse Large B-CellLymphoma and Hodgkin Disease/Lymphoma. 
SPD denotes sum of the product of the diameters. 
 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
Complete 
Response 
Disappearance 
of all 
evidenceof 
disease 
(a) FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET negative 
(b) Variably FDG-avid or 
PETnegative; regression to 
normal size on CT 
Not palpable, nodules 
disappeared 
Infiltrate cleared on repeat biopsy 
indeterminate by 
morphology,immunohistochemistr 
should be negative 
Partial 
Regression of 
>50% decrease in SPD of up to 
>50% decrease in SPD of nodules 
Irrelevant if positive prior to thera 
Response 
measurable 
6largest dominant masses; no 
(for single nodule ingreatest 
cell type should be specified 
disease AND 
increase in size of other nodes 
transverse diameter); no increase in 
no new sites 
(a) FDG-avid or PET positive 
size of liver or spleen 
prior to therapy; one or more 
PETpositive at previously 
involved site 
(b) Variably FDG-avid or 
PETnegative; regression on CT 
Stable 
Disease 
Failure to 
attain CR/PR 
or PD 
(a) FDG-avid or PET positive prior to therapy; PET positive at prior sites of disease AND 
no new sites on CT or PET 
(b) Variably FDG-avid or PET negative; no change in size of previous lesions on CT 
Relapsed 
disease 
or 
Progressive 
disease 
Any new lesion 
or increase by 
50% of 
previously 
involved sites 
from nadir 
(a) Appearance of a new 
lesion(s) >1.5 cm in any axis, 
>50% increase in SPD of more 
than one node, or >50% 
increase in longest diameter of 
a previously identified node >1 
cm in short axis 
(b) Lesions PET positive if 
FDG-avid lymphoma or PET 
positive prior to therapy 
>50% increase from 
nadir in the SPD of any previous 
lesions 
New or recurrent involvement 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
67
 
 
TABLE C. RECOMMENDED RESPONSE CRITERIA FOR LYMPHOMA (not including PET CT) 
 
Response 
Category 
Physical 
Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
Complete  Response 
Normal 
Normal 
Normal 
Normal 
Complete  Response 
(unconfirmed) 
Normal 
Normal 
Normal 
indeterminate 
Normal 
Normal 
>75% decrease 
Normal or 
indeterminate 
Partial Response 
Normal 
Normal 
Normal 
Positive 
Normal 
> 50% decrease 
> 50% decrease 
Irrelevant 
Decrease in liver/spleen 
> 50% decrease 
> 50% decrease 
Irrelevant 
Relapse/Progression 
Enlarging  liver/spleen, 
new sites 
New or increased 
New or increased 
Reappearance 
 
Cheson BD, Horning SJ, Coiffier B et al. Report of an International Workshop to Standardize Response Criteria forNon-Hodgkin’s Lymphoma. 
J of Clin Oncol 17(4); 1999: 1244. 
 
 
TABLE D. 


 P h a s e  1/ 2  St u d y  of  C arfil z o mi b  i n All o g e n ei c  H e m at o p oi eti c  C ell  Tr a n s pl a nt ati o n   
 
 
 
 
 
 
6 8  
 
 
C h e s o n B, Fi s h er R, B arri n gt o n S, et al. R e c o m m e n d ati o n s f or I niti al E v al u ati o n, St a gi n g a n d R e s p o n s e A s s e s s m e nt of H o d g ki n a n d N o n -H o d g ki n 
L y m p h o m a – t h e L u g a n o Cl a s sifi c ati o n. J Cli n O n c ol 2 0 1 4; 3 2: 3 0 5 9-3 0 6 7.  
 
 
 
 
 
 
T A B L E D. ( C O N T’ E D)  


 P h a s e  1/ 2  St u d y  of  C arfil z o mi b  i n All o g e n ei c  H e m at o p oi eti c  C ell  Tr a n s pl a nt ati o n   
 
 
 
 
 
 
6 9  
 
 
C h e s o n B, Fi s h er R, B arri n gt o n S, et al. R e c o m m e n d ati o n s f or I niti al E v al u ati o n, St a gi n g a n d R e s p o n s e A s s e s s m e nt of H o d g ki n a n d N o n -H o d g ki n 
L y m p h o m a – t h e L u g a n o Cl a s sifi c ati o n. J Cli n O n c ol 2 0 1 4; 3 2: 3 0 5 9-3 0 6 7.  
 
 
 
 
 
T A B L E D. ( C O N T’ E D)  


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70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
71 
Cheson B, Fisher R, Barrington S, et al. Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma – the Lugano Classification. J Clin Oncol 2014;32:3059-3067.  
TABLE E. RECOMMENDED RESPONSE CRITERIA FOR MULTIPLE MYELOMA [MM]  
 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
72 
 
 
TABLE E. RECOMMENDED RESPONSE CRITERIA FOR MULTIPLE MYELOMA [CONT’ED] 
 
 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
73 
 
TABLE F. RECOMMENDED RESPONSE CRITERIA FOR WALDENSTROM’S MACROGLOBULINEMIA [WM] 
 
Complete 
Response 
CR 
IgM in normal range, and disappearance of monoclonal protein by immunofixation; no histological 
evidence of bone marrow involvement, and resolution of any adenopathy /organomegaly (ifpresent at 
baseline), along with no signs or symptoms attributable to WM. Reconfirmation of the CR status is 
required by repeat immunofixationstudies. 
VeryGoodPartial 
Response 
VGPR 
A 90% reduction of serum IgM and decrease in adenopathy/organomegaly (if present at baseline) on 
Physical examination or on CT scan. No new symptoms or signs of active disease. 
Partial Response 
PR 
A 50% reduction of serum IgM and decrease in adenopathy/organomegaly (if present at baseline) on 
physical examination or on CTscan.No new symptoms or signs of active disease. 
MinorResponse 
MR 
A 25% but <50% reduction of serum IgM. No new symptoms or signs of active disease. 
StableDisease 
SD 
A <25% reduction and <25%increase of serum IgM without progression of adenopathy/organomegaly, 
cytopenias or clinically significant symptoms due to disease and/or signs of WM. 
Progressive 
Disease 
PD 
A >25% increase in serum IgM by protein electrophoresis confirmed by a second measurement or 
progression of clinically significant findings due to disease (i.e. anemia, thrombocytopenia, leukopenia, 
bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever 38.4°C, drenching 
nightsweats, 10% body weight loss, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia or 
amyloidosis) attributable to WM. 
 
Treon SP, Merlini G, Morra E, et al. Report from the Sixth International Workshop on Waldenstrom's Macroglobulinemia. Clin Lymph Myeloma 
Leukemia 2011; 11:69-73. 
VargheseAM, RawstronAC,AshcroftAJ, et al.Assessment of bone marrow response in Waldenström's macroglobulinemia. Clin Lymph Myeloma 
2009; 9:53-5. Table 1. Summary of Updated Response Criteria adopted at the 6th International Workshop on Waldenstrom's Macroglobulinemia. 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
74 
 
TABLE G. RECOMMENDED RESPONSE CRITERIA FOR ACUTE LYMPHOBLASTIC LEUKEMIA [ALL] 
 
Response Criteria for Blood and Bone Marrow 
CR 
No circulating blasts or extramedullary disease 
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement 
Trilineage hematopoiesis (TLH) and <5% blasts 
Absolute neutrophil count (ANC) >1000/microL 
Platelets  >100,000/microL 
No recurrence for 4 weeks 
CR with incomplete blood count recovery (CRi) 
Recovery of platelets but <100,000 orANC is <1000/microL 
Overall response rate (ORR=CR + CRi) 
Refractory  disease 
Failure to achieve CR at the end of induction 
Progressive disease (PD) 
Increase of at least 25% in the absolute number of circulating or bone marrow blasts or development of extramedullary disease 
Relapsed disease 
Reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a CR 
 
Response Criteria for CNS Disease 
CNS remission:Achievement of CNS-1 status ( ) in a patient with CNS-2 or CNS-3 status at diagnosis. 
CNS relapse: New development of CNS-3 status or clinical signs of CNS leukemia such as facial nerve palsy, brain/eye 
involvement, or hypothalamic syndrome. 
 
Response Criteria for Mediastinal Disease 
CR: Complete resolution of mediastinal enlargement by CT. 
CR Unconfirmed (CRu): Residual mediastinal enlargement that has regressed by >75% in the sum of the product of the greatest 
perpendicular diameters (SPD). 
PR: >50% decrease in the SPD of the mediastinal enlargement. 
PD: >25% increase in the SPD of the mediastinal enlargement. 
No Response (NR): Failure to qualify for PR or PD. 
Relapse: Recurrence of mediastinal enlargement after achieving CR or CRu. 
NCCN Guidelines Version 1.2013 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
75 
 
TABLE H. RECOMMENDED RESPONSE CRITERIA FOR ACUTE MYELOID LEUKEMIA [AML] 
 
 
 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
76 
 
TABLE I. RECOMMENDED RESPONSE CRITERIA FOR CHRONIC MYELOID LEUKEMIA 
[CML] 
 
CRITERIA FOR HEMATOLOGIC, CYTOGENETIC AND MOLECULAR RESPONSE 
 
Complete Hematologic Response [1] 
Complete normalization of peripheral blood counts with leukocyte count <10 x 109/L 
Platelet count < 450 x 109/L 
No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood 
No signs and symptoms of disease with disappearance of palpable splenomegaly 
 
Cytogenetic Response [2] 
Complete- No Ph-positive metaphases 
Partial- 1%-35% Ph-positive metaphases 
Major- 0%-35% Ph-positive metaphases (complete + partial) 
Minor- >35% Ph-positive metaphases 
 
 
Molecular Response [3,4] 
Complete molecular response - no detectable BCR-ABL by QPCR (International scale) 
using an assay with a sensitivity of at least 4.5 logs below the standardized baseline. 
Major molecular response - 3-log reduction in International Scale of BCR-ABL mRNA 
Relapse 
Any sign of loss of response (defined as hematologic or cytogenetic relapse) 
1 log increase in BCR-ABLtranscript levels with loss of MMR should prompt marrow 
evaluation for loss of CCyR but is not itself defined as relapse. 
 
1. Faderl S et al: Chronic myelogenous leukemia: Biology and therapy.Ann Intern Med 1999;131:207 219. 
2. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for 
newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004. 
3. HughesTP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or 
interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 
2003;349:1423-1432. 
4. HughesT, Deininger M, HochhausA, et al. Monitoring CMLpatients responding to treatment with 
tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for 
detecting BCR-ABLtranscripts and kinase domain mutations and for expressing results. Blood 
2006;108:28-37. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE J. 
 
MODIFIED INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR ALTERING NATURAL HISTORY OF 
MYELODYSPLASTIC SYNDROME  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-425. 
 
 
 
 
 
 
 
 
 


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TABLE J. (CONT’ED) 
 
MODIFIED INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR HEMATOLOGIC 
IMPROVEMENT FOR MYELODYSPLASIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-425. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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79
APPENDIX C 
 
 
TABLE A. RECOMMENDED GRADING AND STAGING OF ACUTE GVHD 
 
 
 
 
TABLE B. RECOMMENDED CATEGORIES OF ACUTE AND CHRONIC GVHD 
 
 
 
 


 Phase 1/2 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation  
 
 
 
 
 
 
80 
 
 
TABLE C. CLINCIAL FEATURES OF CHRONIC GVHD 
 
 


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81 
 
 
 
TABLE C. CLINCIAL FEATURES OF CHRONIC GVHD [Cont’ed] 
 
 


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82
 
 
 
TABLE D. RECOMMENDED ORGAN SCORING OF CHRONIC GVHD 
 


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83 
 
 
 
 
TABLE D. RECOMMENDED ORGAN SCORING OF CHRONIC GVHD [Cont’ed] 
 
 


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84 
 
 
APPENDIX D:  NCI-CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the 
National Cancer Institute (NCI) v4.0 
 
Publish Date:  September 15, 2009 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf 
 
 
APPENDIX E: 
AMGEN INC. DRUG SAFETY  
 
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 randomized but 
discontinues 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.  AEs continuing at 30 days post-last  dose  should  have  a  comment  in  the source 
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 laboratory abnormalities must be recorded as AEs on the CRF.  Grade 1 and 2 
abnormalities should only be recorded if they require treatment or are otherwise considered 
clinically significant by the Investigator. 
 
The Principal Investigator may delegate these duties to Sub-investigators and must ensure that 
these Subinvestigators are qualified to perform these duties under the supervision of  the Principal 
Investigator and that they are listed on the FDA Form 1572. 
 
A. 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. 


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• 
Requires  inpatient  hospitalization  or  prolongation  of  an  existing  hospitalization  (except 
scheduled hospitalizations for non-acute, unrelated cause 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. 
 
B. 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 Regulatoru Agencies may have additional requirements 
for expedited safety report submissions. 
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 Amgen 
Inc. Saftey 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. 
[ONLY FOR EUROPE: The Investigator is responsible to create an Annual Safety Report of the 
overall conduct of the specific study for distribution  to  the  EC(s)  and  Regulatory  Agencies. Amgen 
Inc. in addition creates an Annual Safety Report including listings of all Serious Adverse Drug 
Reactions from both Amgen Inc.  sponsored research and Investigator Sponsored Trials, and Amgen 
Inc. submits this report to the Regulatory Agencies in any country where there is clinical development 
or where the product is marketed. Amgen Inc. will provide the Sponsor with  the summary sections 
and overall conclusions of this Annual Safety Report.]Additionally, the Investigator is responsible for 
reporting adverse events to Amgen Inc. as described below: 
 
Expedited Reporting by Investigator to Amgen Inc. 
The Investigator must inform Amgen Inc. 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 


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86 
 
 
SUSARs}, but in no case any later than 1 business day from the submission date. This must be 
documented on a FDA 3500A MEDWATCH or CIOMS I (for EU studies) form.  This form must be 
completed and supplied to Amgen Inc. in English. 
 
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 MEDWATCH or 
CIOMS I form, and submitted to Amgen Inc. in the same timelines as outlined above. The Amgen Inc.  
protocol and the institutional protocol number should be included on all reports to Amgen Inc.. 
 
All other SAE’s will be sent to Amgen Inc. on a biannual basis in the form of a line listing in 
English. The line listing must include the following information; patient initials, date of birth, 
sex, SAE onset date, SAE stop date, event name (term), outcome, date of first dose of study 
drug(s), date of last dose of study drug(s) prior to the event, action taken with study drug(s) the 
Investigator’s assessment of causality (relationship to carfilzomib), and the Investigator’s 
assessment of expectedness to carfilzomib. The sponsor reserves the right to review the CRFs or 
source documents in response to any inquires by regulatory agencies that the sponsor may 
receive. 
 
Amgen Global Safety 
Safety contact information: 
- 
Hotline: Amgen Safety 800-77-AMGEN (800-772-6436) 
- 
Safety Fax: 1-888-814-8653 
- 
Secure connection email: svc-ags-in-us@amgen.com  
 
C. 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, Amgen Global Safety must be notified within 
24 hours of the Investigator, designee, or site personnel learning of the pregnancy (See Amgen 
Global 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 Amgen Global Safety.  
 
If the outcome  of the pregnancy meets a criterion for immediate classification as  an SAE— 
spontaneous abortion (any congenital anomaly detected in an  aborted  fetus  is  to  be documented), 
stillbirth, neonatal death, or congenital anomaly—the Investigator should repeat the procedures for 
expedited reporting of SAEs as outlined above.