Clinical trial NCT01941316
Conditions: Small Cell Lung Carcinoma Non Small Cell Lung Carcinoma Irinotecan Sensitive Cancers
Keywords: Carfilzomib Irinotecan Small Cell Lung Cancer Non Small Cell Lung Cancer Ovarian Cancer Gastric Cancer Esophageal Cancer Cervical Cancer
Sponsor: Cancer Research and Biostatistics Clinical Trials Consortium
Start date: 2013-11-01; Completion date: 2019-07-01
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to determine a well-tolerated dose of Carfilzomib in combination with Irinotecan (Phase 1b portion of the study) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers and to assess the 6 month survival of relapsed small cell lung cancer patients treated with this combination therapy. \*\*The Phase 1b portion of the study is now complete\*\*.

Phase 2 portion of the study. The safest, maximally tolerated dose established as established in Phase 1 for Phase 2 is as follows -- Carfilzomib will be provided at 20/36 mg/m\^2 with Irinotecan dosed at 125 mg/m\^2. The purpose of the Phase 2 portion of the study is to assess 6 month survival of relapsed small cell lung cancer ins subjects treated with this combination therapy.

Detailed description:
Small cell lung cancer accounts for approximately 15% of all lung cancer diagnoses in the United States (US), with 60-80% response rates to platinum-based chemotherapy in extensive disease. Despite its sensitivity to chemotherapy, small cell lung cancer is characterized by its tendency to spread to other locations in the body such as the bloodstream and other organs such as the liver. Currently, the only FDA-approved second-line therapies are oral and parenteral topotecan, although irinotecan is also commonly used in primary and relapsed disease. Novel combination therapies are desperately needed in this disease. in order to improve survival.

Carfilzomib (also known as Kyprolis) is an anti-cancer drug classified as a selective proteasome inhibitor. Proteasome inhibition affects the levels of numerous cell cycle control proteins, apoptosis (i.e., cell death), cell adhesion, angiogenesis, and chemoresistance proteins. Chemically, it is similar to epoxomicin.

Carfilzomib and other proteasome inhibitors interrupt cellular pathways integral to the survival of small cell lung cancer, namely the apoptotic pathway involving activated Nuclear Factor-kB (referenced as NF-kB). NF-kB activates the transcription of anti-apoptotic and proliferation genes, mediating tumor cell survival in response to cytotoxic stress thus resulting in chemoresistance, a common problem in small cell lung cancer. Carfilzomib prevents the breakdown of IkappaB (referenced as IkB), a protein which inhibits NF-kB, controls levels of the anti-apoptotic gene Bcl-2 and the tumor suppressor p53. Overexpression of Bcl-2, a key mediator of resistance to apoptosis following chemotherapy, which is an important problem in small cell lung cancer.

In this trial, Carfilzomib is combined with Irinotecan. Irinotecan, a camptothecins, inhibits topoisomerase I, thought to be important in the growth and spread of cancer. As a class, camptothecins have shown efficacy in small cell lung cancer in a variety of settings.

Topoisomerase-1 is thought to cause apoptosis via mechanisms other than NF-kB, adding to the potential synergy of these compounds. In addition, topoisomerase-1 is overexpressed in the majority of subjects with small cell lung cancer and decreased degradation of this enzyme is expected to lead to further enhancement of this mechanism of apoptosis

The pivotal phase III study which led to FDA approval of topotecan in relapsed small cell lung cancer was by Von Pawel et al, and included 211 subjects with sensitive (\> 60 days since prior therapy) relapse and randomized them to either topotecan (107 subjects) daily for 5 days or to cyclophosphamide, doxorubicin, and vincristine (CAV), each given every 21 days. Topotecan showed no significant improvement in the median time to progression (13.3 weeks vs.12.3 weeks, p=0.552) or median survival (25 weeks vs. 24.7 weeks, p=0.795), however, subjects treated with topotecan had improvement in cancer-related symptoms (dyspnea, hoarseness, anorexia, and fatigue) as well as hematologic toxicity. Irinotecan, has established activity in small cell lung cancer, as well as non-small cell lung cancer, colorectal cancer and ovarian cancer.

In this Phase 2 study patients will be treated with the Maximum Tolerated Dose (MTD) of Carfilzomib 20/36 mg/m\^2 as stepped up dosing determined in Phase 1b and 125mg/m\^2 of Irinotecan.

Arms: arm 1: Phase II: Stratified, single arm trial using a starting dose of 20/36 mg/m\^2 of carfilzomib and 125 mg/m\^2 of irinotecan, in small cell lung cancer patients who have relapsed on a prior platinum regimen.

Stratification for phase II component:

1. Platinum sensitive disease: initial response to platinum-based chemotherapy with progression \> 90 days after last treatment.
2. Platinum refractory disease: No response to platinum-based chemotherapy or progression within 90 days of completing platinum-based therapy. Subjects that progressed during or within one month of completion of platinum-based chemotherapy will be excluded. arm 2: Cohort 1 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 1 used a starting dose of 20/27 mg/m\^2 of carfilzomib in combination with 125 mg/m\^2 of irinotecan. arm 3: Cohort 2 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 2 used a starting dose of 20/36 mg/m\^2 of carfilzomib in combination with 125 mg/m\^2 of irinotecan. arm 4: Cohort 3 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 3 used a starting dose of 20/45 mg/m\^2 of carfilzomib in combination with 125 mg/m\^2 of irinotecan.
Interventions: intervention 1: Carfilzomib intervention 2: Irinotecan
Intervention descriptions: intervention 1: 20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks. intervention 2: 125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Investigator-Sponsored Trial 
STUDY PROTOCOL  
 
 
CRAB CTC Study Number:  11-001  
Version 9.0 
Date of Original Protocol: January 17 , 2013 
Amendment #1: April 30, 2013 
Amendment #2: August 21, 2013 
Amendment #3: November 20, 2013 
Amendment #4: November 14, 2014 
Amendment #5: November 18, 2014 
Amendment #6: February 7, 2015 
Amendment #7: February 14, 2018 
 
 
Study Title:  Phase 1b/II Trial of Carfilzomib with Irinotecan in Irinotecan-Sensitive 
Malignancies (Phase Ib) and Small Cell Lung Cancer Subjects (Phase II) Who Have 
Progressed on Prior Platinum-based Chemotherapy  
(Onyx #IST Reference Number:  CAR-IST-553/Amgen Protocol Number 20159842) 
 
IND Number: 117350  
Institution Name:  CRAB Clinical Trials Consortium (multi-site study) 
 
Principal Investigator Information: 
Name:  Susanne M. Arnold, MD 
Address: 800 Rose Street, cc445; Lexington, KY  40536 
Phone No:  859-323-8043 
Fax No: 859-257-7715 
Email Address: smarno0@uky.edu 
 
Co-Investigators:  Listed below 
 
Statistician:  John J. Crowley, PhD 
 
Data Manager:   Vicki Green 
 
 


Key Investigators and Study Personnel Contact Sheet 
 
                                         Sponsor/ Contract Research Organization - CRAB Clinical Trials Consortium 
Cancer Research And Biostatistics Clinical Trials Consortium (CRAB CTC) 
1730 Minor Avenue, Suite 1900, Seattle, WA  98101-1468 
 
KEY INVESTIGATOR AND STUDY PERSONNEL CONTACT SHEET (UPDATED 1 OCTOBER 2014) 
 
Phase 1b/II Trial of Carfilzomib with Irinotecan in Small Cell Lung Cancer Subjects Who Have Progressed on Prior 
Platinum-based Chemotherapy  
 
SPONSOR-INVESTIGATOR: 
Susanne M. Arnold, MD  
 
BIOSTATISTICIANS 
 
John Crowley, PhD  
Ph:  (206) 839-1719 
Fax:  (206) 652-4612 
Email:  johnc@crab.org 
 
 
 
Kari Chansky 
Ph:  (206) 839-1783 
Fax:  (206) 652-4612 
Email:  karic@crab.org 
 
 
 
 
 
 
CRAB CTC OPERATIONS OFFICE: 
 
Amy Stoll-D’Astice 
Program Manager, CRAB CTC 11-0001 Operations 
1730 Minor Ave., Suite 1900 
Seattle, WA 98101-1468 
Ph: (602) 570-2383  
 
 Email: amys@crab.org 
 
CRAB CTC CONTRACTING: 
 
Doug Mounce 
Grants and Contract Manager 
Ph: (206) 839-1787 
Email: dougm@crab.org 
 
CRAB CTC REGULATORY AFFAIRS 
 
Grace Powell 
Regulatory/Quality Assurance Manager 
Ph:  (206) 839-1790 
Fax:  (206) 342-1688 
Email:  gracep@crab.org 
 
CRAB DATA MANAGEMENT : 
 
Vicki Green, Data Coordinator 
(Subject Registration and Data Submission) 
Ph:  (206) 342-1692   
Fax:  (206) 342-1688 
Email:  webhelpCRS@crab.org 
 
CRAB SITE MONITORING 
 
Dona Marrah 
Clinical Monitor Manager 
Ph: (206) 652-1341 
Email: donam@crab.org 
 
REPORTING SERIOUS ADVERSE EVENTS 
 
See protocol Section 9.5 
Report to CRAB Operations Office 
Ph: (206) 342-1692 within 24 hours of the SAE 


ADDITIONAL KEY INVESTGATOR AND STUDY CONTACTS 
 
  
OTHER CONTACT INFORMATION: 
 
SPONSOR – INVESTIGATOR AND MEDICAL 
MONITOR 
(also responsible for treatment and dose modification 
questions) 
 
Susanne M. Arnold, MD 
University of Kentucky Markey Cancer Center 
800 Rose Street, cc445; Lexington, KY  40536 
Ph :  (859) 323-8043 
Fax:  859-257-7715 
Email: smarno0@uky.edu 
 
 
 
 
 
DRUG DISTRIBUTION 
 
Carfilzomib:  Provided by Amgen.   
Email: DrugSupport@Amgen.com 
 
 
CORRELATIVE SAMPLE COLLECTION KITS 
 
Dr. Mark Leggas 
Department of Pharmaceutical Sciences 
College of Pharmacy 
University of Kentucky 
789 South Limestone, Room 323 
Lexington, KY 40536-0596 
E-mail: mark.leggas @uky.edu 
(859) 257-2633 Office 
(859) 257-7564 Fax 
Email: mark.leggas@uky.edu 
 
CRAB CTC Co-Investigators and Participating Sites:  
 
Susanne M. Arnold, MD 
University of Kentucky Markey Cancer Center 
800 Rose Street 
Lexington, KY  40536 
 
 
 
Glen J. Weiss, MD – Phase I only 
Western Regional Medical Center, Inc 
14200 W. Celebrate Life Way 
Goodyear, AZ  85338 
Michael A. Thompson, MD, PhD 
Aurora Health Care, Aurora Cancer Care 
2801 W. Kinnickinnie River Parkway, Suite 930 
Milwaukee, WI  53215 
 
John T. Hamm, MD 
Norton Cancer Institute, Norton Healthcare Pavilion 
315 E. Broadway 
Louisville, Ky  40202 
Rachel Sanborn, MD 
Providence Portland Medical Center 
4805 NE Glisan Street 
Portland, OR  97213 
 
Joseph Rosales, MD 
Virginia Mason Cancer Institute 
1100 9th Ave, Seattle, WA  98101 
 
Maria Baggstrom, MD 
Washington University 
School of Medicine 
4990 Childrens Place 
St, Louis, MO  63110 
 
Maurice Willis, MD 
University of Texas Medical Branch 
301 University Boulevard 
Galveston, TX 77555 
 
 


Investigator Signature Sheet 
 
I have read the attached protocol, CRAB CTC Study 11-001 and agree that it contains all the 
necessary details for performing the study. 
 
I will provide copies of the amended protocol and of the preclinical and clinical information on the 
test article, which was furnished to me by the Sponsor, to all members of the study team 
responsible to me who participate in the study.  I will discuss this material with them to assure that 
they are fully informed regarding the test article and the conduct of the study. 
 
Once the protocol has been approved by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), I will not modify this protocol without obtaining the prior approval of the 
Sponsor and of the IRB/IEC.  In the event that the CRAB CTC issues any protocol modifications 
and/or any informed consent form (ICF) modifications, I will not implement any such 
modifications until approval has been granted by the IRB/IEC. 
 
The investigational drug will not be transferred to any third party, and upon completion of the 
study at my site, any unused supplies of investigational agent will be returned in accordance with 
the protocol. 
 
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
(GCP) [current International Conference of Harmonization (ICH) guidelines], and the Declaration 
of Helsinki including all amendments, and the US 21 Code of Federal Regulations dealing with 
clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations). 
 
 
 
 
 
Investigator's Signature 
 Date 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
Investigational Site Name 
  
 
 


PROTOCOL SYNOPSIS 
TITLE: 
CTC 11-001: Phase 1b/II Trial of Carfilzomib with Irinotecan 
in Irinotecan-Sensitive Malignancies (Phase Ib) and Small Cell 
Lung Cancer Subjects (Phase II) Who Have Progressed on 
Prior Platinum-based Chemotherapy  
(Amgen IST Reference Number:  CAR-IST-553) 
 
OBJECTIVES: 
Primary Objectives: 
Phase 1b: Determine maximum tolerated dose (MTD) of 
Carfilzomib (Day 1, 2, 8, 9, 15, and 16) in combination with 
Irinotecan (Days 1, 8 and 15) in subjects with relapsed small and 
non-small cell lung cancer or other irinotecan-sensitive cancers. 
 
Phase II: Assess 6 month survival of relapsed small cell lung 
cancer in subjects treated with this combination therapy. 
 
Secondary Objectives: 
Phase 1b: Response rate, safety/tolerability, biomarker endpoints 
(see below). Biomarker testing to occur for all subjects in Phase 
1b. 
 
 
Phase II: response rate, safety/tolerability, progression-free 
survival and biomarker endpoints:  
 Chymotrypsin-like activity in PBMC (LMP7 and b5 
activity) as a measure of carfilzomib’s effect on 
proteasome activity in 15 subject in each stratum. 
 Topoisomerase-I protein expression as a measure of 
carfilzomib’s capacity to prevent irinotecan induced 
topoisomerase-I degradation in 15 subjects in each 
stratum. 
 Gamma-H2AX protein expression in PBMC, as a 
measure of irinotecan-mediated DNA damage and as a 
measure of carfilzomib’s capacity to prevent irinotecan 
induced topoisomerase-I degradation in 15 subjects in 
each stratum. 
o Topoisomerase-I expression by immunohistochemistry will be 
determined in banked tissue, if available, in all subjects, as a 
biomarker of response. 
 
STUDY DESIGN: 
Study Design:  
1.  Phase 1b: standard 3+3 design using five dose levels of 
Carfilzomib.  
2.  Phase II:   A single arm trial of this therapy (using the MTD as 
determined in Phase Ib) in 88 small cell lung cancer subjects who 
have progressed on prior platinum based therapy. Stratified by 
platinum sensitive vs. platinum refractory disease (see Section 
3.1).   


STUDY 
POPULATION: 
 
Phase Ib: Advanced small or non-small cell lung cancer, or other 
cancer in which irinotecan therapy has been shown to be effective 
and for whom no curative therapy exists. 
 
Phase II:  Extensive stage small cell lung cancer with progression 
or recurrence after exactly one platinum-containing regimen 
 
 
 
 
SECONDARY 
ENDPOINTS: 
 
 
 
 
 
 
 
 
Secondary Objectives: 
Phase 1b: Response rate, safety/tolerability, biomarker endpoints 
(see below).  Biomarker testing to occur for all subjects in Phase 
1b. 
 
Phase II: response rate, safety/tolerability, progression-free 
survival and biomarker endpoints:  
 
 Chymotrypsin-like activity in PBMC (LMP7 and b5 
activity) as a measure of carfilzomib’s effect on 
proteasome activity in 15 subjects in each stratum. 
 Topoisomerase-I protein expression in PBMC as a 
measure of carfilzomib’s capacity to prevent irinotecan 
induced topoisomerase-I degradation in 15 subjects in 
each stratum. 
 Gamma-H2AX protein expression in PBMC, as a 
measure of irinotecan-mediated DNA damage and as a 
measure of carfilzomib’s capacity to prevent irinotecan 
induced topoisomerase-I degradation in 15 subjects in 
each stratum. 
 
o Topoisomerase-I expression by immunohistochemistry will be 
determined in banked tissue, if available, in all subjects, as a 
biomarker of response. 
 
 
 
 
 
 


SCHEMA 
 
Phase I portion 
 
Subject Registration  
 
 
 
Up to 6 cycles* of Irinotecan + Carfilzomib at assigned dose level (see Section 6.2.1) 
 
*at investigator discretion and in absence of criteria for removal from treatment (see section 8.0) 
 
 
 
Post treatment follow-up: 30 days or until drug-related toxicities resolve to grade 1 or less, 
whichever occurs last   
 
 Temporary closure after all subjects accrued to finalize determination of Phase II dose 
 
 
 
 
Phase II portion 
 
Subject Registration and stratification 
 
 
 
Up to 6 cycles* of Irinotecan + Carfilzomib at assigned dose level (see Section 6.2.4) 
 
*at investigator discretion and in absence of criteria for removal from treatment (see section 8.0) 
 
 
 
 
Post treatment follow-up:  2 years after initial registration, or until death, or until study closure  
whichever occurs first  
 
 
A subject may be enrolled to either the Phase I portion or the Phase II portion, but not both. 


TABLE OF CONTENTS 
INVESTIGATOR-SPONSORED TRIAL .............................................................................1 
STUDY PROTOCOL ..............................................................................................................1 
Key Investigators and Study Personnel Contact Sheet ..................................................2 
Investigator Signature Sheet ..........................................................................................4 
PROTOCOL SYNOPSIS ........................................................................................................5 
TABLE OF CONTENTS ........................................................................................................8 
1 
INTRODUCTION......................................................................................................15 
1.1 
Disease Specific Background ..........................................................................15 
1.2 
Proteasome Background ..................................................................................15 
1.3 
Carfilzomib Background ..................................................................................15 
1.3.1 
CARFILZOMIB Toxicology STudies ..............................................15 
1.3.2 
Carfilzomib Preclinical Antitumor Activity .....................................16 
1.3.3 
Phase 1 Experience with Carfilzomib as a Monotherapy .................17 
1.3.4 
Phase 2 Experience with Carfilzomib as a monotherapy ..................18 
1.3.5 
Updated Experience with Carfilzomib ..............................................20 
1.4 
Dose Rationale .................................................................................................22 
1.5 
Study Rationale ................................................................................................25 
2 
OBJECTIVES ............................................................................................................28 
2.1 
Primary Objective ............................................................................................28 
2.2 
Secondary Objectives: .....................................................................................28 
3 
EXPERIMENTAL PLAN .........................................................................................30 
3.1 
Study Design ....................................................................................................30 
3.2 
Number of Centers ...........................................................................................30 
3.3 
Estimated Study Duration and recruitment ......................................................30 
4 
SUBJECT SELECTION ...........................................................................................32 
4.1 
Inclusion Criteria .............................................................................................32 
4.2 
Exclusion Criteria ............................................................................................34 
4.3 
Stratification Factors for phase II component: .................................................35 
5 
SUBJECT REGISTRATION/ENROLLMENT .....................................................36 
6 
TREATMENT PROCEDURES ...............................................................................37 
6.1 
Drug Preparation and Administration. .............................................................37 
6.2 
TREATMENT PLAN ......................................................................................38 
6.2.1 
Phase I Portion of the Study..............................................................38 
6.2.2 
Evaluation for dose-limiting Toxicity, Phase i only .........................39 


6.2.3 
DOSE escalation scheme -  for phase i only .....................................40 
6.2.4 
Phase II Portion of the Study ............................................................40 
6.3 
Dose Reductions/Adjustments .........................................................................41 
6.3.1 
Dose Levels .......................................................................................41 
6.3.2 
Dose Reductions for CARfilzomib and irinotecan Hematologic 
Toxicities: .........................................................................................42 
6.3.3 
Dose Reductions of carfilzomib and irinotecan for Non-Hematologic 
Toxicities...........................................................................................43 
6.3.4 
Additional information regarding MYELODYSPLASTIC 
SYNDROME AND ACUTE MYELOID LEUKEMIA ...............45 
6.3.5 
Additional information regarding toxicity ........................................46 
6.3.6 
Missed Doses ....................................................................................49 
6.3.7 
Changes in Body Surface Area (BSA) ..............................................49 
6.4 
Safety Considerations ......................................................................................49 
6.5 
Concomitant Medications ................................................................................50 
6.5.1 
Required Concomitant Medications .................................................50 
6.5.2 
Optional and Allowed Concomitant Medications.............................50 
6.5.3 
Excluded Concomitant Medications .................................................50 
7 
STUDY TESTS AND OBSERVATIONS: ...............................................................51 
8 
STUDY DISCONTINUATION ................................................................................53 
8.1 
Criteria for Removal from Protocol Treatment: ..............................................53 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice eCRF.....................................................................................................53 
8.2 
Post Treatment Follow-up................................................................................53 
9 
ADVERSE EVENTS .................................................................................................54 
9.1 
Adverse Events Definitions .............................................................................54 
9.2 
Causality ..........................................................................................................55 
9.3 
Adverse Events Reporting Procedures.............................................................55 
9.3.1 
Comprehensive Adverse Events and Potential Risks for Carfilzomib 
(CAEPR) ...........................................................................................56 
9.3.2 
Adverse Events and Potential RISKS FOR irinotecan .....................62 
9.4 
Serious Adverse Events Definitions ................................................................65 
9.5 
Serious Adverse Event Reporting and Documentation Requirements ............66 
9.6 
Pregnancy .........................................................................................................71 
10 
CORRELATIVE STUDIES ......................................................................................74 
10.1 
Laboratory Correlative Studies ........................................................................74 
11 
STATISTICAL ANALYSIS .....................................................................................77 


11.1 
ADDITIONAL Sample Size Considerations ...................................................78 
11.2 
Interim Analysis ...............................................................................................78 
11.3 
Planned Methods of Analysis ..........................................................................78 
12 
INVESTIGATIONAL PRODUCT...........................................................................80 
12.1 
Carfilzomib Description ...................................................................................80 
12.1.1 
Formulation .......................................................................................80 
12.1.2 
Storage ..............................................................................................80 
12.1.3 
Reconstitution and administration ....................................................80 
12.1.4 
Accountability ...................................................................................81 
12.1.5 
CARFILZOMIB DRUG ORDERING .............................................81 
12.2 
Irinotecan .........................................................................................................82 
12.2.1 
Irinotecan Description .......................................................................82 
12.2.2 
Formulation .......................................................................................83 
12.2.3 
TOXICOLOGY ................................................................................83 
12.2.4 
PHARMACOLOGY .........................................................................83 
12.2.5 
Storage ..............................................................................................84 
12.2.6 
Accountability ...................................................................................84 
12.2.7 
Irinotecan DRUG ORDERING ........................................................85 
13 
REGULATORY OBLIGATIONS ...........................................................................86 
13.1 
Institutional review board/independent ethics committee ...............................86 
13.2 
Informed Consent.............................................................................................86 
13.3 
Compliance with Laws and Regulations..........................................................86 
13.4 
Regulatory Documentation Requirements .......................................................88 
13.5 
Subject Confidentiality ....................................................................................88 
14 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ...........................................90 
14.1 
Protocol Amendments or changes in study conduct ........................................90 
14.2 
Study termination .............................................................................................90 
14.3 
Study Documentation and Archive ..................................................................91 
14.4 
Disclosure and confidentiality .........................................................................91 
14.5 
publication of results ........................................................................................91 
14.6 
Study Monitoring .............................................................................................92 
14.6.1 
Phase Ib Only:  Mandatory Bi-Monthly TeleConferenceS...............92 
14.6.2 
Phase II Only:  Mandatory quarterly TeleConferenceS ....................93 
14.6.3 
Site Monitoring .................................................................................93 
14.7 
Data submission requirements .........................................................................95 


15 
REFERENCES ...........................................................................................................96 
APPENDIX A:  NCI-CTCAE VERSION 4.0 ......................................................................99 
APPENDIX B:  ASSESSMENT OF EFFICACY (RECIST 1.1 CRITERIA) ................100 
 
 
 


LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
C 
degrees Centigrade 
F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
ASaT 
All Subjects as Treated 
AST 
aspartate aminotransferase 
bid 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
Cmax 
maximum or peak concentration of a drug after its administration 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form(s) 
CRO 
clinical research organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
Deciliter 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep venous thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
full analysis set 
FCBP 
females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 
h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 


ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
MR 
minimal response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QDx5 
daily dosing for five days 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
RP2D 
recommended phase II dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SPEP 
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
tumor lysis syndrome 
TTP 
time to tumor progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 


VGPR 
very good partial response 
WBC 
white blood count 
 


1 
INTRODUCTION   
1.1 
DISEASE SPECIFIC BACKGROUND 
 
Small cell lung cancer accounts for approximately 15% of all lung cancer diagnoses in the United 
States (US)[1], with 60-80% response rates to platinum-based chemotherapy in extensive disease.  
Despite its sensitivity to chemotherapy, small cell lung cancer is characterized by extensive disease 
dissemination at presentation and the overall prognosis remains poor, with a 2-year overall survival 
of less than 5% and a median survival of approximately 9-11 months[2].  This poor prognosis is 
attributable, in part, to the lack of effective salvage regimens for this disease.  Currently, the only 
FDA-approved second-line therapies are oral and parenteral topotecan, although irinotecan is also 
commonly used in primary and relapsed disease.  Novel combination therapies are desperately 
needed in this disease in order to improve survival. 
1.2 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a wide 
variety of protein substrates within normal and transformed cells.  Intracellular proteins targeted for 
degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation system.  
Ubiquitinated proteins are cleaved within the proteasome by one or more of three separate threonine 
protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a caspase-like activity.   
 
1.3 
CARFILZOMIB BACKGROUND 
Carfilzomib (PX-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the chymotrypsin-
like active site of the 20S proteasome.  Carfilzomib is structurally and mechanistically distinct from 
the dipeptide boronic acid proteasome inhibitor bortezomib (Velcade®).  In addition, when measured 
against a broad panel of proteases including metallo, aspartyl, and serine proteases, carfilzomib 
demonstrated less reactivity against non-proteasomal proteases when compared to bortezomib[3, 4] 
 
1.3.1 
CARFILZOMIB TOXICOLOGY STUDIES 
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by the drug maker, 
Onyx, carfilzomib was administered to rats and monkeys as two complete two-week cycles of QDx5 
with nine days rest[5].  Administration to rats at 12 mg/m2, the severely toxic dose in 10% of animals 
(STD10), caused > 90% proteasome inhibition in red blood cells one hour after dosing.  Overall, 
stronger inhibition of the proteasome and longer duration of inhibition was tolerated with 


carfilzomib compared with bortezomib.  Daily administration of bortezomib at anti-tumor doses is 
not tolerated in animals, and therefore daily bortezomib has not been given in the clinic.  A dose-
dependent decrease in proteasome activity was demonstrated in animals, and equivalent levels of 
proteasome inhibition were achieved with administration of carfilzomib as either an intravenous 
(IV) push or an IV infusion.  The dose-limiting toxicities (DLTs) of carfilzomib in both the rat and 
monkey 28 day GLP toxicity studies included toxicity to the gastrointestinal tract, bone marrow, 
pulmonary, and cardiovascular systems.  No behavioral or histopathological signs of neurotoxicity 
were observed, and carfilzomib does not cross the blood-brain barrier. 
In 6-month rat and 9-month chronic toxicity studies, carfilzomib was administered on Days 1, 2, 8, 
9, 15, and 16 of a 28-day cycle, mimicking the active anti-tumor regimen being used in ongoing 
Phase II studies in myeloma and solid tumors[3].  Tolerability was excellent, with no evidence of 
peripheral (or central) neurotoxicity, including neuropathology, observed, even at high doses.  This 
is in stark contrast to that observed with bortezomib[6, 7].  DLTs included effects on the 
gastrointestinal, renal, pulmonary, and cardiovascular systems and appeared to relate to Cmax 
effects.  Of note, neutropenia was not observed; rather, transient neutrophilia was seen following 
acute dosing.  Renal, cardiovascular and gastrointestinal toxicities were similar to those observed 
with bortezomib.  Finally, cyclical thrombocytopenia, likely due to inhibition of platelet budding 
from megakaryocytes, was similar to that seen with bortezomib.  Proteasome inhibition in the blood 
in excess of 90% was achievable at well-tolerated doses, which contrasts with the ~70% proteasome 
inhibition achievable 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. 
1.3.2 
CARFILZOMIB PRECLINICAL ANTITUMOR ACTIVITY 
Based upon the results of in vitro and in vivo studies, it is anticipated that the more intense and 
longer duration of proteasome inhibition that can be achieved with carfilzomib will result in 
enhanced anti-tumor activity relative to bortezomib.  Continuous (72 hr) exposure to carfilzomib is 
associated with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived 
cell lines in culture[3, 8].  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[3, 8]. 


The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice implanted with 
a variety of tumor cell lines.  In a human colorectal adenocarcinoma model HT-29, administration 
of carfilzomib on a twice-weekly Day 1, Day 2 schedule resulted in significant reduction in tumor 
size and was superior to a twice-weekly Day 1, Day 4 schedule using the same dose of carfilzomib, 
and a once-weekly dosing schedule using twice the dose level.  Bortezomib at its MTD has no 
activity in this xenograft model using the standard Day 1, Day 4 schedule[3]. 
1.3.3 
PHASE 1 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed[9].  During the dose escalation portion of the trial, 36 
subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with Multiple 
Myeloma (MM), Non-Hodgkin’s Lymphoma (NHL), Waldenström’s Macroglobulinemia, and 
Hodgkin’s Lymphoma (HL) were enrolled on the study.   
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 
1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 dose level, one of eight subjects 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 subject continued on study for the remainder of Cycle 1 before having 
disease progression.   At the 27 mg/m2 dose level, one of six subjects experienced a DLT during 
Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing.  In 
subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
constellation of findings that appeared to be the clinical sequellae of rapid tumor lysis syndrome 
(TLS) and/or cytokine release.  This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion.  On the second day, three of five subjects with 
multiple myeloma experienced an increase in creatinine to Grade 2 (including the subject with the 
DLT).  This elevation was rapidly reversible and all three subjects were rechallenged with 
carfilzomib without recurrence of the events.  Interestingly, all three subjects had a rapid decline in 
serum and/or urine M-protein levels; two subjects achieved a PR and the third subject achieved a 
minimal response (MR).  There were no consistent changes in potassium, calcium, phosphorous, or 
uric acid levels although some increases in LDH and other markers of tumor lysis were noted.  
Because of the possible TLS and reversible creatinine elevations, hydration and very-low dose 
dexamethasone prophylaxis were instituted in subsequent studies and have essentially eliminated 
clinically significant TLS/creatinine elevations and the other “first-dose” effects.   


Hematologic toxicities were primarily mild or moderate.  The thrombocytopenia reported with 
carfilzomib is cyclical and similar to that reported with bortezomib.  The cause and kinetics of the 
thrombocytopenia following treatment are different from those of standard cytotoxic agents.  To 
maximize the likely benefit of carfilzomib, subjects with thrombocytopenia should be supported as 
clinically indicated rather than having treatment reduced due to thrombocytopenia. 
Of the 36 evaluable subjects enrolled in PX-171-002, 20 had MM[7].  Four MM subjects achieved a 
partial response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 mg/m2 dose, and two of 
five at the 27 mg/m2 dose.  The responses have been rapid in onset, beginning in some subjects after 
1-2 doses.  The duration of response (DOR) ranged from 134 to 392 days. The minimal effective 
dose was 15 mg/m2 wherein >80% proteasome inhibition in peripheral blood and mononuclear cells 
was observed one hour after dosing.  The median number of prior therapies for subjects on this trial 
was five, and responses were seen in subjects who had relapsed from (including some refractory to) 
bortezomib and/or immunomodulatory agents.  Stable disease also occurred in four NHL and five 
MM subjects, with subjects on therapy for up to 409 days.  Such prolonged therapy, at “full” twice-
weekly doses, is not possible with bortezomib.  These results led to the initiation of two Phase 2 
studies. 
1.3.4 
PHASE 2 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
Two Phase 2 clinical studies are ongoing with carfilzomib in MM subjects, PX-171-003-A0 (N=46) 
in relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM.  In both studies, subjects 
were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  In these studies 
there were four cases of suspected or documented TLS prior to institution of the prophylaxis 
guidelines.  Since these guidelines were implemented, no further cases of TLS have been reported 
including in >350 additional subjects with relapsed or refractory MM treated in ongoing Phase II 
studies.  In both studies, the most common adverse events were fatigue, anemia, thrombocytopenia 
(primarily cyclical), gastrointestinal, and dyspnea.  Almost all were Grades 1 or 2.  There were 
reported cases of increases in serum creatinine that were primarily < Grade 2 and were transient, 
rapidly reversible, and non-cumulative.  A very low rate of treatment-emergent peripheral 
neuropathy, 2.2% Grade 3/4, was observed in PX-171-003-A0 despite the fact that 78% of subjects 
had Grade 1/2 neuropathy upon study entry[10].   
The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these subjects that 
entered the study with progressive disease and were refractory to their most recent therapy, often 
including bortezomib and/or an immunomodulatory drug (usually lenalidomide).  The median time 


to progression on the PX-171-003-A0 study was 5.1 months with a DOR of 7.4 months (mean follow 
up of 7.6 months) [10].   
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.  Subjects receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  The study 
completed enrollment of 266 subjects by the end of 2009 and may form the basis for an accelerated 
approval NDA filing by the end of 2010.  To date, this dosing schedule has been well tolerated[9].  
An independent Safety Oversight Group (SOG) evaluated the safety data from the 40 of 250 subjects 
to be enrolled on the 20/27 schedule and agreed that the trial should proceed without modification.  
No cases of TLS were observed and rates of BUN and creatinine elevation dropped sharply, with 
Grade 3/4 renal impairment dropping to 2.2% in A1 (from 15% in A0), most likely due to hydration 
and very low dose dexamethasone.  The other most common adverse events were similar to the A0 
portion of the study.  Treatment-emergent peripheral neuropathy remains low on this portion of the 
study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date on PX-171-003-A1[10].  
In addition, anemia rates in the PX-171-003-A1 (higher dose) were lower than those reported in the 
PX-171-003–A0 portion of the study, possibly indicating that the higher dose of carfilzomib is 
achieving better clearing of neoplastic cells in the bone marrow allowing superior normal marrow 
reconstitution.  Rates of thrombocytopenia and neutropenia were similar in the two cohorts, with 
Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date.[10]  
In PX-171-004, a first cohort of subjects received 20 mg/m2.  The subset of subjects (N=54) that 
had not seen bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the 
bortezomib treated subjects (N=33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR) [11, 12].  
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 subjects who have not previously been treated with 
bortezomib and, even in bortezomib-treated subjects, substantial anti-tumor activity is observed.  Of 
note, disease control (PR + MR + SD) was achieved in ~65% of subjects with progressive MM 
entering the study.  Subjects 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.  
The protocol was amended to allow subjects to increase to 27 mg/m2 in Cycle 2 or later based on 
tolerability, similar to that used in PX-171-003 – A1.   


Further information about the Phase 2 studies is presented in the Investigator’s Brochure. 
1.3.5 
UPDATED EXPERIENCE WITH CARFILZOMIB  
As of 12 January 2015, approximately  2949 individual subjects have been treated with carfilzomib 
as participants of Phase 1, 2, and 3 Onyx-sponsored clinical studies. Of these subjects, 137 subjects 
with solid tumors have been treated with carfilzomib in completed Onyx-sponsored clinical studies.  
As of 12 Janaury 2015, Onyx Pharmaceutical Co, Ltd has enrolled 65 subjects in 3 studies being 
conducted in Japan. The clinical development of carfilzomib initially focused on patients with 
relapsed and refractory multiple myeloma, assessing carfilzomib as monotherapy in these patients 
with few therapeutic options. Subsequently, carfilzomib is being evaluated as a component of 
combination therapy for treatment in earlier lines of therapy for patients with multiple myeloma, 
including newly diagnosed multiple myeloma patients. 
Carfilzomib for Injection was approved in 2012 in the United States (US) (brand name Kyprolis) 
under the US Food and Drug Administration’s (FDA) accelerated approval program for the 
treatment of patients with relapsed and refractory multiple myeloma who have received at least 2 
prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated 
disease progression on or within 60 days of completion of the last therapy. Carfilzomib received 
approval in Israel (under the State of Israel Ministry of Health), Argentina (under the National 
Administration of Medicaments, Food and Medical Technology [ANMAT]), and Mexico (under the 
Federal Commission for the Protection against Sanitary Risks [COFEPRIS]) in 2014. These 
approvals, including accelerated approval in the US, were based on the results of the were based on 
the results of the Phase 2 PX-171-003 – Part 2 (A1) study, where an overall response rate (ORR) of 
22.9%, duration of response (DOR) of 7.8 months, progression-free survival (PFS) of 3.7 months, 
and overall survival (OS) of 15.4 months were observed.  The approved carfilzomib dose is 20 
mg/m2 during Cycle 1, and if tolerated, the dose is increased to 27 mg/m2 during Cycle 2, given 
twice weekly for 3 of every 4 weeks, with infusion durations of 2 to 10 minutes.  
The clinical development of carfilzomib initially focused on patients with relapsed and refractory 
multiple myeloma, assessing carfilzomib as monotherapy in these patients with little or no 
therapeutic options.  Subsequently, carfilzomib is being evaluated as a component of combination 
therapy for treatment in earlier lines of therapy for patients with multiple myeloma, including newly 
diagnosed multiple myeloma patients.  The clinical program has also expaneded to include solid 
tumors (e.g. small cell lung cancer [SCLC] and pediatric lymphoblastic leukemia (ALL). 


Results from Phase 3 Trials 
Five phase 3 studies have been completed or are still ongoing.  A thorough and comprehensive 
assessment of carfilzomib safety was conducted by Onyx with safety information available from a 
large clinical development program.  Important adverse drug reactions (ADRs) identified from the 
pivotal phase 3 studies PX-171-009 (ASPIRE) and PX-171-011 (FOCUS) as well as across the 
integrated safety database have been well-characterized as documented in the Investigator’s Drug 
Brochure for carfilzomib.  There was no evidence of cumulative or new-onset toxicity with 
prolonged exposure to carfilzomib.  Overall, the safety and efficacy data from the clinical program 
support continued development of carfilzomib in subjects with multiple myeloma and solid tumors 
and expansion to the pediatric acute lymphoblastic leukemia (ALL) population.  As of January 2015, 
study 2011-003 (ENDEAVOR), Study 2012-005 (CLARION), and study CFZ014 (A.R.R.O.W.) 
remain ongoing. 
The clinical development program for carfilzomib has provided the ability to assess safety across 
patient populations with a broad spectrum of baseline characteristics relevant to the indicated 
patients with multiple myeloma, including patients with the following characteristics in Phase 2 and 
3 multiple myeloma studies: (1) advanced disease; Onyx Pharmaceuticals, Inc. Investigator’s 
Brochure Carfilzomib for Injection  (2) refractory and heavily pretreated; (3) newly diagnosed 
disease; (4) multiple comorbidities (e.g., renal insufficiency and renal failure, anemia, 
thrombocytopenia, or cardiovascular disease); (5) pre-existing peripheral neuropathy; (6) prior 
bortezomib therapy (including a substantial number of patients with multiple myeloma refractory to 
bortezomib or who cannot tolerate bortezomib); (7) various ages (age range of 21 to 91 years); (8) 
similar proportion by sex to the general population; and (9) a substantial proportion of patients of 
African American ethnicity. 
The safety profile  remains  consistent with the mechanism of action of proteasome inhibitors, but 
with predictably lower rates of peripheral neuropathy, based on the epoxyketone structure that 
improves proteasome inhibition selectivity. Extensive analysis in renally impaired patients has 
indicated that no dose adjustment for baseline renal insufficiency is required. The independent 
efficacy of carfilzomib monotherapy also obviates the need for high doses of steroids, making the 
carfilzomib regimen steroid-sparing and an important treatment option for patients who need to 
avoid the toxicity associated with therapeutic doses of corticosteroids. Analysis of the substantial 
proportion of patients who continued on carfilzomib therapy for extended durations indicated that 
the drug was well tolerated, without cumulative or late-effect toxicity. 


1.4 
DOSE RATIONALE 
Data supports 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 i shows 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 subjects being treated for >10 cycles without cumulative toxicities. 
By the end of 2009, 269 subjects with relapsed and refractory multiple myeloma have been enrolled 
in the PX-171-003-A1 study. The goal of dose escalating to 27 mg/m2 beginning with Cycle 2 is to 
improve ORR, DOR, and TTP. 
Safety and efficacy results are available for 2 completed phase 3 studies, PX-171-009 (ASPIRE) 
and Study PX-171-011 (FOCUS).  FOCUS was an open-label phase 3 study of carfilzomib versus 
a combination of corticosteroids and cyclophosphamide as supportive care.  Carfilzomib as a single 
agent was well tolerated at a dose 20 mg/m2 and 27 mg/m2 in cycles 10 and higher.  The study did 
not show superiority of carfilzomib over supportive care in overall survival; however, carfilzomib 
as monotherapy did show a higher overall response rate as compared to that of supportive care.  
Results from phase 3 study ASPIRE comparing carfilzomib, lenalidomide, and dexamethasone 
(CRd) versus lenalidomide and dexamethasone (Rd) in subjects with relapsed multiple myeloma 
showed that patients in the CRd arm showed significantly longer rates of progression free survival.  
Stepped up dosing of 20/27 mg/m2 during cycles 1-12 and 27 mg/m2 was well tolerated with 
improvement in overall quality of life reported.  Three other phase 3 studies 2011-003 
(ENDEAVOR), 2015-005 (CLARION), and CFZ014 (A.R.R.0.W.) remain ongoing with very good 
responses reported. 
In multiple preclinical studies, the tolerability of carfilzomib in rats has been shown to be 
significantly higher when administered as a 30 minute infusion as compared to a rapid IV 
bolus.  Toxicities observed with IV bolus injection of carfilzomib above the MTD at a dose of 48 
mg/m2 include evidence of prerenal azotemia (transient increases in BUN > creatinine) as well as 
lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred in ~50% of 
animals at 48 mg/m2 when carfilzomib was given as a bolus. Administration of the same dose (48 
mg/m2) as a 30 minute continuous infusion was well tolerated, with no changes in BUN and 


creatinine and substantially reduced signs of lethargy, piloerection, or dyspnea.  Moreover, all 
animals in the infusion treatment groups survived.  The only toxicity observed following infusion 
of carfilzomib for 30 minute was gastrointestinal bleeding.  The reduced toxicity seen with dosing 
by infusion may reflect the reduced Cmax of carfilzomib 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  in the multiple myeloma (MM) setting when administered as a 30 minute 
infusion has been determined to be 20/56 mg/m2.  Twenty-seven mg/m2 of carfilzomib (bolus 
administration over 2-10 minutes) is well tolerated in MM subjects overall and can be tolerated for 
>12 cycles in late stage MM subjects with substantial comorbidities.  
A phase 1b/2 dose escalation study (PX-171-007) of single agent carfilzomib administered was 
completed  and as of 19 July 2011,  65 subjects with solid tumors  received  treatment in the l Phase 
2 portion of the study at the 20/36 mg/m2 MTD established in the phase 1b portion (bolus 
administration over 2-10’). A review of the tolerability of 36 mg/m2 carfilzomib in these subjects  
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 subjects completed > 12 cycles of therapy at 36 mg/m2 with no evidence 
of cumulative toxicity.  There were no significant DLTs observed; the majority of discontinuations 
on the study were due to progressive disease. Because of the long-term tolerability of carfilzomib, 
the Phase 1b portion of this study was reopened, and a separate arm for multiple myeloma was 
added.  
In the PX-171-007 trial, more recently subjects have been treated with carfilzomib given as a 30-
minute infusion in order to potentially minimize Cmax-related infusion events. The protocol was 
amended and doses of 20/36 (20 mg/m2 given on Days 1 and 2 of cycle 1 only; followed by 36 
mg/m2 for all subsequent doses), 20/45, 20/56 mg/m2 and so forth are being investigated.  Doses of 
20/56 mg/m2 are currently being given in two separate cohorts of subjects 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 4mg/dose to 8mg with 
the 56mg/m2 doses in order to reduce fevers and hypotension.  As of March 20, 2010, seven subjects 
have received 20/56mg/m2 and are tolerating it.  Subjects 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 subjects. 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. 
In addition to the above observations, a phase I study of carfilzomib in subjects 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 subjects 
with substantial renal impairment (CrCl < 30, including subjects on dialysis) without dose 
adjustment.[14]  These data indicate that carfilzomib does not exacerbate underlying renal 
dysfunction, and confirm the “pre-renal” etiology of the BUN/creatinine elevations observed with 
IV bolus carfilzomib. 
In the advanced and refractory multiple myeloma population, the Phase 3 Study PX-171-011 
(FOCUS) did not meet the primary objective of demonstrating superiority of carfilzomib 
monotherapy over the active doublet therapy in the control arm (corticosteroids and optional 
cyclophosphamide). The median OS with carfilzomib monotherapy was 10.2 months versus 10.0 
months for active control. The PFS was similar in both study arms of PX-171-011 (carfilzomib 
monotherapy 3.7 months versus active control arm 3.3 months, HR = 1.091 [95% CI: 0.843–1.410]). 
The efficacy observed in the monotherapy program supported the development of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone, based on the hypothesis that this 
combination may result in the ability to deliver optimized proteasome inhibition leading to improved 
efficacy. Results from the randomized, pivotal, Phase 3 Study PX-171-009 (ASPIRE) demonstrated 
that carfilzomib in combination with lenalidomide (Revlimid) and low-dose dexamethasone (CRd) 
in subjects with relapsed multiple myeloma has unprecedented efficacy with an 8.7-month 
improvement in median PFS when compared with (Revlimid) lenalidomide with low-dose 
dexamethasone (Rd) (HR = 0.69), and a median PFS of 26.3 months with CRd treatment. Data from 
Study PX-171-009 (ASPIRE) was submitted to regulatory authorities in the first quarter of 2015 for 
marketing authorization (currently in review as of January 2015) for the use of carfilzomib in 
combination with lenalidomide and dexamethasone for the treatment of patients with multiple 
myeloma who have received at least 1 prior therapy. 
 


1.5 
STUDY RATIONALE  
Proteasome inhibition affects the levels of numerous cell cycle control proteins, apoptosis, cell 
adhesion, angiogenesis, and chemoresistance proteins.[13,14]  Carfilzomib and other proteasome 
inhibitors interrupt cellular pathways integral to the survival of small cell lung cancer,[15-17] namely 
the dysregulated apoptotic pathway involving activated nuclear factor-kB (NF-kB).[18]  NF-kB 
activates the transcription of anti-apoptotic and proliferation genes, mediating tumor cell survival in 
response to cytotoxic stress and resulting in chemoresistance, a common problem in small cell lung 
cancer. Carfilzomib prevents proteasomal degradation of IkB, the inhibitor of NF-kB, and also 
modulates levels of the anti-apoptotic gene Bcl-2 and the tumor suppressor p53.  Overexpression of 
Bcl-2, a key mediator of resistance to apoptosis following chemotherapy, is an important problem 
in SCLC;[17] the vast majority of SCLC cases have bcl-2 overexpression, and low levels of bcl-2 and 
b1-integrin are associated with improved survival in SCLC[19].  Topoisomerase-1 is thought to cause 
apoptosis via mechanisms other than NF-kB, adding to the potential synergy of these compounds.  
In addition, topoisomerase-1 is overexpressed in the majority of subjects with SCLC [18] and 
decreased degradation of this enzyme is expected to lead to further enhancement of this mechanism 
of apoptosis.  
The hypothesis that proteasome inhibition will augment the effect of systemic chemotherapy in solid 
tumors is not new.  In fact, earlier studies using the compound Bortezomib (VELCADE®, 
Millennium) which only reversibly inhibits the 26S proteasome, with Carboplatin and Gemcitabine 
showed promising response rates and median survival of 11 months in non-small cell lung cancer 
(NSCLC)[20]. Other studies have not shown improvement in response rate or survival with the 
combination of proteasome inhibitor and Docetaxel or Pemetrexed,[21] despite substantial preclinical 
information which would have predicted benefit[18, 22-24]. The use of Carfilzomib in combination 
with a topoisomerase inhibitor is expected to differ from previous efforts with other proteasome 
inhibitors because of its sustained proteasome inhibition and its potential synergy with this class of 
drugs. 
Camptothecins 
Camptothecins inhibit topoisomerase I.  As a class, camptothecins have shown efficacy in small 
cell lung cancer in a variety of settings.  Several phase II studies demonstrated clinical benefit 
including  the trials of Perez-Soler et al., who showed clinical benefit in 10 out of 32 subjects with 
extensive stage SCLC in the second line with parenteral topotecan, 1.25 mg/m2 daily on Days 1-5 
every 21 days[2] and Ardizzoni et al. who used a higher dose (1.5 mg/m2) but the same schedule, in 


101 subjects with relapsed extensive stage disease with median overall survival (6.9 months for 
sensitive subjects and 4.7 months for refractory subjects (P=0.002).[25]  The pivotal phase III study 
which led to FDA approval of topotecan in relapsed small cell lung cancer was by Von Pawel et 
al,[26] and included 211 subjects with sensitive (> 60 days since prior therapy) relapse and 
randomized them to either topotecan (107 subjects) daily for 5 days or to cyclophosphamide, 
doxorubicin, and vincristine (CAV), each given every 21 days. Topotecan showed no significant 
improvement in the median time to progression (13.3 weeks vs.12.3 weeks, p=0.552) or median 
survival (25 weeks vs. 24.7 weeks, p=0.795), however, subjects treated with topotecan had 
improvement in cancer-related symptoms (dyspnea, hoarseness, anorexia, and fatigue) as well as 
hematologic toxicity.  
Another camptothecin, irinotecan, has established activity in small cell lung cancer, as well as non-
small cell lung cancer, colorectal cancer and ovarian cancer.  As a single agent, Negoro and 
colleagues treated 35 subjects with 100 mg/m2 with a response rate of 50% in untreated subjects and 
33% in previously treated subjects.[27]  Additional phase II studies of weekly irinotecan by Masuda, 
et al[28], demonstrated an objective response rate of 47% and a median survival of 26 weeks (similar 
to other camptothecins).  Le Chevalier and colleagues[29] used an every 3-week schedule of 
irinotecan, 350 mg/m2, given to 32 chemotherapy-naive SCLC subjects and showed an objective 
response rate of 16% and a median survival of 4.5 months.  Thus, the median survival of 
camptothecins in the second –line setting in SCLC ranges from 24 to 35 weeks, with those subjects 
in sensitive relapse having a median survival of 4 to 8 weeks longer than those with refractory 
relapse.  In addition, irinotecan has also been demonstrated to be effective when combined with 
cisplatin in the front line setting, in extensive stage small cell lung cancer.  A Japanese study by 
Noda, and colleagues demonstrated superiority of this combination when compared to cisplatin and 
etoposide.[30]  While, these results were not replicated in a Southwest Oncology Group (SWOG) 
study, the combination is considered an alternative to cisplatin and etoposide in this disease.[31]  The 
similar efficacy and favorable toxicity of weekly irinotecan delivery justifies its use in the current 
proposal.  
Rationale for Carfilzomib sequencing and combination with topoisomerase inhibitors 
Sequencing information for Carfilzomib and other chemotherapeutic drugs is limited.  Extrapolating 
from data using bortezomib, it was shown by several groups that bortezomib sensitized NSCLC and 
pancreatic cancer cells to gemcitabine, as well as inducing apoptosis in vitro and in vivo.[18],[32] 


Sequence dependent enhanced activity was observed by Mortenson and colleagues when bortezomib 
was given after gemcitabine/carboplatin in NSCLC cell line studies.[23]   
Inactivation of proteasome function allows for increased apoptosis and potentially enhanced 
antitumor effects in response to treatment with many chemotherapeutic agents. Combination 
treatment of Carfilzomib with a Topoisomerase-I (Topo-I) inhibitor (e.g., a camptothecin analogue) 
is anticipated to be at least additive and potentially synergistic as the apoptosis induced by 
camptothecins in cancer cells may not involve NF-κB. In addition, proteasome inhibition may 
interfere with Topo-I degradation, a necessary step in DNA damage repair after exposure to Topo-I 
poisons.  Thus, we hypothesize that Carfilzomib will enhance the anti-tumor efficacy of Irinotecan 
in relapsed small cell lung cancer. 
Rationale for MTD 
The phase Ib component of the current trial  has completed enrollment.  A total of 22 patients were 
screened with 16 being enrolled.  No DLTs were observed at the 20/27 mg/m2 dose level.  Two 
patients experienced DLTs at the 20/45 mg/m2 dose.  One event was grade 4 thrombocytopenia 
lasting ≥ 7days and the other was ≥ grade 3 diarrhea.   Cohort 2 (20/36 mg/m2) included 6 patients, 
with one patient experiencing a DLT.  The MTD was established at the dose level investigated in 
Cohort 2.  The recommended phase II dose  has been determined to be: Carfilzomib 20/36 mg/m2 
(stepped up dosing) with Irinotecan 125 mg/m2. The phase II component will investigate this 
combination in patients with  relapsed small cell lung cancer. 


2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
 
Phase 1b: Determine maximum tolerated dose (MTD) of Carfilzomib (Day 1, 2, 8, 9, 15, and 
16) in combination with Irinotecan (Days 1, 8 and 15) in subjects with relapsed small and 
non-small cell lung cancer or other irinotecan-sensitive cancers. 
 
Phase II: Assess 6 month survival of relapsed small cell lung cancer in subjects treated with 
this combination therapy. 
 
2.2 
SECONDARY OBJECTIVES: 
 
Phase 1b study: Response rate, safety/tolerability, and biomarker endpoints:  
− Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity): 
relative to the start of irinotecan infusion: pre-dose, 90 min, 2 hr, 5.5 hr on Day 1 of 
Cycle 1, and pre-carfilzomib infusion on Day 2 of Cycle 1, in all subjects.  
− Irinotecan-mediated DNA damage by gamma-H2AX protein expression in PBMC 
obtained from all subjects relative to the start of irinotecan infusion: pre-dose, 90 min, 2 
hr, 5.5 hr on Day 1 of Cycle 1, and pre-carfilzomib infusion on Day 2 of Cycle 1. 
− Topoisomerase-I protein expression in PBMC.   
− When available, banked tumor tissue for immunohistochemical expression of 
Topoisomerase-I in all subjects.  
 
Phase II study: response rate, safety/tolerability, progression-free survival and biomarker 
endpoints:  
− Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity): 
relative to the start of irinotecan infusion: pre-dose, 90 min, 2 hr, 5.5 hr on Day 1 of 
Cycle 1, and pre-carfilzomib infusion on Day 2 of Cycle 1, in 15 subjects in each 
stratum of Phase II.  
− Irinotecan-mediated DNA damage by gamma-H2AX protein expression in PBMC 
obtained from all subjects relative to the start of irinotecan infusion: pre-dose, 90 min, 2 
hr, 5.5 hr on Day 1 of Cycle 1, and pre-carfilzomib infusion on Day 2 of Cycle 1 in 15 
subjects in each stratum. 


− Topoisomerase-I protein expression in PBMC in 15 subjects in each stratum   
− When available, banked tumor tissue for immunohistochemical expression of 
Topoisomerase-I in all subjects.  


3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
1.  Phase 1b: standard 3+3 design using five dose levels of Carfilzomib.  Two dose de-escalations 
are built into the protocol for safety. 
 
  
Table 2. Dose escalation schema 
  3+3 design 
Doses 
Carfilzomib* 
Irinotecan 
 Cohort -2 
20 mg/m2 
  75 mg/m2 
 Cohort -1 
20 mg/m2 
100 mg/m2 
 Cohort 1 
20/27 mg/m2 
125 mg/m2 
 Cohort 2 
20/36 mg/m2 
125 mg/m2 
 Cohort 3 
20/45 mg/m2 
125 mg/m2 
 Cohort 4 
20/56 mg/m2 
125 mg/m2 
 Cohort 5 
20/70 mg/m2 
125 mg/m2 
 Cycle 1 Day 1 & Day 2 doses are 20 mg/m2.  All subsequent days as specified, 
i.e. 20/27 mg/m2 means Cycle 1 Day 1 & Day 2 doses are 20 mg/m2 and all 
other days are 27mg/m2. 
 
Phase II: Stratified, single arm trial using MTD of Carfilzomib 20/36 mg/m2 with Irinotecan 125 
mg/m2 as established from Phase Ib, in up to 88 small cell lung cancer subjects who have relapsed 
on a prior platinum regimen.   
Stratification for phase II component:.  Patients will be accrued in two separate strata; each 
stratum has its own accrual target and may be closed or open to accrual independently: 
a. Platinum sensitive disease: initial response to platinum-based chemotherapy with 
progression > 90 days after last treatment. 
b. Platinum refractory disease: No response to platinum-based chemotherapy or progression 
within 90 days of completing platinum-based therapy.  Subjects that progressed during or 
within one month of completion of platinum-based chemotherapy will be excluded. 
3.2 
NUMBER OF CENTERS 
A minimum of 8 investigative study sites will participate on this trial. 
3.3 
ESTIMATED STUDY DURATION AND RECRUITMENT 
Study duration/timelines: September 2013 – December 2018. 


Recruitment: phase 1b: 6 to 9 month recruitment; phase II: 18 to 24 month recruitment.   


4 
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA   
 
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study.   
Criteria to the Phase II study are below, criteria specific only to the Phase Ib portion are 
grayed, . 
 
1. Subjects must have histologically or cytologically-confirmed diagnosis of progressive or 
recurrent malignancy as follows: 
a. Phase Ib:  advanced small or non-small cell lung cancer, or other cancer in which 
irinotecan therapy has been shown to be effective and for whom no curative therapy 
exists.  Subjects who progressed during or within one month of completing platinum-
based chemotherapy will be excluded. Subjects who received primary curative 
chemoradiation therapy, but who recur within the primary tumor site, previously 
radiated field or with distant metastases are also allowed to participate. Subjects 
who have clinical evidence of recurrent cancer do not require a confirmatory biopsy 
to be eligible for this trial. No limit will be placed on prior regimens received, but 
prior irinotecan is not allowed. 
b. Phase II:  extensive stage small cell lung cancer with tumor progression or recurrence 
after treatment with 1 platinum-containing regimen for recurrent or metastatic 
disease.  Subjects who progress during or within one month of completing platinum-
based chemotherapy will be excluded. Subjects who received primary curative 
chemoradiation therapy for limited disease, but who recur within the primary tumor 
site, previously radiated field or with distant metastases are  allowed to participate. 
Subjects who have clinical evidence of recurrent small cell lung cancer do not require 
a confirmatory biopsy to be eligible for this trial.  Prior irinotecan is not allowed. 
2. Subjects must have measurable disease per RECIST criteria 1.1 (see Appendix B-section 1) 
performed within 28 days prior to enrollment to treatment. Eligible subjects must be 
registered within 3 working days prior to initiation of protocol chemotherapy.  All other 
required tests to assess non-measurable disease must be performed within 42 days prior to 
enrollment to treatment.  
3. Subjects with known brain metastases are eligible only if he/she has been treated for brain 
metastasis, are asymptomatic after treatment, have a stable CT or MRI of the brain within 
28 days of enrollment to treatment and are not receiving corticosteroid therapy to control 
symptoms from brain metastasis. Only a non-enzyme inducing anticonvulsant (e.g., Keppra) 


will be permitted for those subjects requiring anticonvulsants. (Topical and/or inhaled 
steroids are allowed.) 
4. Subjects may have received previous radiation therapy, but it must have been completed at 
least 21 days prior to enrollment to treatment and the subject should have recovered from all 
associated toxicities. Measurable disease must be present outside the previous radiation field 
or a new lesion inside the radiation port must be present. There must be no anticipated need 
for concurrent radiation therapy during protocol treatment. 
5. Subjects may have received prior surgery provided that at least 28 days have elapsed since 
major surgery (thoracic or other major surgeries) and the subject has recovered from all 
associated toxicities. Subjects must have disease outside of the previous surgical resection 
area or a new lesion must be present. 
6. Subjects may have received prior chemotherapy provided that at least 14 days have elapsed 
from last dose of chemotherapy and the subject has recovered from all associated toxicities. 
7. Subjects must have a serum creatinine ≤ the institutional upper limit of normal OR a 
creatinine clearance ≥ 60 cc/min, measured or calculated (Cockcroft-Gault formula), 
obtained within 14 days prior to enrollment to treatment. Eligible subjects must be registered 
within 3 working days prior to initiation of protocol chemotherapy.   
8. Subjects must have adequate hepatic function as documented by a bilirubin ≤ 2 x the 
institutional upper limit of normal, an alkaline phosphatase ≤ 2 x the institutional upper limit 
of normal, and an SGOT  ≤ 2 x the institutional upper limit of normal all obtained within 14 
days prior to enrollment to treatment.  
9. Subjects must have an ANC ≥ 1,500/μl and a platelet count ≥ 100,000/μl obtained within 14 
days prior to enrollment to treatment.  
10. Subjects must be 18 years of age or older. 
11. Subjects must have a Zubrod Performance Status as follows (see Appendix B – section 4): 
a. Phase Ib:   
0 or 1 
b. Phase II:   
0, 1 or 2 
12. Subjects must not be pregnant or nursing. Women/men of reproductive potential must have 
agreed to use an effective contraceptive method (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
13. Male subjects must agree to practice contraception.  


14. All subjects must be informed of the investigational nature of this study and must sign and 
give written informed consent in accordance with institutional and federal guidelines.  
 
4.2 
EXCLUSION CRITERIA 
1. No prior irinotecan or carfilzomib 
2. Must not have evidence of leptomeningeal metastases. 
3. Must be no anticipated need for concurrent radiation therapy during protocol treatment. 
4. Subjects that progressed during or within one month of completion of first-line platinum-
based chemotherapy will be excluded. 
5. Subjects must not be pregnant or lactating females. 
6. Must have had no major surgery within 28 days prior to enrollment to treatment. 
7. Must not have acute active infection requiring treatment (systemic antibiotics, antivirals, or 
antifungals) within 14 days prior to enrollment to treatment. 
8. Must not have known human immunodeficiency virus infection. 
9. Must not have known active or clinically significant hepatitis A, B or C infection. 
10. Must not have had any unstable angina or myocardial infarction within 4 months prior to 
enrollment to treatment, NYHA Class III or IV heart failure, uncontrolled angina, history 
of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus 
syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction 
system abnormalities unless subject has a pacemaker. 
11. Must not have any uncontrolled hypertension or uncontrolled diabetes within 14 days prior 
to enrollment to treatment. 
12. Must not have any evidence of moderate or severe pulmonary hypertension. 
13. Must not have any evidence of other clinically active cancer and have no history of prior 
malignancy within the past 3 years with the exception of a) adequately treated basal cell 
carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix 
or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen 
levels; or d) cancer considered cured by surgical resection or unlikely to impact survival 


during the duration of the study, such as localized transitional cell carcinoma of the bladder 
or benign tumors of the adrenal glands or pancreas. 
14. Must not have any significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 
days prior to enrollment to treatment. 
15. Must not have any known history of allergy to Captisol® (a cyclodextrin derivative used to 
solubilize carfilzomib). 
16. Must have no contraindication to any of the required concomitant drugs or supportive 
treatments, including hypersensitivity to all anticoagulation and antiplatelet options, 
antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac 
impairment. 
17. Must not have any other clinically significant medical disease or condition that, in the 
Investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give 
informed consent.  
 
4.3 
STRATIFICATION FACTORS FOR PHASE II COMPONENT: 
In the phase II component of the study, subjects will be stratified according to the following: 
Platinum sensitive disease: an initial response to platinum-based chemotherapy with 
subsequent progression observed greater than 90 days after last platinum treatment OR 
Platinum refractory disease: No response to platinum-based chemotherapy or 
progression within 90 days of completing platinum-based therapy.  Subjects that 
progressed during or within one month of completion of platinum-based chemotherapy will 
be excluded. 


5 
SUBJECT REGISTRATION/ENROLLMENT 
 
Eligible subjects must be registered within 3 working days prior to initiation of protocol 
chemotherapy.   
This study uses a web based subject registration/enrollment system for data submission, through 
the data management services of Cancer Research And Biostatistics (CRAB).  The subject 
registration (“registration”) form is accessed online through the study website https://ctc-11-
001.crab.org/Login.aspx.  Access is protected and available to authorized users only.  For 
questions or assistance using this site, please contact:  webhelpCRS@crab.org.   
 


6 
TREATMENT PROCEDURES 
6.1 
DRUG PREPARATION AND ADMINISTRATION.   
 
 Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. 
The lyophilized product is reconstituted with Sterile Water for Injection to a final carfilzomib 
concentration of 2.0 mg/mL prior to administration.  Refer to Study Manual for full 
instructions.  The dose will be calculated using the subject’s actual BSA at baseline, or Day 1.  
Subjects with a BSA > 2.2 m2 will receive a dose of carfilzomib based upon a 2.2 m2 BSA.   
 For subjects considered at risk for TLS, oral hydration may be given as follows:  
30 mL/kg/day (approximately 6 to 8 cups of liquid per day) continuing up to the time of 
treatment.   
 IV hydration will be given prior to carfilzomib during Cycle 1.  This will consist of 250 to 
500 mL normal saline or other appropriate IV fluid given over 30 to 60 minutes.  If lactate 
dehydrogenase (LDH) or uric acid is elevated > 1.5 times IULN (and/or in subjects considered 
still at risk for TLS) at Cycle 2 Day 1, then the recommended IV hydration should be given 
additionally before each dose in Cycle 2.  The goal of the hydration program is to maintain 
robust urine output (e.g., ≥ 2 L/day).  Subjects should be monitored periodically during this 
period for evidence of fluid overload. Note: On Days 1, 8 and 15 of cycle 1, irinotecan is given 
prior to carfilzomib and this satisfies the prehydration requirement, provided the irinotecan is 
mixed in at least 250 mL of fluid. 
 If the subject has a dedicated line for carfilzomib administration, the line must be flushed with 
a minimum of 20 mL of normal saline prior to and after drug administration.     
 Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses during Cycle 1 
and after that as described in section 6.5.1.  
 Carfilzomib will be given as an IV infusion over approximately 30 minutes. The dose will be 
administered at a facility capable of managing hypersensitivity reactions.  Subjects will remain 
at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 
and following the dose on Cycle 2 Day 1.  During these observation times, post dose IV 
hydration (between 250 mL and 500 mL normal saline or other appropriate IV fluid 
formulation) may be given over 30 to 60 minutes.  Subjects should be monitored periodically 
during this period for evidence of fluid overload. 


 Irinotecan is commercially available and supplied in amber vials and appears as a pale yellow 
transparent solution.  Two vial sizes are available: 2 ml vials containing 40 mg of drug and 5 ml 
vials containing 100 mg of drug.  Prior to administration, irinotecan will be diluted with 5% 
dextrose in water (preferred diluent) or 0.9% sodium chloride solution to a total volume of 250-
500 ml (final concentration of 0.12 to 2.8 mg/ml). Irinotecan will be administered intravenously 
over 90 minutes prior to Carfilzomib infusion.  
 Dose adjustments for Carfilzomib or Irinotecan do not need to be made for weight gain/loss 
of < 10% 
6.2 
TREATMENT PLAN 
 
6.2.1 
PHASE I PORTION OF THE STUDY 
 
AGENT  
DOSE  
 
ROUTE  
 
DAYS  
INTERVAL 
Irinotecan  
125 mg/m2 
 
IV infusion  
 
1, 8, 15 
q 28 days 
 
 
 
 
 
(over 90 min) 
 
Carfilzomib 
20/ * mg/m2 
 
IV infusion  
 
1, 2, 8, 9 
q 28 days 
 
 
 
 
 
(over 30 min)  
15 and 16 
 
* Cycle 1 Day 1 & Day 2 doses are 20 mg/m2.  All subsequent days as specified, i.e. 20/27 mg/m2 means Cycle 1 Day 1 & Day 2 
doses are 20 mg/m2 and all other days are 27mg/m2. 
 
Dosage schedule, phase 1b:  
 
   
3+3 design 
Doses
Carfilzomib*
Irinotecan
 Cohort -2 
20 mg/m2 
75 mg/m2 
 Cohort -1 
20 mg/m2 
100 mg/m2 
 Cohort 1 
20/27 mg/m2 
125 mg/m2 
 Cohort 2 
20/36 mg/m2
125 mg/m2
 Cohort 3 
20/45 mg/m2
125 mg/m2
 Cohort 4 
20/56 mg/m2 
125 mg/m2 
 Cohort 5 
20/70 mg/m2
125 mg/m2
* Cycle 1 Day 1 & Day 2 doses are 20 mg/m2.  All subsequent days as specified, 
i.e. 20/27 mg/m2 means Cycle 1 Day 1 & Day 2 doses are 20 mg/m2 and all 
other days are 27mg/m2. 
Additional cycles of therapy may be administered provided the subject meets all of the following 
at the beginning of each cycle prior to treatment on Day 1 (at most 2 days prior to Day 1 of the 
next cycle): 
 
ANC ≥ 1,500/µL. 
 
Platelet count ≥ 100,000/µL. 


 
All other Grade 2, 3 or 4 non-hematological toxicities have resolved as required in section 
6.3.3. 
 
Serum creatinine ≤ 1.5 x IULN OR measured or calculated creatinine clearance ≥ 60 
mL/min using the Cockcroft-Gault. 
6.2.2 
 EVALUATION FOR DOSE-LIMITING TOXICITY, PHASE I ONLY  
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 A).  
A DLT is defined as any of the below treatment emergent toxicities with attribution (possibly, 
probably or definitely related) to one or more of the study drugs that occur during Cycle 1.   
Toxicities that occur in subsequent cycles will be handled through dose modifications (Section 
6.3) but will not figure into the definition of MTD.  Patients will be considered evaluable for DLT 
if they receive the assigned doses and schedule of chemotherapy throughout Cycle 1 or develop a 
DLT. If a patient does not develop a DLT, but does not complete Cycle 1 for any reason, then that 
patient will be considered not evaluable for DLT and be replaced.  
Non-hematologic: 
 ≥ Grade 2 neuropathy with pain 
 ≥ Any Grade 3 or 4 adverse event (excluding grade 3 nausea, vomiting, diarrhea lasting < 7 
days or grade 3 fatigue).   
 ≥ Grade 3 nausea, vomiting, or diarrhea lasting > 7 days despite maximal 
antiemetic/antidiarrheal therapy  
 Grade 5 toxicity 
 
Note: Abnormal non-hematologic laboratory values > grade 3 will be considered a DLT if they 
are determined to be clinically significant (i.e. result in dose interruption, delay or dose 
modification during cycle 1 or in a significant side effect as determined by the investigator) and 
possibly, probably or definitely related to study drug.  If baseline value is elevated (or decreased) 
prior to enrollment, an increase (or decrease) will not be considered a DLT unless it worsens by 2 
grades and is determined to be clinically significant by the treating investigator. 
Hematologic: 
 Grade 4 neutropenia  (ANC < 0.5 x 109/L) lasting for ≥ 7 days   
 Febrile neutropenia (ANC <  1.0 x 109/L with a fever ≥ 38.3ºC)  
 Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) lasting ≥ 7 days despite dose delay 
 Grade 3-4 thrombocytopenia associated with bleeding 
 Grade 5 toxicity 


6.2.3 
DOSE ESCALATION SCHEME -  FOR PHASE I ONLY 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-limiting 
toxicities (DLT) are defined above.     
 
Number of Subjects with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered 
dose (highest dose administered).  Three (3) 
additional subjects will be entered at the next 
lowest dose level if only 3 subjects were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more subjects at this dose level. 
a. If 0 of these 3 subjects experience DLT, 
proceed to the next dose level. 
b. If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
Three (3) additional subjects will be entered 
at the next lowest dose level if only 3 subjects 
were treated previously at that dose. 
<1 out of 6 at highest dose level 
below the maximally 
administered dose 
This is generally the recommended phase II 
dose. At least 6 subjects must be entered at the 
recommended phase II dose. 
 
 
6.2.4 
PHASE II PORTION OF THE STUDY 
 
AGENT  
DOSE  
 
ROUTE  
 
DAYS        INTERVAL 
Irinotecan  
125 mg/m2 
 
IV infusion   
1, 8, 15 
q 28 days 
 
 
 
 
 
(over 90 min) 
 
Carfilzomib 20/36 mg/m2  
IV infusion   
1, 2, 8, 9 
q 28 days 
 
 
 
 
 
(over 30 min)  
15 and 16 
* Cycle 1 Day 1 & Day 2 doses are 20 mg/m2.  All subsequent days as specified, i.e. 20/27 mg/m2 means Cycle 1 
Day 1 & Day 2 doses are 20 mg/m2 and all other days are 27mg/m2. 
 
Additional cycles of therapy may be administered provided the subject meets all of the 
following at the beginning of each cycle: 


 
ANC ≥ 1,500/µL. 
 
Platelet count ≥ 100,000/µL. 
 
All other Grade 2, 3 or 4 non-hematological toxicities have resolved as required in section 
6.3.3. 
 
Serum creatinine ≤ 1.5 x ULN OR measured or calculated creatinine clearance ≥ 60 mL/min 
using the Cockcroft-Gault. 
 
6.3 
DOSE REDUCTIONS/ADJUSTMENTS  
6.3.1 
DOSE LEVELS  
Carfilzomib – Phase I portion of the study  
Starting Dose  Dose Level -1   
Dose Level -2 
20/27 mg/m2  
20/20 mg/m2  
Hold 
20/36 mg/m2  
20/27 mg/m2  
20/20 mg/m2 
20/45 mg/m2  
20/36 mg/m2  
20/27 mg/m2  
20/56 mg/m2  
20/45 mg/m2  
20/36 mg/m2 
20/70 mg/m2  
20/56 mg/m2  
20/45 mg/m2  
 
 


Carfilzomib – Phase II portion of the study  
Starting Dose  
Dose Level -1  
 
Dose Level -2 
20/36 mg/m2  
20/27 mg/m2  
 
20/20 mg/m2 
* Cycle 1 Day 1 & Day 2 doses are 20 mg/m2.  All subsequent days as specified, i.e. 20/27 mg/m2 means Cycle 1 Day 1 & Day 2 
doses are 20 mg/m2 and all other days are 27mg/m2. 
 
In the event that carfilzomib is held on Day 2, 8, 9, 15 and/or 16 of therapy, missed doses are not 
to be made up.  All dose reductions are permanent and no dose re-escalation will be allowed on 
this trial. 
 
Irinotecan- Phase I and II portions of the study 
 
Starting Dose  
Dose Level -1  
Dose Level -2 
125 mg/m2 
 
100 mg/m2 
 
75 mg/m2 
*If Dose level -1 is utilized 
In the event that irinotecan is held on Day 8 and/or Day 15, missed doses are not to be made up.  
All dose reductions are permanent and no dose re-escalation will be allowed on this trial. 
6.3.2 
DOSE REDUCTIONS FOR CARFILZOMIB AND IRINOTECAN 
HEMATOLOGIC TOXICITIES: 
The following table outlines the dose reduction guidelines for carfilzomib and irinotecan for 
thrombocytopenia and neutropenia that occurs at any point during the prior cycle: 
Event Name 
Neutropenia 
Grade of Event 
Recommended Action for 
Carfilzomib 
Recommended Action for 
Irinotecan 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose 
Hold* until < Grade 2.  Resume 
at one dose level lower, if 
indicated.** 
Grade 4 
Hold* until < Grade 2.  Resume 
at one dose level lower, if 
indicated.** 
Hold* until < Grade 2.  Resume 
at one dose level lower, if 
indicated.** 
*Subjects requiring a delay of >3 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
No prophylactic growth factor support is allowed in cycle 1, but growth factor support in the 
event of neutropenia is encouraged and should be administered at the discretion of the 
treating physician and per National Comprehensive Cancer Network Guidelines 
(http://www.nccn.org). 
 
 
Event Name 
Thrombocytopenia 
Grade of Event 
Recommended Action for 
Recommended Action for 


Carfilzomib 
Irinotecan 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose. 
Grade 3 
No change in dose 
Hold* until < Grade 2.  Resume at 
one dose level lower, if 
indicated.** 
Grade 4 
Hold* until < Grade 2.  Resume 
at one dose level lower, if 
indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if 
indicated.** 
*Subjects requiring a delay of >3 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
 
6.3.3 
DOSE REDUCTIONS OF CARFILZOMIB AND IRINOTECAN FOR NON-
HEMATOLOGIC TOXICITIES 
Dose adjustment guidelines for non-hematologic toxicities that occur at any point during the prior 
cycle are summarized as follows: 
Event name 
Recommended Action 
Recommended Action 
Grade of Event 
Carfilzomib 
Irinotecan 
Allergic reaction/hypersensitivity 
 
 
Grade 2 – 3 
Hold until ≤ Grade 1, 
reinstitute at full dose. 
No change in dose 
Grade 4 
Discontinue 
No change in dose 
Tumor lysis syndrome  
(≥ 3 of following: ≥ 50% increase in 
creatinine, uric acid, or phosphate; ≥ 
30% increase in potassium; ≥ 20% 
decrease in calcium; or ≥ 2-fold 
increase in LDH 
Hold carfilzomib until all 
abnormalities in serum 
chemistries have resolved.  
Reinstitute at full doses. 
Hold irinotecan until all 
abnormalities in serum 
chemistries have resolved.  
Reinstitute at full doses. 
Infection  
Grade 3 or 4 
Hold carfilzomib until 
systemic treatment for 
infection complete.  If no 
neutropenia, restart at full dose.  
If neutropenic, follow 
neutropenic instructions. 
Hold irinotecan until 
systemic treatment for 
infection complete.  If no 
neutropenia, restart at full 
dose.  If neutropenic, 
follow neutropenic 
instructions. 
Peripheral Neuropathy  
Grade 2 treatment emergent with 
pain or Grade 3neuropathy 
Continue to dose.  If 
neuropathy persists for more 
than two weeks hold 
carfilzomib until resolved to ≤ 
Gr 2 without pain. Then restart 
at 1 dose decrement if 
indicated.** 
No change in dose 
Peripheral Neuropathy  
Grade 4 neuropathy 
Discontinue 
Discontinue  
Serum creatinine elevation  
Grade 2, 3 or 4  
Hold until ≤ Grade 1. Resume 
at one dose level lower, if 
indicated.** 
Hold until ≤ Grade 1. 
Resume at one dose level 
lower, if indicated.** 


Hepatic Impairment  
Grade 
3 
or 
4 
elevation 
of 
transaminases or bilirubin 
Hold Carfilzomib until < Grade 
2.  Resume at one dose level 
lower, if indicated.** 
Hold Irinotecan until < 
Grade 2.  Resume at one 
dose level lower, if 
indicated.** 
Congestive heart failure  
Grade 3 or 4 
Any subject with symptoms of 
grade 3 or 4 congestive heart 
failure, whether or not drug 
related, must have the dose 
held until resolution to grade 2 
or less, or return to baseline, 
after which treatment may 
continue at 1 dose decrement, 
or the subject may be 
withdrawn from the study.  If 
no resolution after 2 weeks, the 
subject will be withdrawn from 
the study. 
No change in dose 
Pulmonary Hypertension Grade 2, 
3, or 4 
Hold Carfilzomib until < Grade 
2.  Resume at one dose level 
lower, if indicated.** 
No change in dose 
Diarrhea 
 
 
 
      Grade 2 or Grade 3 lasting < 3 
days*  
No change in dose 
Hold Irinotecan until < 
Grade 2.  Resume at same 
dose level. 
      Grade 3 (lasting > 3 days) or 4* 
Hold Carfilzomib until < Grade 
2.  Resume at one dose level 
lower, if indicated.** 
Hold Irinotecan until < 
Grade 2.  Resume at one 
dose level lower, if 
indicated.** 
*Recommended management:  Loperamide antidiarrheal therapy dosage schedule:  4 mg at first 
onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum dosage:  
16 mg/24 hours) Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
Nausea/Vomiting  
 
 
 
      Grade 2 
No change in dose. 
Hold Irinotecan until < 
Grade 2.  Resume at same 
dose level. 
      Grade 3  
No change in dose 
Hold Irinotecan until < 
Grade 2.  Resume at one 
dose level lower, if 
indicated.** 


      Grade 4 
Hold Carfilzomib until < Grade 
2.  Resume at one dose level 
lower, if indicated. ** 
Hold Irinotecan until < 
Grade 2.  Resume at one 
dose level lower, if 
indicated. ** 
Other Non-Hematologic Toxicity 
 
 
 
Other non-hematologic toxicity 
assessed as drug--related > Grade 3 
Hold dose until toxicity 
resolves to < Grade 2 or 
baseline.  Resume at one dose 
level lower, if indicated. **. 
Hold dose until toxicity 
resolves to < Grade 2 or 
baseline.  Resume at one 
dose level lower, if 
indicated. **. 
*Subjects requiring a delay of >3 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
6.3.4 
ADDITIONAL INFORMATION REGARDING MYELODYSPLASTIC 
SYNDROME AND ACUTE MYELOID LEUKEMIA 
 
Based on an analysis of myelodysplastic syndrome (MDS) and acute myeloid leukemia 
(AML) conducted in May 2014, 9 cases were identified (4 MDS and 5 AML), 4 of which (2 
MDS and 2 AML) were reported by the investigator as related to carfilzomib. Of the 9 
cases, 7 are from company-sponsored clinical studies, 2 are from ISTs and none were 
identified from the postmarketing experience. 
 
A medical review of the 9 cases revealed that 8 of the events of MDS/AML were reported in the 
setting of underlying relapsed/refractory multiple myeloma in subjects previously treated with 
multiple chemotherapy regimens and radiation; 2 of these 8 subjects also had a prior history of 
MDS prior to study entry.  The ninth case was reported from an IST for subjects with 
underlying relapsed AML and acute lymphoblastic leukemia, and thus, this report of AML did 
not represent a new disorder for that subject. 
 
There is an inherent increased risk of developing secondary malignancies in multiple 
myeloma patients, including MDS and AML independent of therapy.  Approximately 10,000 
cases of MDS are diagnosed annually in the US, corresponding to an annual age- adjusted 
incidence rate of approximately 3.3 to 3.4 per 100,000.  Using population-based data from 
Sweden, there is an 11.51-fold (95% CI: 8.19–15.74) increased risk of AML/MDS for 
patients diagnosed with MM, including both treated and untreated patients, compared with 
Swedish general population, corresponding to an incidence rate of 139 per 100,000 person-
years (Mailankody 2011).  Prior treatment exposure to other chemotherapy agents including 


melphalan, lenalidomide, and thalidomide contribute to the risk; MDS and/or AML are 
documented in the labeling for these agents. 
 
All 9 subjects had other risk factors (e.g., prior treatment exposure to other chemotherapy agents 
including melphalan, lenalidomide, and thalidomide; all of which include MDS and/or AML 
documented in their labeling).  Three of the 9 subjects actually had a previous diagnosis of MDS 
or AML at study entry.  Therefore, a meaningful causal association with the administration of 
carfilzomib could not be established.  Events of MDS or AML will continue to be monitored in 
the clinical study and postmarketing setting. 
 
Finally, in addition to these 9 cases, 5 cases (2 MDS and 3 AML) were reported in the 
1110 control arm subjects enrolled into 1 of 4 ongoing, company-sponsored, Phase 3 clinical 
studies.  None of these 5 subjects were exposed to carfilzomib. These 5 cases serve to 
emphasize the elevated inherent risk for MDS/AML experienced by myeloma patients 
independent of treatment exposure. 
 
6.3.5 
ADDITIONAL INFORMATION REGARDING TOXICITY  
6.3.5.1 
Increased Creatinine or Decreased CrCl 
No dose adjustment is required in patients with mild, moderate, or severe renal impairment or 
patients on chronic dialysis. Since dialysis clearance of carfilzomib concentrations has not been 
studied, the drug should be administered after the dialysis procedure. The renal safety profile of 
carfilzomib provides evidence of its tolerability in heavily pretreated patients with multiple 
myeloma and concomitant renal insufficiency (Harvey 2012). A PK study (Study PX-171-005) was 
conducted in 50 multiple myeloma subjects who had various degrees of renal impairment. 
Carfilzomib was administered IV over 2 to 10 minutes, on 2 consecutive days, weekly for 3 weeks 
(Days 1, 2, 8, 9, 15, and 16) every 28 days. Subjects received an initial dose of 15 mg/m2, which 
could be escalated to 20 mg/m2 starting in Cycle 2, if 15 mg/m2 was well tolerated in Cycle 1. 
Escalation of the carfilzomib dose to 27 mg/m2 at Cycle 3 and beyond was allowed for subjects who 
tolerated the 20 mg/m2 dose in Cycle 2. Results from this study suggest that subjects with mild to 
severe renal dysfunction, including dialysis patients, can receive CFZ at doses shown to be 
efficacious and well-tolerated in multiple myeloma patients with normal renal function. 


6.3.5.2 
Infections 
Subjects with grade 3 or 4 active or suspected infections should have treatment withheld until 
infection has resolved and anti-infective treatment has been completed.  After the infection has 
resolved and anti-infective treatment has been completed, treatment may continue at the original 
dose.  If there is no resolution of toxicity after 3 weeks, the subject will be withdrawn from the study. 
6.3.5.3 
Congestive Heart Failure (CHF) 
Any subject with symptoms of grade 3 or 4 CHF or any other suspected acute cardiac event, whether 
or not drug related, must have the dose held until resolution.  After the event has resolved or returned 
to baseline, treatment may continue at 1 dose decrement, with the approval of the  Medical Monitor, 
or the subject may be withdrawn from the study.  If there is no resolution of CHF after 2 weeks, the 
subject will be withdrawn from the study. 
6.3.5.4 
Pulmonary Hypertension 
Pulmonary arterial hypertension 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. 
6.3.5.5 
Myocardial Infarction 
Death due to cardiac arrest has occurred within a day of carfilzomib administration. New onset or 
worsening congestive heart failure or myocardial ischemia have occurred following administration 
of carfilzomib. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, and 
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 NYHA Class III and IV heart failure, myocardial infarction in 
the preceding 6 months, or conduction abnormalities uncontrolled by medications were not eligible 
for the clinical studies. These patients may be at greater risk for cardiac complications. Dyspnea, 
predominately Grade 1 and 2, was reported in 35% of subjects enrolled in clinical studies (see 
Section 6.7, Undesirable Effects). Evaluate patients with dyspnea based on the clinical presentation 
and manage accordingly. Unless otherwise specified in the individual protocol, reduce or interrupt 
dose as appropriate. 


6.3.5.6 
Hepatic Toxicity 
Cases of hepatic failure, including fatal cases, have been reported (< 1%). Carfilzomib can cause 
elevations of serum transaminases and bilirubin. Monitor liver enzymes frequently. Please use 
section 6.3.3 as a guide to reduce or interrupt carfilzomib dose. 
6.3.5.7 
Posterior Reversible Encephalopathy Syndrome 
Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible posterior 
leukoencephalopathy syndrome (RPLS), is a rare, neurological disorder, which can present with 
seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and 
neurological disturbances, along with hypertension.  The diagnosis is confirmed by 
neuroradiological imaging.  If diagnosed early and treated, the symptoms of PRES may be 
reversed.  Cases of PRES have been reported in patients receiving carfilzomib.  Discontinue 
carfilzomib if PRES is suspected.  The safety of reinitiating carfilzomib therapy in patients 
previously experiencing PRES in not known. 
6.3.5.8 
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Carfilzomib does not need to be 
held in the following cases: 
 Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days with adequate treatment of anti-
emetics or anti-diarrheals)  
 Grade 3 fatigue (unless persisting for >14 days) 
 
Neither Carfilzomib nor Irinotecan need to be held in the following cases: 
 Alopecia 
 ≥ Grade 3 hyperglycemia attributed to dexamethasone 
6.3.5.9 
Other Grade 3 or 4 Non-hematologic toxicities 
Hold all treatment until toxicities resolve to < Grade 2. Upon resolution resume treatment and 
decrease irinotecan one dose level. If toxicities do not resolve within three weeks, subject shall be 
removed from study 
6.3.5.10 
Other 
Any other dose modifications in study treatment that are not described above may be performed at 
the discretion of the treating investigator, provided that criteria for subject withdrawal from study 
treatment have not been met. 


6.3.5.11 
For treatment modification questions, please contact Dr. Susanne Arnold at 859-
257-5522 or email at: smarno0@uky.edu. 
6.3.6 
MISSED DOSES 
Missed doses will not be replaced during a cycle.   
6.3.7 
CHANGES IN BODY SURFACE AREA (BSA)  
Dose adjustments for carfilzomib or irinotecan do not need to be made for weight gains/losses of 
≤ 10%.  Subjects with a Body Surface Area (BSA) of greater than 2.2 m2 will receive a capped dose 
of carfilzomib based upon a 2.2 m2 BSA.  Subjects with BSA greater than 2.2 m2 will receive the 
prescribed dose of irinotecan without a cap. 
6.4 
SAFETY CONSIDERATIONS 
Based upon the experience in the Phase 1 and 2 clinical studies with carfilzomib, in approximately 
700 subjects, the following observations are noted:  
 A “first dose effect” has been seen, 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 
Day 2, which may be the clinical sequellae of rapid tumor lysis and/or cytokine release.    
 Should a “first dose” effect occur at any point during Cycle 1 or 2, treatment with high dose 
glucocorticoids (e.g. methylprednisolone 50–100 mg) is recommended.  In addition, intravenous 
fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be available for 
immediate use and instituted, as medically indicated.  
 Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses during the first 
cycle and after that as per section 6.5.1. Subjects with active or suspected infection of any kind 
that required systemic treatment should not be dosed with carfilzomib until the infection has 
resolved and if being treated with anti-infective, the course of antibiotics has been completed.  
 Subjects should have anemia corrected in accordance with the Institutional guidelines. 
Carfilzomib and Irinotecan treatment 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.  Subjects should be advised about diarrhea caused 
by Irinotecan and should have loperamide readily available at home. 


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 Day 
1 through the end of the subject’s study participation.  Any change in concomitant medications must 
be recorded.   
6.5.1 
REQUIRED CONCOMITANT MEDICATIONS 
Female subjects of child-bearing potential must agree to use dual methods of contraception for the 
duration of the study.  Male subjects must agree to use a barrier method of contraception for the 
duration of the study if sexually active with a female of child-bearing potential. 
Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses during the first 
cycle..  A higher dose of dexamethasone may be used per institutional standard.  If treatment-related 
fever, rigors, chills, and/or dyspnea are observed following any dose of carfilzomib after 
dexamethasone has been discontinued, the subject should receive treatment for infusion reaction per 
the investigator’s institutional standard and dexamethasone (8 mg PO/IV) should be re-instituted 
and administered prior to all subsequent doses.  
All subjects must receive prophylaxis with hydration (see Section 6.1). 
6.5.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
Subjects may receive RBC or platelet transfusions if clinically indicated in accordance with 
institutional guidelines.  FDA approved bisphosphonates are allowed.  Subjects may receive 
antiemetics and antidiarrheals as necessary, but these should not be administered unless indicated.  
Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically in cycle 1 of therapy.  
Vitamins and supplements should be recorded on the concomitant medication page.  All transfusions 
and/or blood product related procedures must be recorded on the appropriate form. 
6.5.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with other investigative anticancer therapies or other investigational  
agents is not allowed.  


7 
STUDY TESTS AND OBSERVATIONS: 
 Phase Ib Study Calendar:  
Required Studies 
 
Cycle 1 
Cycle 2,4,6 
Cycle 3, 5 
 
 
 
Day 
Day 
 
 
 
Screen 
within 
2weeks 
unless 
specified 
1 
2 
8 9 
15 
16 
1 
2 
8
9
15 
16 
22 
1 
2 8 9 15 
16 
Off study 
Follow-up@ 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Performance Status and 
Weight 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Toxicity Assessment  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Disease Assessment 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan ¶ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Brain CT/MRI # 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG# 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential 
 
X* 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X 
 
X  
X 
 
X 
X 
Serum chemistries § 
X* 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X 
 
X  
X 
 
X 
X 
Serum Magnesium 
X* 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum or urine 
Pregnancy Test 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Irinotecan √ 
 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X 
 
X  
X 
 
 
 
Carfilzomib √     (study 
provided) 
 
X 
X 
X X 
X 
X 
X 
X 
X
X
X 
X 
 
X 
X X X 
X 
X 
 
 
Dexamethasone 8 mg+ 
 
X 
X 
X X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD/Correlative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmcodynamic blood 
tests £ 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Submission & 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.3) must be repeated every8 weeks until disease progression. Once off study, 
the frequency of this scan may be reduced to every 3 months until disease progression. 
#Prestudy, and then as clinically indicated 
* This test is required prestudy within 2 weeks of starting study medication. 
§ Sodium, potassium, calcium, chloride, creatinine, magnesium, SGOT, SGPT, alkaline phosphatase, total bilirubin prior to treatment on Day 1 of each cycle (at most 
2 days prior to Day 1 of the next cycle);  Sodium, potassium, chloride, creatinine, prior to treatment on Day 8 & 15 
√ After completion of Cycle 6 and if the subject has not met criteria for disease progression, carfilzomib and irinotecan may be continued at the discretion of the 
sponsor and treating physician.  
+ Dexamethasone 8 mg prior to all carfilzomib doses during the first cycle and after that as per section 6.5.1. 
£ PD:  Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity) and gamma-H2AX and Topoisomerase-I expression  Day 1: The sampling 
times relative to the start of irinotecan infusion: Pre-irinotecan, 90 min, 2 hours, 5.5 hours; Day 2: pre-carfilzomib infusion 
& Submit tumor block or 10 unstained slides of pre-existing tumor 
@ Follow-up will be for 30 days after last treatment or until all drug-associated (possible, probably or definite) toxicities have resolved to Grade 1 or less


Phase II Study Calendar: 
Required Studies 
 
Cycle 1 
Cycle 2,4,6 
Cycle 3, 5 
 
 
 
Day 
Day 
 
 
 
Screen 
within 2 
weeks 
unless 
specified 
1 
2 
8 9 
15 
16 
1 
2 
8
9
15 
16 
22 
1 2 8 
9 
15 
16 
Off study 
Follow-up@ 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X  
 
 
 
 
X 
X 
Performance Status and 
Weight 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X  
 
 
 
 
X 
X 
Toxicity Assessment  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X  
 
 
 
 
X 
X 
Disease Assessment 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X  
 
 
 
 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan ¶ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Brain CT/MRI # 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG# 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential 
 
X* 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X  
X 
 
X 
 
X 
X 
Serum chemistries § 
X* 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X  
X 
 
X 
 
X 
X 
Serum Magnesium 
X* 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X  
 
 
 
 
X 
X 
Serum or urine 
Pregnancy Test 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Irinotecan √ 
 
X 
 
X 
 
X 
 
X 
 
X
 
X 
 
 
X  
X 
 
X 
 
 
 
Carfilzomib √     (study 
provided) 
 
X 
X 
X X 
X 
X 
X 
X 
X X
X 
X 
 
X X X 
X 
X 
X 
 
 
Dexamethasone 8 mg 
 
X 
X 
X X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/PD/Correlative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmcodynamic blood 
tests £ 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Submission & 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.3) must be repeated after ever two cycles of treatment until disease 
progression. Once off study, the frequency of this scan may be reduced to every 3 months until disease progression. 
#Prestudy, and then as clinically indicated 
* This test is required prestudy within 2 weeks of starting study medication. 
§ Sodium, potassium, calcium, chloride, , creatinine, magnesium, SGOT, , alkaline phosphatase, total bilirubin prior to treatment on Day 1 of each cycle (at most 2 days 
prior to Day 1 of the next cycle);  Sodium, potassium, chloride, creatinine, prior to treatment on Day 8 & 15 
√ After completion of Cycle 6 and if the subject has not met criteria for disease progression, carfilzomib and irinotecan may be continued at the discretion of the 
investigator-sponsor and treating physician.  
+ Dexamethasone 8 mg prior to all carfilzomib doses  during the first cycle and after that as per section 6.5.1. 
£ PD:  In first 15 subjects in each stratum: Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity), Gamma-H2AX  and 
Topoisomerase-I  in PBMC Day 1: The sampling times relative to the start of irinotecan infusion: Pre-irinotecan, 90 min, 2 hours, 5.5 hours; Day 2: pre-carfilzomib 
infusion 
& All subjects: Submit tumor block or 10 unstained slides of pre-existing tumor 
@ Follow-up will be every 3 months for up to 2 years 


8 
STUDY DISCONTINUATION 
 
8.1 
CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT: 
 
a. Completion of 6 cycles of chemotherapy. 
 
b. Progression of disease or symptomatic deterioration (as defined in Appendix B-Section 2). 
 
c. Unacceptable toxicity. 
 
d. Treatment delay for any reason for greater than 3 weeks 
 
e. At the discretion of the treating physician 
 
f. The subject may withdraw from the study at any time for any reason. 
 
Subjects will receive up to 6 cycles of therapy. Subjects who are deemed to be clinically benefitting 
from this therapy by the treating physician, may be considered for further treatment at the discretion 
of the sponsor, Amgen, the treating physician and the study PI.  
ALL REASONS FOR DISCONTINUATION OF TREATMENT MUST BE DOCUMENTED 
IN THE OFF TREATMENT NOTICE ECRF 
 
8.2 
POST TREATMENT FOLLOW-UP 
 
Phase Ib: All subjects will be followed for 30 days after last treatment and until all drug-associated 
(possible, probably or definite) toxicities have resolved to Grade 1 or less.   
 
Phase II: All subjects will be followed every 3 months until death or for 2 years after initial 
registration, or until death, or until study closure whichever occurs first. 


9 
ADVERSE EVENTS 
9.1 
ADVERSE EVENTS DEFINITIONS  
An AE is any untoward medical occurrence in a study subject administered an investigational 
product and that does not necessarily have a causal relationship with this treatment.  
An AE therefore can be any unfavorable and unintended sign (including laboratory 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.  
A suspected adverse reaction means any AE for which there is reasonable possibility that the drug 
caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. An adverse reaction means any AE caused by a drug. This means 
there is reason to conclude that the study drug caused the event.  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the current 
Investigators Brochure (IB) or prescribing information for a marketed compound or is not listed at 
the specificity or severity that has been observed; or is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. In addition, AEs 
or suspected adverse reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular study drug is considered “unexpected.” 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
to describe the event and for assessing the severity of AEs (see Appendix D).  Any events 
representing a change in the CTCAE Grade need to be reported on the AE case report form.  This 
includes any change in laboratory values.   
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history. 


9.2 
CAUSALITY 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:   
 Yes:  The event is suspected to be related if:  
 there is a clinically plausible time sequence between onset of the AE and administration of 
study treatment; and/or 
 there is a biologically plausible mechanism for the study treatment to cause or contribute to 
the AE; and/or  
 the event responds to withdrawal of the study medication (dechallenge) and/or recurs with 
rechallenge (when clinically feasible); and/or 
 the AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, or 
procedures 
 No:  
 the AE is more likely to be explained by the subject’s clinical state, underlying disease, 
concomitant medication, study or non-study procedure; and/or 
 the time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
 the event is unlikely to be related to the investigational product(s) 
 
9.3 
ADVERSE EVENTS REPORTING PROCEDURES 
All AEs,  any new event with an onset date after the subject signs consent for study participation or 
changes to any pre-existing abnormalities that occur after initiation of treatment 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 Adverse Events and SAE eCRFs, as part of the CRAB CTC Electronic Data Capture (EDC) 
system. 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for 
AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.03.  A copy of the CTCAE version 4.03 can be downloaded from the CTEP web 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Attribution of the AE: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 


Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
All AEs that are considered possibly, probably or definitely related to study drug must be followed 
to resolution or stabilization if improvement is not expected.  
Baseline abnormalities will be captured as part of the medical history as described in section 9.1.  
AEs should be reported from the time of 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 site Principal Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and determining that documentation of the event is adequate.   
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 Subinvestigators 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.   
 
9.3.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS FOR 
CARFILZOMIB (CAEPR) 
The following side effects and conditions to watch for have been observed and may be due to 
carfilzomib. 


Body 
System 
Very Common 
(may affect 
more than 1 in 
10 people) 
Common 
(may affect up to
1 in 10 people) 
Uncommon 
(may affect up to
1 in 100 people) 
Rare 
(may affect up to 
1 in 1000 people)
Blood 
Low red blood 
cell count, which 
may cause 
tiredness and 
fatigue; 
 
Low platelets, 
which may cause 
easy bruising or 
bleeding; 
 
Low white blood 
cell count, which 
may decrease 
your ability to 
fight infection 
Low white blood 
cell count, which 
may be 
associated with 
fever; 
Hemolytic uremic 
syndrome (HUS) 
(see ‘Conditions 
you need to look 
out for’) 
Thrombotic 
thrombocytopenic 
purpura (TTP) 
(see ‘Conditions 
you need to look 
out for’); 
 
Thrombotic 
microangiopathy 
(see ‘Conditions 
you need to look 
out for’) 
Heart 
 
Heart failure*, and 
heart problems 
including rapid, 
strong or irregular 
heartbeat 
Heart attack; 
 
Reduced blood 
flow to the heart; 
 
Abnormal amount 
of fluid between 
the heart and the 
lining around the 
heart; 
 
Swelling and 
irritation of the 
lining around the 
heart 
 
Lung 
Shortness of 
breath; 
 
Cough, cough 
with phlegm 
Blood clot in the 
lungs; 
Fluid in the lungs; 
Nose bleed; 
Change in voice 
or hoarseness; 
Pain in throat; 
Wheezing; 
Pulmonary 
hypertension (see 
‘Conditions you 
Lung problems 
see ‘Conditions 
you need to look 
out for’); 
 
Bleeding in the 
lungs 
 


 
 
Body 
System 
Very Common 
(may affect 
more than 1 in 
10 people) 
Common 
(may affect up to
1 in 10 people) 
Uncommon 
(may affect up to 
1 in 100 people) 
Rare 
(may affect up to
1 in 1000 people)
 
 
need to look out
for’) 
 
 
Eye 
 
Blurred vision; 
Cataract 
 
 
Intestine 
Diarrhea; 
Nausea; 
Constipation; 
Vomiting; 
Stomach Pain 
Indigestion; 
Toothache 
Perforation in 
stomach, small 
intestine, or large 
bowel; 
 
Bleeding in the 
stomach and 
bowels 
 
General 
Tiredness 
(fatigue); 
 
Fever; 
 
Swelling of the 
hands, feet or 
ankles; 
Chills; 
General 
weakness; 
Pain; 
Feeling too hot; 
Pain, swelling, 
irritation or 
discomfort where 
you received the 
injection into your 
vein; 
 
Infusion reactions 
(see ‘Conditions 
you need to look 
out for’) 
Multi-organ failure  
Liver 
 
Liver problems 
including an 
increase in your 
liver enzyme in 
the blood 
Liver failure; 
 
Itchy skin, yellow 
skin, very dark 
urine and very 
pale stools which 
may be caused by 
a blockage in the 
flow of bile from 
the liver 
(cholestasis) 
 
Infections 
Respiratory tract 
infection; 
 
Pneumonia 
Sore throat; 
Bronchitis; 
Runny nose or 
nasal congestion; 
 
Urinary tract 
infection; 
 
Inflammation of 
the nose and 
throat; 
 
 


 
 
Body 
System 
Very Common 
(may affect 
more than 1 in 
10 people) 
Common 
(may affect up to
1 in 10 people) 
Uncommon 
(may affect up to 
1 in 100 people) 
Rare 
(may affect up to
1 in 1000 people)
 
 
Flu-like symptoms
(influenza); 
 
Serious infection 
in the blood 
(sepsis); 
Viral infection; 
Infection and/or 
irritation of your 
stomach and 
bowels; 
 
Lung infection 
 
 
Metabolism 
Decreased 
appetite 
Dehydration 
Tumor lysis 
syndrome (TLS) 
(see “Conditions 
you need to look 
out for’) 
 
Bone and 
Muscle 
Back pain; 
Joint pain; 
Pain in limbs, 
hands or feet; 
 
Muscle spasms 
Bone and muscle 
pain; 
Chest pain; 
Muscle 
weakness; 
 
Aching muscles 
 
 
Nervous 
System 
Headache; 
Dizziness; 
Numbness 
Abnormal 
sensation such as 
tingling or 
decreased 
sensation in arms 
and/or legs 
Bleeding in the 
brain 
Posterior 
reversible 
encephalopathy 
syndrome (PRES) 
(see ‘Conditions 
you need to look 
out for’) 
Psychiatric 
Insomnia 
(difficulty 
sleeping) 
Anxiety 
 
 
Kidney 
 
Kidney problems, 
including 
decreased ability 
to make urine, 
increased 
creatinine in the 
blood, and kidney 
failure needing 
dialysis 
 
 
Skin 
 
Rash; 
 
 


 
 
 
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Body 
System 
Very Common 
(may affect 
more than 1 in 
10 people) 
Common 
(may affect up to
1 in 10 people) 
Uncommon 
(may affect up to 
1 in 100 people) 
Rare 
(may affect up to 
1 in 1000 people)
 
 
Itchy skin;
 
Redness of the 
skin; 
 
Increased 
sweating 
 
 
Tests 
Changes to blood 
tests (decreased 
blood levels of 
potassium, 
increased blood 
levels of sugar 
and/or 
creatinine) 
Changes to blood 
tests (decreased 
blood levels of 
sodium, 
magnesium, 
protein, calcium 
or phosphate, 
increased blood 
levels of calcium, 
uric acid, 
potassium, 
bilirubin, or c- 
reactive protein) 
 
 
Immune 
System 
 
 
Allergy to 
carfilzomib 
 
Blood 
Vessels 
High blood 
pressure 
(hypertension) 
Low blood 
pressure 
(hypotension); 
 
Blood clots in the 
veins; 
 
Flushing 
Stroke; 
Bleeding; 
Extremely high 
blood pressure 
(see ‘Conditions 
you need to look 
out for’) 
 
Ear and 
labyrinth 
 
Ringing in the 
ears 
 
 
*The risk of developing heart failure when receiving carfilzomib is higher if you are 75 years 
of age or older. This risk is also higher if you are Asian. 
 
Subjects will be advised to inform the study staff if they develop any of the following: 
 
Chest pains, shortness of breath, or if there is swelling of your ankles and 
feet, which may be symptoms of heart problems. 
 
 
Difficulty breathing, including shortness of breath (dyspnea) at rest or with 
activity or a cough, rapid breathing, feeling like you can't breathe in enough air, 
wheezing, or cough, which can be signs of lung problems. 


 
 
 
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 
Extremely high blood pressure, severe chest pain, severe headache, 
confusion, blurred vision, nausea and vomiting, or severe anxiety, which may 
be signs of a condition known as hypertensive crisis. 
 
 
Shortness of breath with everyday activities or at rest, irregular heartbeat, 
racing pulse, tiredness, dizziness, and fainting spells, which can be signs of a 
condition known as pulmonary hypertension. 
 
 
Swollen ankles, feet or hands, loss of appetite, passing less urine, or 
abnormal blood test results, which may be symptoms of kidney problems or 
kidney failure. 
 
 
Irregular heartbeat, kidney failure or abnormal blood test results which may 
be associated with Tumor Lysis Syndrome, which can be caused by the 
rapid breakdown of tumor cells. 
 
 
A reaction to carfilzomib infusion, which can include the following symptoms: 
fever, chills or shaking, joint pain, muscle pain, facial flushing or swelling, 
weakness, shortness of breath, low blood pressure, fainting, chest tightness, 
or chest pain. 
 
 
Unusual bruising or bleeding, such as a cut that does not stop bleeding in a 
normal amount of time or internal bleeding such as coughing up blood, 
vomiting up blood, dark tarry stools, or bright red blood in your stools. 
 
 
Leg pain (which could be a symptom of blood clots in the deep veins of the leg), 
chest pain or shortness of breath (which may be a symptom of blood clots in 
the lungs). 
 
 
Yellowing of your skin and eyes (jaundice), abdominal pain or swelling, 
nausea or vomiting, which could be signs of liver problems, including liver 
failure. 
 
 
Bleeding, bruising, weakness, confusion, fever, nausea, vomiting and 
diarrhea, and acute kidney failure, which may be signs of a blood condition 
known as Thrombotic Microangiopathy (including Thrombotic 
Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS). 
 
 
 
Headaches, confusion, seizures, blindness, and high blood pressure 
(hypertension), which may be symptoms of a neurologic condition known 
as Posterior Reversible Encephalopathy Syndrome (PRES). 
 
 
The following side effects have been seen in people who received carfilzomib.  It is unknown 
if they were caused by carfilzomib: 
 Tiredness, infection, and easy bruising or bleeding which may be symptoms of a blood 
condition known as Myelodysplastic syndrome/Acute Myeloid Leukemia 
(MDS/AML). 
 
 
Tenderness of pain in the abdomen that gets more intense with motion or touch, abdominal 


 
 
 
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bloating or distention, nausea and vomiting, diarrhea, constipation or the inability to pass gas 
which may be symptoms of swelling of the thin tissue that lines the inner wall of the 
abdomen and covers most of the abdominal organs. 
Driving and Using Machines 
Subjects may experience fatigue, dizziness, fainting, and/or a drop in blood pressure after 
treatment with carfilzomib. This may impair your ability to drive or operate machinery. If 
you have these symptoms, you should not drive a car or operate machinery. 
Hydration Risks 
There may be risks associated with over hydrating so it is important to follow the study 
physician’s  instructions regarding how much water or other fluids you should drink. Over 
hydration can cause side effect to your heart, lungs, and kidneys. 
 
9.3.2 
ADVERSE EVENTS AND POTENTIAL RISKS FOR IRINOTECAN 
Irinotecan is FDA approved for all cancers treated in this clinical trial.  Please refer to the 
package insert for a full adverse event listing.  Risks and side effects related to Irinotecan 
include those which are: 
 
Likely Side Effects:  those occurring in more than 20% of subjects (or more than 20 out 
of 100 persons) who received Irinotecan: 
 Thrombocytopenia that could result in bleeding including serious and life-threatening 
bleeding 
 Anemia  
 Changes in liver function.  These changes are usually detected by blood test only and 
are not associated with any symptoms.  These changes usually do not require treatment. 
 Fatigue 
 
Constipation 
 Nausea or vomiting 
 Leukopenia and neutropenia that could lead to the risk of infection including serious 
and life-threatening infection 
 Diarrhea 
 Abdominal cramping, gas and bloating 
 Constipation 
 Shortness of breath 
 Cough or runny nose 


 
 
 
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 Mouth sores  
 Anorexia  
 Weight loss 
 Alopecia 
 Rash 
 Fever and chills 
 Dizziness 
 Pain 
 Increased salivation 
 Excessive tearing 
 Flushing 
 Sweating 
 Infection 
Less Likely Side Effects:  those occurring in 5-20% of subjects (or 5 to 20 out of 100 
persons) who received Irinotecan 
 Allergic reactions (including hives, rash, itching, collapse, low blood pressure) 
 Decrease in proteins in the blood stream and/or Malnutrition 
 Rash  
 Mouth sores 
 Hair loss (scalp or body) 
 Vomiting 
 Weight loss 
 Shortness of breath 
 Dehydration 
 Hypotension  
 Neuropathy  
 Flushing 
 Changes in electrolytes. 
 
Changes in liver function.   
 Taste alterations or loss of appetite 
 Difficulty walking 


 
 
 
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 Dizziness 
 Severe Thrombocytopenia bleeding including serious and life-threatening bleeding 
 Severe Anemia  
 Reversible difficulty speaking 
 
Rare and/or Potentially Serious Side Effects: those occurring in less than 5% of subjects 
(or in less than 5 out of 100 persons) who received carfilzomib; side effects can be serious 
enough to be life-threatening or even fatal in rare cases: 
 Muscle weakness 
 Severe anorexia 
 Fever with or without neutropenia 
 Liver damage  
 Life threatening infection 
 Arterial/venous (artery/vein) blood clotting 
 Myocardial ischemia 
 Colitis, bowel obstruction 
 Pulmonary fibrosis which includes symptoms such as- difficulty breathing, including 
shortness of breath (dyspnea) at rest or with activity or a cough, rapid breathing, 
feeling like you can't breathe in enough air, or wheezing, which can be signs of lung 
problems 
  
 Death 
Reproductive risks: 
Subjects should not become pregnant or father a baby while on this study because the drug in 
this study could affect an unborn child.  It is not known if carfilzomib is transferred to breast 
milk.  Potential subjects who are breastfeeding will be required to discontinue nursing during 
treatment with carfilzomib and for an additional 30 days following their last treatment with 
carfilzomib. 
Irinotecan may cause fetal harm when administered to pregnant women.  Animal studies have 
revealed evidence of harm to an unborn baby as well as birth defects.  Potential risks could 
include complications such as miscarriage or birth defects.  Potential subjects who are 
breastfeeding will be required to discontinue nursing during treatment with irinotecan and for 
an additional 30 days following their last treatment with irinotecan. 


 
 
 
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If you are of childbearing potential, you must use contraception during and for 30 days after 
the last dose of carfilzomib and irinotecan.  Examples of contraceptive methods with a failure 
rate of less than 1% per year include tubal ligation, male sterilization, hormonal implants, 
established, proper use of combined oral or injected hormonal contraceptives, and certain 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods such as a condom 
and a cervical cap) may be combined to achieve a failure rate of less than 1% per year.  Barrier 
methods must always be supplemented with the use of a spermicide. 
 
Male subjects who have had a vasectomy and testing has shown that there is no sperm present 
in the semen, the use of birth control method in this study is not required.  Otherwise, male 
subjects must: 
 Let their female partner know he is participating in this study. 
 Practice abstinence or use a condom during treatment in addition to 30 following final 
treatment with carfilzomib. 
 
Male subjects must not donate sperm during treat and for an additional 30 days following their 
last treatment with carfilzomib.  To prevent exposure of the unborn child to carfilzomib 
through semen, the male subject must agree to the use of a condom during vaginal sex. 
 
9.4 
SERIOUS ADVERSE EVENTS DEFINITIONS 
An SAE is one that meets the following criteria:  
 Death 
 Life threatening experience defined as any adverse experience that places the subject, in 
the view of the Investigator, at immediate risk of death at the time of occurrence; i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 Requires inpatient hospitalization or prolongation of an existing hospitalization (except 
scheduled hospitalizations for non-acute, unrelated 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. 


 
 
 
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9.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
The Investigator-sponsor must be notified of the occurrence of any SAE within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event. All SAEs occurring from 
the time of subject consent 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 Investigator-sponsor is responsible for notifying the appropriate health authorities (HAs), 
ethics committees (ECs), and investigators, of any expedited, annual, or other periodic safety 
reports in accordance with applicable regulations.   
The Investigator is also responsible for notifying the local ECs in accordance with local 
regulations. Reporting will be coordinated through the CRAB CTC Operations Office.  
Generally, Expedited Safety Reports are all SAEs that are assessed to be unexpected and 
possibly, probably or definitely related to study drug(s), as specified in ICH E2B guidelines: 
Clinical Safety Data Management Data Elements for Transmission of Individual Case Safety 
Reports.   However, certain Regulatory Agencies may have additional requirements for 
expedited safety report submissions. 
Any safety report submission will cross reference the Amgen investigational new drug (IND) 
or clinical trial approval (CTA) number.at the time of submission.   
Expedited Reporting by Investigator to Amgen 
The Investigator-sponsor must inform Amgen by fax at the contact information listed below 
for all SUSARs that are judged as reasonably related to the Amgen study drug. Site will 
transmit the final MedWatch of that event to Amgen within twenty-four (24) hours of 


 
 
 
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submitting the report to the applicable regulatory authority.  CRAB is responsible for 
facilitating communication with the Investigator-Sponsor and Amgen. 
For regulatory reporting purposes, an event of “Death, Cause Unknown” from the study shall 
be processed as a SUSAR.  All forms must be completed and provided to Amgen in English. 
The Individual Case Safety Report (ICSR) may be referred to as an individual safety report or 
SAE Report, including Pregnancy Exposure Reports and Follow up Reports. The ICSR must 
be as complete as possible, at a minimum including event reference number, protocol name 
and number, investigator contact information, specific patient identifiers (e.g., initials, patient 
number, date of birth or age, or gender), the name of the suspect Study Drug, the date and 
dosage(s) of exposure, event,  the date(s) of event, country of event, “Serious” Criteria, 
Relationship/causality of Study Drug, Hospitalization history for the event, Event 
status/outcome, Relevant history (including diagnostics, laboratory values, radiographs, 
concomitant medications, and event treatment, and narrative summary.  
Sponsor shall be responsible for collecting all SAEs and Pregnancy and Lactation Exposure 
Reports and will exercise commercially reasonable due diligence to obtain follow-up 
information on incomplete SAE or Pregnancy and Lactation Exposure Reports. In the event 
that the Company requires clarification or further information on individual SAE or Pregnancy 
and Lactation Exposure Reports, Company will not contact non-party investigators directly, 
but will route all such inquiries through Site for forwarding to such investigator(s). Site will 
be responsible to ensure such inquiries are completed and timely provided to Company. 
The Principal Investigator (Sponsor) will ensure the site investigator’s initial report (FDA 
3500A MedWatch is as complete as possible, and at a minimum includes the serious adverse 
event term (s), subject identifier, date of event awareness, an assessment of the causal 
relationship between the event and each 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 by the 
site investigator on a follow-up MedWatch form,   
The Principal Investigator (Sponsor) will submit information not available at the time of the 
initial report (e.g., an end date for the SAE, discharge summaries, lot numbers, relevant 


 
 
 
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laboratory values, scan data and autopsy reports) which are received after the initial report and 
must be documented on a follow-up form, and submitted to Amgen in the same timelines as 
outlined above.  Sponsor shall be responsible for obtaining follow-up information for the SAEs 
and demonstrate diligence in attempting to obtain such information by, among other things, 
maintaining written records of such attempts. 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 documented in the appropriate case report forms per the Institution’s 
guidelines.   The Amgen protocol number (CAR-IST-553) and the institutional protocol 
number should be included on all reports to Amgen.   
Other aggregate analysis including reports containing safety data generated during the course 
of the study is to be submitted to Amgen at the time the sponsor ISS submits to anybody 
governing research conduct i.e. RA, IRB etc. Final study report including unblinding data when 
applicable and reports of unauthorized use of a marketed product to be submitted to Amgen at 
the time the sponsor ISS submits to anybody governing research conduct i.e. RA, IRB etc. but 
not later than one calendar year of study completion 
Sponsor will provide an annual IND report to Amgen. Reports containing safety data generated 
during the course of the study is to be submitted to Amgen at the time the sponsor submits to 
anybody governing research conduct, i.e. regulatory authorities and IRBs.   Sponsor will 
support reconciliation of all ICSRs at the end of the study at a minimum. 
Amgen Drug Safety and Pharmacovigilance Contact Information (Safety Reports will be 
submitted to Amgen by CRAB CTC Operations Office, on behalf of the site investigator and 
sponsor): 
Amgen Global Safety Contact Information: 
• 
Drug Safety Reporting Fax 
• 
Toll-free US 888-814-8653  
Email (Only for sponsors with a secure email connection with Amgen): 


 
 
 
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 svc-ags-in-us@amgen.com 
Drug Safety Reporting by secure e-mail can be established upon request.  
 
9.5.1 Instructions for Rapid Notification of Serious Adverse Events 
The site principal investigator has the obligation to report all serious adverse events to the 
CRAB CTC Operations Office and to the governing IRB.  The CRAB CTC Operations Office 
will further report the SAE to the FDA and to Amgen Global Safety 
All events reported to the CRAB CTC Operations Office by the investigator are to be filed 
utilizing the Form FDA 3500A (MedWatch) Form.  
All events must be reported, by phone at 206-342-1692.  Supporting documents are to be 
sent via FAX at 206-342-1688, to the CRAB CTC Operations Office within 24 hours of 
learning of its occurrence. This includes serious, related, labeled (expected) and serious, 
related, unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 
days following completion of active protocol therapy must be reported within 5 working days. 
Any serious adverse event occurring after the subject has been enrolled and until 30 days after 
the subject has stopped study participation must be reported. This includes the period in which 
the study protocol interferes with the standard medical treatment given to a subject (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of 
concomitant medication). 
Serious adverse events occurring more than 30 days after study discontinuation need only be 
reported if a relationship to the Amgen study drug is suspected.  
GUIDELINES FOR EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS 
(SAEs) 
1. Within 24 hours of the event, call the CRAB Operations Office at 206-342-1692.  In 
addition, investigators are asked to complete the SAE Preliminary Report Form and 
FAX to CRAB at 206-342-1688.   The form can be accessed through the study website. 
2. Within 2 calendar days, send the following to the CRAB CTC Operations Office: 
a. 
SAE Reporting Coversheet 


 
 
 
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b. 
A copy of the FDA Form 3500A, including investigator’s attribution1 of the event 
c. 
IRB notification documentation, as applicable 
d. 
Other data as requested during the telephonic report 
3. Within 7 calendar days of discharge, if the subject was hospitalized: A copy of the 
hospital discharge summary 
4. In addition, the following guidelines apply: 
These guidelines apply to subjects accrued to FDA research protocols which use 
investigational anticancer agents.  The following events, when attributed as possibly, probably, 
or definitely related to the agent(s), must be reported in an expedited fashion: 
a. 
Any AE/SAE which is life threatening (Grade 4) or fatal (Grade 5) and unexpected 
(is not listed as a known toxicity, or is of greater severity or specificity than listed 
toxicity).2,3,4 
b. 
Any AE/SAE which is fatal (Grade 5), even if it is an expected toxicity. 4 
c. 
Any SAE occurring in a subject after providing informed consent, while receiving 
study drug, and until four weeks after stopping study drug, within 24 hours of 
learning of its occurrence, even if not felt to be drug related. 
The SAE report, documented on FDA Form 3500A, must be sent within 7 calendar days to 
the CRAB CTC Operations Office as indicated below: 
send copies of items listed under “2”  above to: 
Cancer Research And Biostatistics 
Attn:  CRAB CTC/SAE Program 
1730 Minor Ave, Suite 1900 
Seattle, WA  98101-1468 
OR fax to:  206-342-1688 
                                                 
1 Attribution:  Whether the event was definitely not, unlikely, possibly, probably, or definitely related to protocol 
treatment. 
2 For grading events, please use the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
3 Known toxicities are listed in the Drug Information, Introduction, and Informed Consent Form sections of the 
protocol. 
4 A report shall be submitted if the adverse event is definitely, probably, or possibly related to the agent(s).  
Events judged definitely not treatment related should not be reported, except that all deaths while on treatment or 
within 30 days after treatment must be reported.  Any death more than 30 days after treatment which is felt to be 
treatment-related must also be reported. 


 
 
 
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9.6 
PREGNANCY 
It is not known if carfilzomib is harmful to an unborn or breastfed baby.  If a subject or their 
partner becomes pregnant while receiveing this drug, potential risks could include 
complications such as miscarriage or birth defects.  It is not known if carfilzomib is transferred 
to breast milk.  Potential subjects who are breastfeeding will be required to discontinue nursing 
during treatment with carfilzomib and for an additional 30 days following their last treatment 
with carfilzomib.   
The FDA has assigned Irinotecan to pregnancy category D. It may cause fetal harm when 
administered to pregnant women. Animal studies have revealed evidence of embryotoxicity 
and teratogenicity. There are no controlled data in human pregnancy. If the subject or her 
partner becomes pregnant while receiving this drug, potential risks could include 
complications such as miscarriage or birth defects. Potential subjects who are breastfeeding 
will be required to discontinue nursing during treatment with irinotecan and for an additional 
30 days following their last treatment with irinotecan.   
Pregnant or breastfeeding women and women planning to become pregnant should not 
participate in this study. If a female subject or the female partner of a male subject is unable to 
become pregnant because her healthcare provider has determined that she is postmenopausal 
or she has had her uterus, ovaries, or both fallopian tubes removed, the use of birth control is 
not required during this study.  If a female subject or the female partner of a male subject could 
become pregnant, she must let her partner know she is in the study.  She must agree to discuss 
acceptable pregnancy prevention methods with the study physician and practice abstinence or 
use an acceptable method of birth control.   
Patient of childbearing potential must use contraception during and for 30 days after the last 
dose of carfilzomib and irinotecan.  Examples of contraceptive methods with a failure rate of 
< 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper 
use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. 
Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) 
may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be 
supplemented with the use of a spermicide. 


 
 
 
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If a male subject has had a vasectomy and testing has shown that there is no sperm present in 
the semen, the use of birth control method in this study is not required.  Otherwise, male 
subjects must: 
 Let his female partner know he is participating in this study. 
 Practice abstinence or use a condom during treatment in addition to 30 following final 
treatment with carfilzomib. 
Male subjects must not donate sperm during treat and for an additional 30 days following their 
last treatment with carfilzomib.  To prevent exposure of the unborn child to carfilzomib 
through semen, the male subject must agree to the use of a condom during vaginal sex. 
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 or irinotecan, they must 
inform the study staff right away.  The CRAB CTC Operations Office must be notified within 
24 hours of the Investigator, designee, or site personnel learning of the pregnancy.  Instructions 
are provided below.   
Pregnancy Reporting by Investigator-sponsor to Amgen  
Report Pregnancy and potential infant exposure including Lactation, within ten (10) calendar 
days of Sponsor awareness. Provide to Amgen the SAE reports associated with pregnancy.  
SUSARs are to be reported within twenty-four (24) hours of submitting the report to the 
applicable regulatory authority.  (See Amgen Drug Safety and Pharmacovigilance Contact 
information above).   
If the subject is pregnant, carfilzomib and irinotecan 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 the CRAB CTC Operations Office who 
will inform both the study sponsor as well as Amgen Drug 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 


 
 
 
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documented), stillbirth, neonatal death, or congenital anomaly—the Investigator should repeat 
the procedures for expedited reporting of SAEs as outlined above. 
 
Any pregnancy that occurs during study participation must be reported using the Pregnancy 
Report Forms (please see the instructions below).  To ensure subject safety, each pregnancy 
must be reported to the CRAB Operations Office within 24 hours of learning of its occurrence. 
The pregnancy must be followed-up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects, congenital 
abnormalities or maternal and newborn complications and their relation to study drug. Initial 
and Follow-up Pregnancy Report Forms are accessible online through the study website.  The 
CRAB CTC Operations Office will report the pregnancy and outcome to Amgen Drug Safety.  
The pregnancy, breastfeeding, and birth control information in this protocol is specific to 
carfilzomib.  There may be additional risks to an unborn child or breastfed baby from 
irinotecan, which is also used in this protocol.  This may require study subjects to change the 
type and/or length of time they use birth control.  The length of time breastfeeding must be 
avoided may also change.  Subjects must be instructed to discuss this with their study 
physician.   
 
Instructions for Rapid Notification of Pregnancies 
Each pregnancy commencing during the study must be reported by telephone to the CRAB 
CTC Operations Office at 206-342-1692 within 24 hours of learning of its occurrence. 
Pregnancies and pregnancy follow-up should be reported as directed during the call.  Any 
serious adverse event experienced during pregnancy must be reported as outlined in Section 
9.5.1.  Pregnancy follow-up must describe the outcome of the pregnancy, including any 
voluntary or spontaneous termination, details of the birth, the presence or absence of any 
congenital abnormalities, birth defects, maternal or newborn complications and their relation 
to the study drug. 
 


 
 
 
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10 
CORRELATIVE STUDIES 
 
Pharmacodynamics/Biomarkers (Phase-Ib and Phase-II): The dose dependent proteasome 
inhibition on LMP7 and b5 proteasome subunits will be determined in purified PBMC to 
ensure that the intended effect is achieved in this surrogate tissue. Correlative PD biomarkers 
will be collected from all Phase 1b subjects (up to 24) and the first 15 subjects from each 
stratum of the Phase 2 portion.  If a patient is registered as one of the first 15 patients in each 
stratum, the site will receive notice of  for pharmacokinetic sampling via an auto-email.   The 
response to irinotecan depends on the expression of topoisomerase-I (topo-I). Here, we will 
determine the expression of topo-I in banked tissues to determine if response correlates with 
Topo-I expression. Furthermore, to determine the effect of irinotecan and carfilzomib, we will 
measure the time dependent expression of gamma-H2AX and Topoisomerase-I in purified 
PBMC. We expect that irinotecan/SN-38 mediated DNA damage will increase the expression 
of gamma-H2AX. As topoisomerase-I undergoes proteasome mediated degradation, the 
expression of gamma H2AX declines. We expect that the combination with carfilzomib will 
increase Topo-I stability and sustained gamma-H2AX expression.  
 
10.1 
LABORATORY CORRELATIVE STUDIES 
 
Pharmacodynamics (Phase-Ib and Phase-II): 
 
Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity) 
in all subjects in phase Ib and in 15 subjects in each cohort from phase II study. 
 
Expression of gamma-H2AX and Topoisomerase-I in PBMC in all subjects in all 
subjects in phase Ib and in 15 subjects in each cohort from phase II study. 
 
Expression of Topoisomerase-I in banked tissues in all subjects. Ten unstained slides 
on charged glass slides are preferable.  
Carfilzomib mediated proteasome inhibition will be measured in purified PBMC using 
commercially available reagents. Irinotecan mediated DNA damage and the effect of 
carfilzomib in this process will be determined by time dependent changes in gamma-H2AX 
and Topoisomerase-I expression in purified PBMC. Blood samples for isolation of monocytes 
will be collected in BD Vacutainer CPT Mononuclear Cell Preparation Tubes (8mL) on Day 1 


 
 
 
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and 2 of Cycle 1. When available, tumor tissues will be obtained from participating sites to 
assess the expression of Topoisomerase-I using immunohistochemistry in all subjects. 
 
Collection of Specimen(s) 
Day 01:  Sampling times are relative to the start of irinotecan infusion time: Pre-irinotecan, 
90 min., 2 hr, and 5.5 hr. 
Day 02:  Pre-carfilzomib infusion. 
Handling of Specimens(s) 
1. 
Process each sample (both CPT tubes) individually within 5 minutes following 
sample collection.  Samples should not be placed on ice.  
2. 
Gently invert the tube 8 to 10 times to mix the anticoagulant with the whole 
blood. Do not shake the tube.  
3. 
Keep sample tube at room temperature in the upright position at all times before 
and after blood collection and while waiting for centrifugation.  
4. 
Centrifuge the CPT® tubes containing blood sample at room temperature (18-
25°C) in a horizontal rotor (swing-out head) for 20 minutes at 1800xG. 
5. 
Gently inverted 5-10 times to re-suspend cells (whitish layer) 
6. 
Using a disposable transfer pipet transfer the plasma/PBMC suspension from 
the two CPT® 4mL tubes into a single, 15 mL centrifuge tube 
7. 
Centrifuge the 15 mL tube at 1800xG, for 2 minutes at room temperature (18-
25°C). Carefully pipette and discard all the plasma supernatant. 
8. 
Allow samples to stand upright for 2 minutes on ice and carefully aspirate and 
discard any additional supernatant. NOTE: Please use care so that the cell pellet 
is not disturbed 
9. 
Store tubes on dry ice or transfer to -80°C for storage until shipping. Record the 
time the sample was placed on dry ice or into -80°C as the “time processed” on 
the eCRF. 
10. 
Send a hard copy of the eCRF “Specimen Collection Form” with this package 
Samples should be shipped on Monday, Tuesday or Wednesday only.  Please send 
notification of shipping via email to Dr. Leggas on the day of shipment. 
 


 
 
 
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Shipping of Specimen(s) 
Samples should be shipped on dry ice to: 
Dr. Mark Leggas 
Department of Pharmaceutical Sciences 
College of Pharmacy 
University of Kentucky 
789 South Limestone, Room 323 
Lexington, KY 40536-0596 
E-mail: mark.leggas @uky.edu 
(859) 257-2633 Office 
(859) 257-4550 Fax 
 
 
 
 
 


 
 
 
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11 
STATISTICAL ANALYSIS 
The accrual rate for the phase I component is anticipated to be approximately 2-3 subjects per 
month, with a completion time of 6-9 months.  The accrual rate for the phase II component is 
anticipated to be 3-5 subjects per month and will proceed separately in two strata (platinum-
sensitive vs. platinum-refractory subjects).  
The primary endpoint for the phase II trial is the percent of subjects alive at six months.  We 
will consider the combination of Carfilzomib and Irinotecan to be of interest in platinum 
sensitive subjects if the proportion of subjects alive at six months is 60% or greater, compared 
to a benchmark six-month survival rate of 40%.  With a total of 40 eligible subjects treated at 
the RP2D in the platinum sensitive stratum, we will be able to test the null hypothesis that the 
true survival rate at six months is at most 40% versus the alternative that the true survival rate 
at six months is 60% or greater with a power of 79% and a one sided significance level, alpha 
of .04.  According to this design, if at least 22 subjects out of 40 are alive at six months, we 
can reject the null hypothesis of a 40% six-month survival rate.  This will be considered 
adequate evidence of promising activity for this regimen, and it may be recommended for 
further testing in subsequent studies. If fewer than 22 subjects are alive at 6 months, we will 
consider the regimen insufficiently active in this subject population. We will consider the 
combination of Carfilzomib and Irinotecan to be of interest in platinum refractory subjects if 
the proportion of subjects alive at six months is 45% or greater, compared to a benchmark six-
month survival rate of 25%.  For the platinum refractory stratum, 40 evaluable subjects will 
enable us to test the null hypothesis that the true survival rate at six months is at most 25% 
versus the alternative that the true survival rate at six months is 45% or greater with a power 
of 86% and a one-sided significance level of .054.  If at least 15 subjects out of 40 are alive at 
six months, this will be considered adequate evidence of promising activity, and the regimen 
may be recommended for further testing in subsequent studies. If fewer than 15 subjects are 
alive at 6 months, we will consider the regimen insufficiently active in this subject population.       
 
Secondary endpoints for both phases include response rates, safety/tolerability and the rates of 
specific adverse events, progression-free survival and biomarker endpoints as described in 
sections 10.1 and 10.2. With 40 eligible subjects in each stratum, the 6 month survival rate, 


 
 
 
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and the rates of individual adverse events, can be calculated to within at most +/-16% (95% 
confidence interval) for each individual stratum.  Due to the limited sample size in a Phase II 
setting, correlative studies will be considered exploratory in nature and will be used to 
formulate hypotheses that can be tested using correlative data from a Phase III setting. 
 
11.1 
ADDITIONAL SAMPLE SIZE CONSIDERATIONS 
Based on a standard 3+3 design, the phase I portion of the study will accrue at most 24 subjects.  
An additional 80 evaluable subjects will be needed for phase II. Because some subjects are 
subsequently found to be ineligible after central review, or inevaluable due to receiving no 
treatment after enrollment, accrual beyond 80 subjects is anticipated in order to ensure that 80 
eligible, evaluable  subjects,  are available for analysis. The anticipated number of registrations 
for phase II is therefore approximately 88 subjects. 
11.2 
      INTERIM ANALYSIS  
Interim analyses will be performed separately for each stratum after 30 subjects have been 
accrued. Evaluable subjects that have been on study for 6 months or more will be included in 
the interim analysis, a projected 24 subjects within each stratum. At this time, if a test of the 
alternative hypothesis (six-month survival rate of at least 60% in the platinum sensitive stratum 
or at least 45% in the platinum refractory stratum) is rejected at the .005 level, this will be 
evidence in favor of closing the stratum to further accrual.  The power to reject the alternative 
hypotheses (and exact alpha) will depend on the exact number of subjects analyzed.  For 
example, on the platinum sensitive stratum, if the true survival rate is 40% and 24 subjects are 
available for analysis, then the power to reject the alternative of 60% would be 19% 
(alpha=.0022).    For the platinum refractory stratum, if 24 subjects are available, the power to 
reject the alternative of at least 45% survival at 6 months would be 25% given a true survival 
rate of 25% (alpha=.0036).   
11.3 
PLANNED METHODS OF ANALYSIS 
Six month survival and progression free survival rates, as well as response to treatment, will 
be calculated based on all subjects who receive the recommended Phase II dose of the drug 


 
 
 
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combination. All eligible subjects accrued to phase II who have received at least one dose of 
each drug in the regimen will be considered as evaluable in the phase II analysis.   
Survival will be estimated using the Kaplan-Meier method, separately for each stratum.  
Response and progression will be determined according to RECIST criteria. Overall survival 
is defined as the time between registration and death due to any cause. Subjects last known to 
be alive are censored at date of last contact.  Progression free survival is defined as the date of 
registration to the date of first documentation of progression, or death due to any cause.  
Subjects last known to be alive and progression free are censored at the date of last contact.   
Due to the limited sample size in a Phase II setting, correlative studies will be considered 
exploratory in nature and will be used to formulate hypotheses that can be tested using 
correlative data from a Phase III setting. 
 
 


 
 
 
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12 
INVESTIGATIONAL PRODUCT 
12.1 
CARFILZOMIB DESCRIPTION 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-
((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-
((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. The molecular 
formula is C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an 
inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis.   
12.1.1 
FORMULATION 
Carfilzomib for Injection is supplied as an individually cartooned single-use vial containing a 
dose of 60 mg of Carfilzomib as a white to off-white lyophilized cake or powder.  When 
reconstituted, Carfilzomib contains 2 mg/mL isotonic solution of carfilzomib, 100 mg/mL 
sulfobutylether-beta-cyclodextrin, and 1.9 mg/mL citrate buffer (pH 3 to 4). Each mL of 
reconstituted drug product contains 0.3 mmol (7 mg) of sodium.   
12.1.2 
STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2ºC  to 8ºC under the conditions 
outlined in the separate Pharmacy Manual, in a securely locked area to which access is limited 
to appropriate study personnel.   
12.1.3 
RECONSTITUTION AND ADMINISTRATION 
Aseptically reconstitute each vial of carfilzomib by slowly injecting 29 ml Sterile Water for 
Injection, USP, directing the solution onto the inside wall of the vial to minimize foaming.  
Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of 
any cake or powder occurs.  Do not shake to avoid foam generation.  If foaming occurs, allow 
solution to rest in the vial for about 2 to 5 minutes, until foaming subsides.  After reconstitution, 
carfilzomib is ready for intravenous administration.  The reconstituted product should be a 
clear, colorless solution.  If any discoloration or particulate matter is observed, do not use the 
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When administering in an intravenous back, withdraw the calculated dose from the vial and 
dilute into 50 ml to 100 mL 5% Dextrose Injection, USP intravenous bag.  Immediately discard 
the vial containing the unused portion. The reconstituted solution contains carfilzomib at a 
concentration of 2 mg/ml and is stable at room temperature for four hours (or 24 hours at 2ºC 
– to 8ºC) following reconstitution.   
The IV administration line should be flushed with normal saline or 5% Dextrose Injection, 
USP immediately before and after carfilzomib administration.  Carfilzomib should not be 
administered as a bolus. 
12.1.4 
ACCOUNTABILITY 
Amgen, 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 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 and by regulatory authorities.  
Only sites that cannot destroy unused drug on-site will be required to return their unused supply 
of investigational product. 
12.1.5 
CARFILZOMIB DRUG ORDERING 
 
Carfilzomib will be provided by Amgen. Investigators must order carfilzomib by accessing a 
password protected online, secure website.  Amgen will provide access information to the 
system for all appropriate study personnel after the requirements for study activation at the site 


 
 
 
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have been confirmed.  Please see below for requirements prior to submitting the initial drug 
request.   
An initial startup supply for the first cycle may be ordered prior to subject registration. 
 
Prior to submitting the initial drug request, investigators must first do the following: 
1. Be aware that investigational new drug regulatory best practices mandate that drug 
must be shipped to the single designated pharmacy listed in Box 3 of the FDA-1572 
Form; further dispensation to satellite pharmacies will be the site Principal 
Investigator’s responsibility.  Compliance with Good Clinical Practices for drug 
accountability, storage, dispensation, and documentation is expected. 
2. Prior to the submission of the initial drug request, the site investigator must confirm 
the required regulatory documents have been submitted to the CRAB CTC 
Operations Office at the time of site activation.  Documents to be submitted include:  
site/central IRB approved Informed Consent and site/central IRB approval letter for 
current version of the protocol and informed consent form.  Once completed 
documents have been received, the CRAB CTC Operations Office will forward the 
documents to Amgen prior to the site’s initial drug request. 
   
 
12.2 
IRINOTECAN  
12.2.1 
IRINOTECAN DESCRIPTION 
  
Irinotecan hydrochloride injection is an antineoplastic agent of the topoisomerase I inhibitor 
class. Irinotecan hydrochloride was clinically investigated as CPT-11.  Irinotecan 
hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants 
such as Mappia foetida and Camptotheca acuminata. The chemical name is (S) - [CPT- 1 1, 
(4S)-4, 1 1- diethyl-4-hydroxy-9- 
[(4-piperidinopiperidino) carbonyloxy] -IHpyroano [3',4':6, 7l indolzino [1 ,2-bl 
quino line-3, 14(4H, l2H) dione hydrochloride trihydrate] 


 
 
 
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12.2.2 
FORMULATION 
 
Irinotecan hydrochloride injection is supplied as a sterile, pale yellow, clear, aqueous solution. 
It is available in two single-dose sizes: 2 mL-fill vials containing 40 mg Irinotecan 
hydrochloride, and 5 mL-fill vials containing 100 mg irinotecan hydrochloride. Each milliliter 
of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 
mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The pH of the solution has been 
adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan 
hydrochloride injection is intended for dilution with 5% Dextrose Injection, USP (D5W), or 
0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 
5% Dextrose Injection, USP.  
 
12.2.3 
TOXICOLOGY 
 
Human Toxicity: Virtually all Phase I and II studies of irinotecan have reported neutropenia 
and diarrhea as the dose-limiting toxicities. It is expected that these toxicities will also be 
encountered in this trial. Other Grade 2-3 toxicities seen include nausea and vomiting, 
anorexia, abdominal cramping, cumulative asthenia, thrombocytopenia, renal insufficiency, 
increase in transaminase level and hair loss. Sporadic cases of pulmonary toxicity, manifested 
as shortness of breath and nonproductive cough, have also been reported. 
 
12.2.4 
 PHARMACOLOGY 
 
Pharmacokinetics: Several studies describing the pharmacokinetic characteristics of irinotecan 
(CPT-11) and its active metabolite, SN-38, when administered alone or in combination with 
other agents (including cisplatin) in subjects with small cell or non-small cell lung cancer have 
been reported in published literature. CPT- 11 is converted by carboxylesterases to its more 
active metabolite, SN-38. In vitro, SN-38 is 250 to 1,000 fold more potent than CPT-11 in the 
inhibition of topoisomerase I activity. A reversible, pH-dependent hydrolysis converts the 
closed lactone E ring form of both CPT-11 and SN-38 to the open, carboxylate form of each 


 
 
 
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compound. Only the closed ring (lactone) forms of CPT-11 and SN-38 are effective 
topoisomerase I inhibitors. The mean terminal half-life of SN-38 in plasma is slightly longer 
than that for CPT-11; 11.5 ± 3.8 hours versus 6.3 ± 2.2 hours for the lactone forms. Peak plasma 
concentrations for CPT-11 occur at the end of the infusion. The time to peak for SN-38 is 
highly inter-subject dependent occurring at variable time points 30 to 90 minutes after the end 
of infusion. Murine studies suggest that the liver may concentrate, convert CPT-11 to SN-38, 
and eliminate both compounds as well as the glucuronide conjugate of SN-38 (SN-38G) via 
biliary secretion. In rats, 55% of radiolabeled CPT-11 was excreted unchanged in the bile 
within 24 hours, while 21.7% was transformed to SN-38. It recently was demonstrated that 
plasma concentrations of SN-38G in subjects occur 0.5 to 3 hr after the SN38 peak and plasma 
levels generally exceeded that of SN-38. Overall, 73% of the radioactivity could be recovered 
from the feces of rats and 25% from the urine. Bile concentrations of CPT-11 were 10 to 60 
fold higher than plasma concentrations in one subject during the first 6 hours following 
administration, while bile concentrations of SN-38 were 2 to 9 fold higher. Renal clearance 
has not been reported to be a major route of elimination for these compounds in humans. 
12.2.5 
STORAGE 
 
Storage and Stability: Irinotecan vials must be stored in a cool, dry place, protected from light 
in a locked cabinet accessible only to authorized individuals. Store at 20° to 25°C (68° to 77°F); 
excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Do not freeze. It is 
recommended that the vial should remain in the carton until the time of use.  It is stable for at 
least three years at room temperature. Irinotecan is stable for 24 hours in glass bottles or plastic 
bags after reconstitution with D5W. 
 
Reconstitution and Administration: Irinotecan will be diluted with D5W to a total volume of 
500 ml and infused intravenously over 90 minutes, per institutional standards. Nothing else 
should be added to the bag.  
12.2.6 
ACCOUNTABILITY 
The Investigator will maintain records of each dose of chemotherapeutic drug given.  The 
records will document dose, infusion rate, date given and time given, as per standard of care 


 
 
 
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for Irinotecan.  Drug accountability records must be readily available for inspection by 
representatives of Amgen 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.    
12.2.7 
IRINOTECAN DRUG ORDERING 
Irinotecan is commercially available and will be charged to the subject’s insurance as per 
standard of care.   
 


 
 
 
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13 
REGULATORY OBLIGATIONS 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be provided to the CRAB CTC Operations Office before study initiation. 
Any amendments to the protocol, other than administrative ones, must be reviewed and 
approved by the study sponsor and Amgen. 
13.2 
INFORMED CONSENT 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If the subject cannot read or sign 
the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the subject could not read or sign the documents. No subject can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
13.3 
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 


 
 
 
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(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 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 site Investigator or designee will be responsible for obtaining continuing and not less than 
annual IRB or Ethics Committee reapproval throughout the duration of the study.  Copies of 
the Investigator’s annual report and other significant protocol updates to the FDA, IRB or 
Ethics Committee and copies of the IRB or Ethics Committee continuance of approval must 
be provided by the CRAB CTC Operations Office to Amgen via email PRA Health Services: 
 
PRA Contact: Ms. Maria Bloodgood 
Manager, Investigator Sponsored Studies 
PRA Health Sciences 
Email: mbloodgo@amgen.com 
Phone: 610-268-5074 
 
The site Investigator is also responsible for notifying the FDA , their IRB or Ethics Committee 
of any significant adverse events that are serious and/or unexpected. 
Amgen will provide study sites and the CRAB CTC Operations Office with any expedited 
safety reports generated from any ongoing studies with carfilzomib, changes to the 
Investigator’s Brochure, and any other safety information which changes the risk/benefit 
profile of carfilzomib during the conduct of the study, to allow him/her to fulfill his/her 
obligation for timely reporting to the IRB/ECs and other Investigators participating in the 
study. 
Upon completion of the trial, the Investigator must provide the IRB or Ethics Committee and 
Amgen with a summary of the trial’s outcome. 
 


 
 
 
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13.4 
REGULATORY DOCUMENTATION REQUIREMENTS 
c. The documents listed below must be submitted to the CRAB CTC Operations Office 
prior to the site’s activation of CTC 11-001.  Subject registration will not be permitted 
until all documents have been received.  Documents may be submitted via Fax or email 
to: 
CRAB CTC Operations Office – Regulatory Affairs 
Fax: (206) 342-1688 
Email: webhelpCRS@crab.org  
 Investigator Signature sheet 
 IRB protocol and  consent form approval letter (s) 
 IRB approved consent form 
 OHRP Federal Wide Assurance number 
 IRB membership list if available 
 FDA Form 1572 
 Curriculum Vitaes, Financial Disclosure forms, and Medical Licenses for all 
investigators and sub-investigators listed on the FDA Form 1572 
 Laboratory certification and normal ranges 
 
d. Updates to the documents specified above must be submitted to the CRAB CTC 
Operations Office during the course of the study and will include at the minimum: 
 IRB protocol approval letters for annual, continuing, or modification reviews  
 IRB approval of modified consent form 
 Investigator Signature sheet for each version of the protocol 
 Updated Form 1572 to document changes in investigators or sub-investigators 
13.5 
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, 
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. 


 
 
 
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Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 


 
 
 
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14 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
14.1 
PROTOCOL AMENDMENTS OR CHANGES IN STUDY CONDUCT 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment from the CRAB CTC Operations Office.  All amendments must be approved by 
the Sponsor-Investigator, CRAB CTC, and Amgen before implementation. Amendments 
significantly affecting the safety of subjects, the scope of the investigation or the scientific 
quality of the study require additional approval by the central IRB at each study.  A copy of 
the written approval of the IRB must be provided to the CRAB CTC Operations Office. 
Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects; 
2. significant changes in the study design (e.g. addition or deletion of a control group); 
3. increases in the number of invasive procedures; and 
4. addition or deletion of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator, by the CRAB CTC, or by Amgen in the interests of preserving the 
safety of all subjects included in the trial.  If an immediate change to the protocol is felt to be 
necessary by the investigator and is implemented for safety reasons, the CRAB CTC 
Operations Office must be notified and the central IRB must be informed immediately.   
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB must be kept informed of such administrative 
changes. Examples of administrative changes not requiring formal protocol amendments and 
IRB approval include: 
1. 
changes in the staff used to monitor trials, and 
2. 
minor changes in the packaging or labeling of study drug. 
14.2 
STUDY TERMINATION 
Amgen and the CRAB CTC reserve the right to discontinue the study under the conditions 
specified in the clinical trial agreement. 


 
 
 
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14.3 
STUDY DOCUMENTATION AND ARCHIVE 
 
Records and documents pertaining to the conduct of this study, including CRFs, source 
documents, consent forms, laboratory test results, and medication inventory records must be 
maintained by the Investigator or Institution for the following length of time:  
 For a period of at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region; or  
 At least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product.  
No study records shall be destroyed without prior authorization from Amgen and the CRAB 
CTC Operations Office. 
14.4 
DISCLOSURE AND CONFIDENTIALITY 
The participating CTC investigator agrees to keep all information provided by Amgen and/or 
the CRAB CTC in strict confidence and to request similar confidentiality from his/her staff 
and the IRB/IEC/REB. Study documents provided by Amgen (such as Investigators' Brochures 
and other materials), and by the CRAB CTC (such as study protocol and other materials) will 
be stored appropriately to ensure their confidentiality. The information provided by Amgen 
and/or the CRAB CTC to the investigator may not be disclosed to others without direct written 
authorization from Amgen and the CRAB CTC Operations Office, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the trial. 
14.5 
PUBLICATION OF RESULTS 
Any formal presentation or publication of data from this trial may be considered as a joint 
publication by the Sponsor-Investigator, participating CRAB CTC Investigators, Cancer 
Research And Biostatistics, and Amgen.  For multicenter studies, it is mandatory that the first 
publication be based on data from all study sites, analyzed as stipulated in the protocol, and 
not by investigators acting solely on their own or their institution’s behalf.  Investigators 
participating on multicenter studies agree not to present data gathered from one study site or 
from a subset of study sites before the full, joint initial publication, unless formally agreed to 
by the Sponsor-Investigator, the CRAB CTC Operations Office, and Amgen.   


 
 
 
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The CRAB CTC Operations Office and Amgen must receive copies of any intended 
communication in advance of publication (at least fifteen working days for presentational 
materials and abstracts and thirty working days for manuscripts).   These requirements 
acknowledge CRAB’s responsibility to provide peer input regarding the scientific content and 
conclusions of such publications or presentations.  The Sponsor-Investigator and CRAB CTC 
Operations Office shall have the final authority to determine the scope and content of 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of CRAB CTC and Amgen and, in accord with the trial contract and shall not permit disclosure 
of confidential or proprietary information. 
14.6 
STUDY MONITORING  
14.6.1 
PHASE IB ONLY:  MANDATORY BI-MONTHLY TELECONFERENCES 
A mandatory conference call will take place approximately twice a month during the 
registration period of the Phase Ib portion of the trial.  Less frequent conference calls 
will be held after Phase Ib has completed.  The call will update participating 
investigators on the current status of the trial and will include representatives from the 
study team (lead investigators, biostatisticians, and data management personnel), and 
investigators from all participating institutions.  During the calls, adverse events 
encountered will be discussed and appropriate action taken.  In between these regularly 
scheduled conference calls, participating investigators will be informed of important 
study decisions via email and by study announcements posted to the study website. 
Institutional participation on the conference calls requires identification of an 
investigator contact and a CRC contact.  Prior to registration of the first subject, each 
institution must provide contact names, email addresses, and phone numbers to the 
CRAB CTC Program Manager via email or Clinical Research Services main phone 
line:  206-342-1692.  Institutions will be responsible for keeping this information up-
to-date and must notify the CTC Program Manager of any changes.  The investigator 
and the contact CRC will receive e-mail reminders with the conference call 
information. 


 
 
 
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14.6.2 
PHASE II ONLY:  MANDATORY QUARTERLY TELECONFERENCES 
A mandatory conference call will take place approximately every three months during 
the registration period of the Phase II portion of the trial.  The call will update 
participating investigators on the current status of the trial and will include 
representatives from the study team (lead investigators, biostatisticians, and data 
management personnel), and investigators from all participating institutions.  During 
the calls, adverse events encountered will be discussed and appropriate action taken.  
In between these regularly scheduled conference calls, participating investigators will 
be informed of important study decisions via email and by study announcements posted 
to the study website. 
Institutional participation on the conference calls requires identification of an 
investigator contact and a CRC contact.  Prior to registration of the first subject, each 
institution must provide contact names, email addresses, and phone numbers to the 
CRAB CTC Program Manager via email or Clinical Research Services main phone 
line:  206-342-1692.  Institutions will be responsible for keeping this information up-
to-date and must notify the CTC Program Manager of any changes.  The investigator 
and the contact CRC will receive e-mail reminders with the conference call 
information. 
 
14.6.3 
SITE MONITORING 
Monitoring procedures will be carried out by the Cancer Research And Biostatistics 
(CRAB) Study Monitor, and will be performed remotely on a regular basis to comply 
with Good Clinical Practice guidelines.  Data and safety will be monitored by the 
sponsor-investigator, the biostatistician, and data management personnel.  In addition, 
on-site monitoring visits will occur at least once during the study.  Materials to be 
reviewed include the electronic case report forms (which will be cross-referenced with 
selected source documentation), study-related regulatory documents, and drug 
accountability logs.   
 


 
 
 
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At the conclusion of the on-site monitoring visits, the CRAB Study Monitor will 
complete a written monitoring report and forward it to the site Principal Investigator, 
the Sponsor-Investigator and to the CRAB Clinical Trial Consortium (CTC) Program 
Manager.  The report will include a summary of what the Study Monitor reviewed and 
statements concerning the significant findings/facts, deviations and deficiencies, 
conclusions, actions taken or to be taken, and/or actions recommended to ensure 
compliance.  The site Principal Investigator will be expected to submit any Corrective 
Action Plans, in writing, to the CRAB CTC Program Manager and the CRAB Study 
Monitor. 
 
A copy of the monitoring materials, final monitoring reports, and Corrective Action 
Plan will be kept in the site monitor’s study file at Cancer Research And Biostatistics 
for follow-up at the next monitoring session. 


 
 
 
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14.7 
DATA SUBMISSION REQUIREMENTS 
Investigators must record the information required by the protocol. 
The CTC 11-001 study uses a web based data entry system for data submissions through the 
data management services of Cancer Research And Biostatistics (CRAB).  All study case 
report forms will be accessed online through the study website at: https://ctc-11-
001.crab.org/Login.aspx .  The eCRFs on the screening tab should be completed within 5 
business days following registration to treatment.  All other eCRFs should be completed within 
5 business days following the visit date.  For questions and assistance using the site, please 
contact: WebHelpCRS@crab.org. 


 
 
 
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15 
REFERENCES 
1. 
Jemal, A., et al., Cancer Statistics, 2007. CA Cancer J Clin, 2007. 57(1): p. 43-66. 
2. 
Perez-Soler, R., et al., Treatment of subjects with small-cell lung cancer refractory to 
etoposide and cisplatin with the topoisomerase I poison topotecan. Journal of Clinical 
Oncology, 1996. 14(10): p. 2785-2790. 
3. 
Demo, S.D., et al., Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the 
Proteasome. Cancer Research, 2007. 67(13): p. 6383-6391. 
4. 
Arastu-Kapur, S., et al., Nonproteasomal Targets of the Proteasome Inhibitors 
Bortezomib and Carfilzomib: a Link to Clinical Adverse Events. Clinical Cancer 
Research. 17(9): p. 2734-2743. 
5. 
Kirk, C.J., et al., The Selective Proteasome Inhibitor Carfilzomib Is Well Tolerated in 
Experimental Animals with Dose Intensive Administration. ASH Annual Meeting 
Abstracts, 2008. 112(11): p. 2765-. 
6. 
Bross, P.F., et al., Approval Summary for Bortezomib for Injection in the Treatment of 
Multiple Myeloma. Clinical Cancer Research, 2004. 10(12): p. 3954-3964. 
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Bortexomib 
Summary 
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8. 
Kuhn, D.J., et al., Potent activity of carfilzomib, a novel, irreversible inhibitor of the 
ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood, 
2007. 110(9): p. 3281-3290. 
9. 
Alsina, M., et al., Phase 1 Single Agent Antitumor Activity of Twice Weekly Consecutive 
Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic 
Malignancies. ASH Annual Meeting Abstracts, 2007. 110(11): p. 411-. 
10. 
Jagannath, S., et al., Final results of PX-171-003-A0, part 1 of an open-label, single-
arm, phase II study of carfilzomib (CFZ) in subjects (pts) with relapsed and refractory 
multiple myeloma (MM). ASCO Meeting Abstracts, 2009. 27(15S): p. 8504. 
11. 
Siegel, D., et al., PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent 
Carfilzomib (CFZ) in Subjects with Relapsed or Refractory Myeloma (MM); Updated 
Results From the Bortezomib-Treated Cohort. ASH Annual Meeting Abstracts, 2009. 
114(22): p. 303-. 
12. 
Wang, L., et al., Updated Results of Bortezomib-Naive Subjects in PX-171-004, An 
Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Subjects 
with Relapsed or Refractory Myeloma (MM). ASH Annual Meeting Abstracts, 2009. 
114(22): p. 302-. 
13. 
Niesvizky, R., et al., Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus 
Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and Refractory 
Multiple Myeloma (MM). ASH Annual Meeting Abstracts, 2009. 114(22): p. 304-. 
14. 
Badros, A.Z., et al., Phase I Study of Carfilzomib in Subjects (Pts) with Relapsed and 
Refractory Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency. ASH 
Annual Meeting Abstracts, 2009. 114(22): p. 3877-. 
15. 
Mack, P.C., et al., Integration of the proteasome inhibitor PS-341 (Velcade) into the 
therapeutic approach to lung cancer. Lung Cancer, 2003. 41(Supplement 1): p. 89-96. 
16. 
Schenkein, D., Use of proteasome inhibition in the treatment of lung cancer. Clinical 
Lung Cancer, 2004. 5(Supplement 2): p. S89 -S96. 


 
 
 
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17. 
Scagliotti, G., Proteasome inhibitors in lung cancer. Critical Reviews in 
Oncology/Hematology, 2006. 58(3): p. 177-189. 
18. 
Denlinger, C.E., et al., Proteasome Inhibition Sensitizes Non-Small-Cell Lung Cancer 
to Gemcitabine-Induced Apoptosis. The Annals of Thoracic Surgery, 2004. 78(4): p. 
1207-1214. 
19. 
Lawson, M.H., et al., Bcl-2 and [beta]1-integrin predict survival in a tissue microarray 
of small cell lung cancer. Br J Cancer. 103(11): p. 1710-1715. 
20. 
Davies, A.M., et al., Bortezomib Plus Gemcitabine/Carboplatin as First-Line 
Treatment of Advanced Non-small Cell Lung Cancer: A Phase II Southwest Oncology 
Group Study (S0339). Journal of Thoracic Oncology, 2009. 4(1): p. 87-92 
10.1097/JTO.0b013e3181915052. 
21. 
Scagliotti, G.V., et al., A randomized phase II study of bortezomib and pemetrexed, in 
combination or alone, in subjects with previously treated advanced non-small-cell lung 
cancer. Lung Cancer. 68(3): p. 420-426. 
22. 
Gordon, G., et al., Preclinical studies of the proteasome inhibitor bortezomib in 
malignant pleural mesothelioma. Cancer Chemotherapy and Pharmacology, 2008. 
61(4): p. 549-558. 
23. 
Mortenson, M.M., et al., Effects of the proteasome inhibitor bortezomib alone and in 
combination with chemotherapy in the A549 non-small-cell lung cancer cell line. 
Cancer Chemotherapy and Pharmacology, 2004. 54(4): p. 343-353. 
24. 
Mortenson, M.M., et al., Reduction in BCL-2 levels by 26S proteasome inhibition with 
bortezomib is associated with induction of apoptosis in small cell lung cancer. Lung 
Cancer, 2005. 49(2): p. 163-170. 
25. 
Ardizzoni, A., et al., Topotecan, a new active drug in the second-line treatment of 
small-cell lung cancer: a phase II study in subjects with refractory and sensitive 
disease. The European Organization for Research and Treatment of Cancer Early 
Clinical Studies Group and New Drug Development Office, and the Lung Cancer 
Cooperative Group. Journal of Clinical Oncology, 1997. 15(5): p. 2090-2096. 
26. 
von Pawel, J., et al., Topotecan Versus Cyclophosphamide, Doxorubicin, and 
Vincristine for the Treatment of Recurrent Small-Cell Lung Cancer. Journal of Clinical 
Oncology, 1999. 17(2): p. 658. 
27. 
Fukuoka, M., et al., A phase II study of CPT-11, a new derivative of camptothecin, for 
previously untreated non-small-cell lung cancer. Journal of Clinical Oncology, 1992. 
10(1): p. 16-20. 
28. 
Masuda, N., et al., Phase I and Pharmacologic Study of Weekly Bolus Topotecan for 
Advanced Nonâ€“Small-Cell Lung Cancer. Clinical Lung Cancer. 11(4): p. 271-279. 
29. 
Le Chevalier T, et al. A phase II study of irinotecan (CPT-11) in subjects (pts) with 
small cell lung cancer (SCLC) progressing after initial response to first-line 
chemotherapy (CT). Proceedings of ASCO, 1997. 16. 
30. 
Noda, K., et al., Irinotecan plus Cisplatin Compared with Etoposide plus Cisplatin for 
Extensive Small-Cell Lung Cancer. New England Journal of Medicine, 2002. 346(2): 
p. 85-91. 
31. 
Lara, P.N., et al., Phase III Trial of Irinotecan/Cisplatin Compared With 
Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and 
Pharmacogenomic Results From SWOG S0124. Journal of Clinical Oncology, 2009. 
27(15): p. 2530-2535. 


 
 
 
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32. 
Bold, R.J., et al., Chemosensitization of Pancreatic Cancer by Inhibition of the 26S 
Proteasome. Journal of Surgical Research, 2001. 100(1): p. 11-17. 
33. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer, 2009. 45(2): p. 228-247. 
 
 
 
 


 
 
 
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APPENDIX A:  NCI-CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the  
National Cancer Institute (NCI) v4.0 
 
Publish Date:   June 14, 2010 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 


 
 
 
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APPENDIX B:  ASSESSMENT OF EFFICACY (RECIST 1.1 CRITERIA) 
Criteria for Disease Response Evaluation Using RECIST 1.1 Criteria [33] 
 
1.  Measurability of lesions. 
 
a.  Measurable disease.   
 
 
1) Lesions that can be accurately measured in at least one dimension (longest diameter 
to be recorded) as ≥ 2.0 cm  by chest x-ray, as  ≥ 1.0 cm  by CT or MRI scans, or ≥ 
1.0 cm with calipers by clinical exam. All tumor measurements must be recorded 
in decimal fractions of centimeters (or millimeters). 
 
2) Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS when assessed by scan (CT 
scan slice recommended being no greater than 0.5 cm). 
 
b.   Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to <1.5 cm short 
axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable as are previously radiated lesions that have not progressed. 
 
      c. Notes on measurability: 
 
1.) For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should by performed with breath-hold scanning techniques, if 
possible.  
 
2.) The defined measurability of lesions on CT scan is based on the assumption 
that CT slice thickness is 0.5 cm or less.  If CT scans have slice thickness greater 
than 0.5 cm, the minimum size for a measurable lesion should be twice the slice 
thickness.   
 
3.) PET-CT:  At present, the low dose or attenuation correction CT portion of a 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as 
part of a PET-CT is of identical diagnostic quality to a diagnostic CT, then the 
CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT. 
 
4.) Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. 
 


 
 
 
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5.) Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition simple cysts. 
 
6.) If a target lesion becomes very small some radiologists indicate that it is too 
small to measure.  If the lesion is actually still present, a default measurement 
of 0.5cm should be applied.  If the radiologist believes the lesion has gone, a 
default measurement of 0.0cm should be recorded. 
 
2. Objective status at each disease evaluation.    
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a maximum 
of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be 
identified as target lesions at baseline. All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions.  Measurements must be provided for target measurable lesions, while presence or 
absence must be noted for non-target measurable and non-measurable disease.   
 
a.  Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  No 
disease related symptoms.   Any lymph nodes (whether target or non-target) must have 
reduction in short axis to < 1.0 cm.  All disease must be assessed using the same 
technique as baseline. 
 
b. Partial Response (PR): Applies only to subjects with at least one measurable lesion. 
Greater than or equal to 30% decrease under baseline of the sum of appropriate 
diameters of all target measurable lesions.  No unequivocal progression of non-
measurable disease.  No new lesions.  All target measurable lesions must be assessed 
using the same techniques as baseline. 
 
c.  Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  All 
target measurable lesions must be assessed using the same techniques as baseline. 
 
d.  Progression: One or more of the following must occur:  20% increase in the sum of 
appropriate diameters of target measurable lesions over smallest sum observed (over 
baseline if no decrease during therapy) using the same techniques as baseline, as well 
as an absolute increase of at least 0.5 cm.  Unequivocal progression of non-measurable 
disease in the opinion of the treating physician (an explanation must be provided).   
Appearance of any new lesion/site.  Death due to disease without prior documentation 
of progression and without symptomatic deterioration (see 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans in 
identifying new lesions according to the following algorithm.  
 
 
 
 1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
 
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2) No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation by 
anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to be 
considered progressive disease.  In such a case, the date of progressive disease 
will be the date of the initial abnormal FDG-PET.   
 
e.   Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts should 
be made to obtain objective evidence of progression after discontinuation. 
 
f.  Assessment inadequate, objective status unknown.  Progression or symptomatic 
deterioration has not been documented, and one or more target measurable lesions have 
not been assessed or inconsistent assessment methods were used. 
 
g.  Objective status notes: 
1. “Appropriate diameters” means short axis for lymph nodes; longest diameters 
for all other lesions, 
2. An objective status of PR or stable cannot follow one of CR.  Stable can follow 
PR only in the rare case that tumor increases too little to qualify as progression, 
but enough that a previously documented 30% decrease no longer holds. 
3. In cases for which initial flare reaction is possible (hypercalcemia, increased 
bone pain, erythema of skin lesions), objective status is not progression unless 
either symptoms persist beyond 4 weeks or there is additional evidence of 
progression.   
4. Lesions that appear to increase in size due to presence of necrotic tissue will 
not be considered to have progressed.  
5. For bone disease documented on bone scan only, increased uptake does not 
constitute unequivocal progression. However, increase in the soft tissue 
component of a lesion as measured by CT or MRI would constitute progression. 
6. Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. Increase 
in the size of an existing effusion does not constitute unequivocal progression, 
since the fluid status of the subject could alter the size of the effusion.  
7. If CR determination depends on a lesion for which the status is unclear by the 
required tests, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.   
 
3. Best Response.  This is calculated from the sequence of objective statuses. 
 
a. CR:  Two or more objective statuses of CR a minimum of four weeks apart documented 
before progression or symptomatic deterioration. 
 
b.  PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as CR. 
 


 
 
 
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c.  Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d.  Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e.  Stable/no response:  At least one objective status of stable/no response documented at 
least 6 weeks after registration and before progression or symptomatic deterioration, 
but not qualifying as anything else above. 
 
f. Increasing disease:  Objective status of progression at first assessment after registration, 
not qualifying as anything else above.   
 
g. Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies. 
 
4.  Performance Status   
 
Subjects will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
5.  Progression-Free Survival From the date of registration to first documentation of 
progression or symptomatic deterioration (as defined in 2.d and 2.e), or death due to any cause.  
Subjects last known to be alive and progression-free are censored at date of last contact.   
 
6.  Overall Survival  From the date of registration to the date of death due to any cause.  
Subjects last known to be alive are censored at date of last contact. 


 
 
 
CRAB CTC Study 11-001:  PhaseIb/II Carfilzomib 
IST 
 
 
Confidential 
 
 
Page 104 of 104 
 
 
7.  Time to Treatment Failure  From date of registration to date of first observation of 
progressive disease (as defined in 2.d) , death due to any cause, symptomatic deterioration (as 
defined in 2.e), or early discontinuation of treatment.