Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus Etoposide (C-R-ICE) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Phase: PHASE1
Conditions: CD20 Positive, Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Stage I Diffuse Large B-Cell Lymphoma, Stage II Diffuse Large B-Cell Lymphoma, Stage III Diffuse Large B-Cell Lymphoma, Stage IV Diffuse Large B-Cell Lymphoma
Sponsor: Roswell Park Cancer Institute

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TITLE:     Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus
 Carboplatin Plus Etoposide (C-R-ICE) in Patients with 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Roswell Park Comprehensive Cancer
Center (Roswell Park) Study Number:
I 240813
Initial Date:
Amendment #1:
 Amendment#2:
Amendment #3:
Amendment #4:
Amendment #5:
Amendment #6:
Amendment #7:
Amendment #8:
Amendment #9:
Amendment #10:
Amendment #11:
Amendment #12:
10 May 2013
08 October 2013
25 March 2014 
15 June 2015
11 July 2016
22 December 2016
28 February 2017
27 June 2017
01 February 2018
24 April 2018
10 January 2019
06 February 2019
16 May 2019
IND Number/Holder:
119971
Principal Investigator:
Francisco J. Hernandez-Ilizaliturri, MD
Roswell Park 
Elm & Carlton Streets
Buffalo, New York 14263
716-845-3221
Francisco.Hernandez@RoswellPark.org
Sponsor: Roswell Park 
Industry Supporter: Amgen, Inc. (20159860)
NCT#01959698
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential
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 and shall remain the exclusive property of the party(ies) mentioned above. The use
 of such confidential information must be restricted to the recipient for the 
agreed purpose and must not be disclosed, published, or otherwise communicated
 to any unauthorized persons, for any reason, in any form whatsoever 
without the prior written consent of the party(ies) above.
Study Contacts 
FOR NETWORK SITES: Please contact the RP Network Monitor or any study-related 
questions to sample handling, processing or shipping.
Name
Location
Email
Francisco J. Hernandez-
Ilizaliturri, MD
Principal Investigator
Cory Mavis
Senior Research Specialist
Roswell Park
Department of Medicine 
Lymphoma/Myeloma Laboratory
Room C 304A CCC
francisco.hernandez
@roswellpark.org
cory.mavis@
Roswellpark.org
PD/PK Lab
Roswell Park Bioanalytics, 
Metabolomics & Pharmacokinetics Core 
Facility
Center for Genetics and Pharmacology, 
Room L1-140
Hematologic Procurement 
Shared Resource Facility
Roswell Park 
New Location:
GBSB 5th Floor room 538 (Lab) and 
next door GBSB 5th Floor room 524 
(Lab office area).
Linda Lutgen-Dunckley, Lab 
Manager,845-8098
linda.lutgendunckley
@roswellpark.org
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SYNOPSIS
Title / Phase
Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus 
Carboplatin Plus Etoposide (C-R-ICE) in Patients with Relapsed/Refractory 
Diffuse Large B-Cell Lymphoma (DLBCL)
Roswell Park Study Number
I 240813
Roswell Park Investigator
Francisco J. Hernandez-Ilizaliturri, MD
Sponsor
Amgen, Inc. (20159860)
Study Drug
Carfilzomib
Objectives
Phase I Primary Objectives

To estimate the maximum tolerated dose (MTD) and examine the dose-
limiting toxicities of carfilzomib when administered in combination with
rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in patients
with relapsed/refractory DLBCL.

To assess the toxicity of dose regimen using the CTEP NCI Common
Terminology Criteria for Adverse Events (CTCAE Version 4.0).
Phase Ib Primary Objectives (Expansion Cohort)

To evaluate the safety of carfilzomib (given at maximum tolerated dose
[MTD] as determined in Phase I component of this study) in combination
with R-ICE salvage therapy in relapsed/refractory DLBCL patients.

To achieve an overall response rate (CR and PR) of 70% after 3 cycles of
C-R-ICE in patients between the ages of 18 to 75 with relapsed/refractory
CD20-positive DLBCL previously treated with rituximab-based
immunochemotherapy (e.g., R-CHOP, R-EPOCH, R-HyperCVAD, etc.)
induction.
Secondary Objectives

To determine the feasibility of successful mobilization of autologous stem
cells (i.e., minimum of 2 x 106 CD34+ cells/kg should be collected) to be
used for ASCT. (if applicable)

To determine toxicities associated with C-R-ICE salvage therapy.

To determine the TTP, PFS, and OS followed by ASCT (if applicable);
Disease-free survival in CR patients.

To determine the pharmacokinetics/pharmacodynamics relationship
between carfilzomib’s degree of proteasome inhibition and response rate
along with the time course of thrombocytopenia.

To study differences in clinical outcomes between GCB and non-GCB
relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE.

Correlative translational research studies to include: phenotypic/genotypic
analysis and functional activity (i.e., ADCC and CMC) of patient’s
peripheral blood mononuclear "effector" cells (PBMC), as well as ex vivo
analysis of sensitivity of primary tumor cells to various combinations of
carfilzomib versus bortezomib +/- rituximab;, enzymatic assay for
chymotrypsin-like activity to determine the degree of proteasome inhibition
in primary DLBCL patient samples and patient PBMC specimens;
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explorative analysis to identify potential factors predictive of response to 
therapy will be performed (as part of an NIH-supported R01 grant: R01 
CA136907-0Ab; PI: Francisco J. Hernandez-Ilizaliturri, MD).
Study Design
This is multi-center open-label, prospective Phase I/Ib clinical trial evaluating 
the safety, efficacy, and pharmacokinetics/pharmacodynamics of Carfilzomib + 
standard R-ICE combination therapy in adult patients with relapsed/refractory 
diffuse large B-cell lymphoma. The statistical design is based on a dose-finding 
algorithm to determine the maximal tolerated dose (MTD) of the study regimen 
and an assessment of the efficacy of the treatment for patients as compared to an 
external standard, i.e., R-ICE historical control. All enrolled patients will 
receive the study drug and initiation of the treatment should take place as soon 
as possible following study enrollment. A total of up to 30 evaluable patients 
will be enrolled in the Phase I/Ib component
Target Accrual and Study 
Duration
A maximum of 21 patients for Phase I and 9 patients for Phase Ib expansion 
cohort will be enrolled at Roswell Park. The number of subjects required is a 
function of a currently unknown dose-toxicity relationship. Accrual is expected 
to take up to 10 years.
Study Procedures
Disease Evaluation: Prior to study, at time of restaging; between Cycle 2 Day 15 
to Cycle 2 Day 28 following Cycle 3 but before ASCT and at the end of 
treatment evaluation, then every 4 months (±2 weeks) for 1 year, then every 6 
months (±2 weeks) for 2 years, then once a year (±2 weeks) for 2 years for a 
total of 5 years, then as clinically indicated.  The follow up period will begin at 
the end of study evaluation visit for patients that became ineligible for transplant 
for any reason but did not meet criteria for disease progression.  The follow up 
period for patients that go on to transplant will begin at the Day +100 bone 
marrow biopsy.   Patients that progress at any time will be followed for survival 
status only on a yearly basis.  
Adverse Events: From first dose of study drug until 30 days after receiving last 
dose of study drug.
Hematology and Chemistry: Prior to study, Day 1 of each cycle, and post 
treatment follow-up.
Performance Status: Prior to study, Day 1 of each cycle, and post treatment 
follow-up.
History and Physical Examination Prior to study, Day 1 of each cycle, and post 
treatment follow-up.
Electrocardiogram: Prior to study
Statistical Analysis

Phase I: The actual sample size for the Phase I population depends on the
unknown dose-toxicity profile of the treatment and the maximum sample
size is 21 patients.

Phase Ib (Dose expansion cohort): The sample size calculation for the
Phase Ib was based on testing the hypotheses concerning the proportion of
the population who experience an objective response (i.e., CR or PR)
described above. This design requires a total of up to 30 patients (it will
include the patients treated in the Phase I phase and 9 patients enrolled in
the dose expansion cohort). This will achieve approximately 80.1% power
to detect differences of 20 percentage points (50% versus 70%).
The primary objective of the Phase I part of this study is to determine the MTD 
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of the proposed regimen defined as the dose of carfilzomib added to standard R-
ICE chemotherapy. The basic design of the Phase I trial will utilize a standard 
3+3 dose-finding scheme which is a special case of the A + B design described 
by Lin and Shih (2001). Rationale behind the design is nested in the assumption 
that both the probabilities of toxicity and efficacious response are continuous 
monotonic non-decreasing functions of the dose.
The objective of the Phase Ib component is examination of the efficacy and 
toxicity of the addition of carfilzomib to R-ICE at the MTD dose.
The primary objective of the Phase Ib component is to assess the efficacy of the 
study treatment arm as compared to historical control. The primary efficacy 
endpoint will be best overall response rate (PR+CR) within following 3 cycles 
of C-R-ICE therapy (as demonstrated by whole body PET-CT and dedicated CT 
scans following Cycle 3 of therapy).
PK/PD Analysis: A pharmacologically-driven PK/PD model will be developed 
to elucidate the temporal relationship between carfilzomib concentrations and 
the time course of proteasome inhibition, along with temporal relationships with 
thrombocytopenia and neutropenia. This model will allow assessment of the 
dose and schedule at which carfilzomib facilitates maximal proteasome 
inhibition and thus lead to an increase response rate, while modulating the 
degree of severe toxicities. In addition, the effect of concomitant administration 
of rituximab, ifosfamide, carboplatin, and etoposide will be incorporated into 
the model to assess their potential effects on efficacy and/or toxicity.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant initials) ___________________________
Title: Phase I Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus 
Etoposide (C-R-ICE) in Patients with Relapsed/Refractory Diffuse Large B-cell 
Lymphoma (DLBCL)
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES or “N/A” for patient enrollment.
Date
1.
Histological confirmation of relapsed/refractory CD20 positive diffuse 
large B-cell lymphoma.  Network sites must submit slides to Roswell 
Park for Central Review and confirmation.
2.
Ann Arbor Stage I – Stage IV DLBCL at the time of relapsed/refractory 
disease to be eligible
3.
Measurable or assessable disease is required. Measurable tumor size (at 
least one node measuring 2.25 cm2 in bidimensional measurement) per 
CT scan, other radiological study, and/or physical exam.
4.
Patients must have received at least 1 prior rituximab-based 
immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.).
5.
≥ 2 weeks since major surgery.
6.
Patients must not  have any significant toxicity associated with prior 
surgery, radiation therapy, chemotherapy, or immunotherapy, per PI 
discretion
7.
Age ≥ 18 years and ≤ 75 years of age.
8.
Life expectancy ≥ 3 months.
9.
Karnofsky Score (KS) ≥ 50 (Appendix B).
10. Adequate hepatic function, with serum ALT/AST ≤ 3.5 times the upper 
limit of normal in the absence of a history of Gilbert's disease (or pattern 
consistent with Gilbert’s), within 14 days prior to starting therapy.
11. Adequate bone marrow reserve (If patient has cytopenias due to bone 
marrow involvement, these requirements are not applicable):

Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior 
to starting therapy.

Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to starting 
therapy (subjects may be receiving red blood cell [RBC] transfusions 
in accordance with institutional guidelines).

Platelet count ≥ 50 × 109/L (≥ 20 × 109/L if lymphoma involvement 
in the pre-treatment bone marrow is found) within 14 days prior to 
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES or “N/A” for patient enrollment.
Date
starting therapy.
12. Patients must have a serum creatinine of ≤ 1.5 mg/dL; if creatinine
> 1.5 mg/dL creatinine clearance must be > 60 mL/min within 7 days
prior to treatment either measured or calculated using a standard
Cockcroft and Gault formula. Refer to Appendix C.
13. Written informed consent in accordance with federal, local, and
institutional guidelines.
14. Females of childbearing potential (FCBP) must agree to ongoing
pregnancy testing and to practice contraception. Should a woman become
pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician
immediately.
15. Male subjects must agree to practice contraception.
16. No known hypersensitivity to murine products.
17. Patients must have normal baseline cardiac function based upon
echocardiogram or gated blood pool scan (MUGA) with an ejection
fraction ≥ 50%.
18. Patients who test positive for HepC Ab are eligible provided all of the
following criteria are met: a) bilirubin ≤ 2 x upper limit of normal; b)
ALT/AST ≤ 3 x upper limit of normal; and c) clinical evaluation to rule
out cirrhosis.
19. Specific guidelines will be follow regarding inclusion of
relapsed/refractory DLBCL based on Hepatitis B serological testing as
follow:
•
HBsAg negative, HBcAb negative, HBsAb positive patients are
eligible.
•
Patients who test positive for HBsAg are ineligible (regardless of
other Hepatitis B serologies).
•
Patients with HBsAg negative, but HBcAb positive (regardless of
HBsAb status) should have a HBV DNA testing done and protocol
eligibility determined as follow:

If HBV DNA is positive, the subject will be excluded from 
the study.

If HBV DNA is negative, the subject may be included but 
must undergo at least every 2 months HBV DNA PCR 
testing from the start of treatment throughout the duration 
the treatment course.
Investigator Signature: ___________________________________
Date: ___________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials)________________________
Medical Record No.: (Network sites use participant initials) _______________________
Title: Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin 
Plus Etoposide (C-R-ICE) in Patients with Relapsed/Refractory Diffuse Large B-
Cell Lymphoma (DLBCL)
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “NO” or “N/A” for patient enrollment
Date
1.
Patients with NHL other than DLBCL; including “transformed” DLBCL.
2.
Known to be seropositive for HIV. An HIV test is not required for entry 
on this protocol, but is required if the patient is perceived to be at risk.
3.
Positive serology for HBV defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of 
HBsAb status), a HepB DNA test will be performed and if positive the 
subject will be excluded.
4.
Patients with symptomatic brain involvement.
5.
Peripheral neuropathy of Grade 2 or greater severity as defined by the 
National Cancer Institute’s (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. Patients with Grade 2 or higher 
(NCI-CTC) neuropathy.
6.
Myocardial infarct within 6 months before enrollment, New York Heart 
Association (NYHA) Class II or greater heart failure, uncontrolled 
angina, severe uncontrolled ventricular arrhythmias, clinically significant 
pericardial disease, or electrocardiographic evidence of acute ischemia.
7.
Uncontrolled intercurrent illness including, but not limited to, active 
infection, poorly controlled hypertension, diabetes mellitus or other 
serious medical or psychiatric conditions that could interfere with 
adherence to or completion of this study.
8.
Pregnant or breastfeeding.
9.
Patient has received other investigational drugs within4weeks before 
enrollment.
10. Chemotherapy within 3 weeks of the first scheduled study treatment.
11. Less than 2-year disease free from another primary malignancy (other 
than squamous or basal cell carcinoma of the skin, “in-situ” carcinoma of 
the cervix or breast, superficial bladder carcinoma, or previously treated 
localized prostate cancer with normal PSA levels). Patients are not 
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “NO” or “N/A” for patient enrollment
Date
considered to have a “currently active” malignancy if they have 
completed anti-cancer therapy, are considered by their physician to be at 
less than 30% risk of relapse and at least 2 years have lapsed.
12. Major surgery, other than diagnostic surgery, within 2 weeks.
13. Known history of allergy to Captisol® (a cyclodextrin derivative used to 
solubilize carfilzomib).
14. Medical condition requiring chronic use of high dose systemic 
corticosteroids (i.e., doses of prednisone higher than 10 mg/day or 
equivalent).
15. Prior HDC-ASCT.
16. Active CNS disease defined as symptomatic meningeal lymphoma or 
known CNS parenchymal lymphoma. A lumbar puncture demonstrating 
DLBCL at the time of registration to this study is not exclusion for study 
enrollment.
Patient meets all entry criteria:
  Yes
  No
If “NO”, do not enroll patient in study.
Investigator Signature: ___________________________________
Date: __________
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TABLE OF CONTENTS
1.
Background.........................................................................................................................15
1.1.
Front-Line Therapy of Patients with DLBCL ....................................................................15
1.1.1. Multidisciplinary Management of Early Stage DLBCL.....................................................16
1.1.2. Approach of Advanced-Stage DLBCL...............................................................................16
1.2.
New Challenges in the Management of R-CHOP Relapsed/Refractory DLBCL ..............18
1.3.
The Ubiquitin-Proteasome Pathway in the Development, Maintenance and Progression of 
Cancer................................................................................................................................19
1.4.
Carfilzomib.........................................................................................................................20
1.4.1. Toxicology Studies .............................................................................................................20
1.4.2. Carfilzomib Pre-Clinical Antitumor Activity.....................................................................21
1.4.3. Phase I Experience with Carfilzomib as a Monotherapy....................................................25
1.4.4. Phase II Experience with Carfilzomib as a Monotherapy ..................................................26
1.4.5. Experience with Carfilzomib in Combination with Lenalidomide and Dexamethasone ...27
2.
Rationale.............................................................................................................................28
2.1.
Dose Rationale....................................................................................................................29
3.
Objectives ...........................................................................................................................31
3.1.
Phase I Primary Objectives.................................................................................................31
3.2.
Phase Ib Primary Objectives (Expansion cohort)...............................................................31
3.3.
Secondary Objectives .........................................................................................................31
4.
Methodology.......................................................................................................................32
4.1.
Study Design.......................................................................................................................32
4.2.
Target Accrual and Study Duration....................................................................................33
5.
Subject Selection ................................................................................................................33
5.1.
Inclusion Criteria ................................................................................................................33
5.1.1 Disease Specific..................................................................................................................33
5.1.2 Prior Treatment...................................................................................................................33
5.1.3 Demographic.......................................................................................................................33
5.1.4 Laboratory...........................................................................................................................33
5.1.5 Medical/Ethical...................................................................................................................34
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5.2.
Inclusion of Women and Minorities...................................................................................35
5.3.
Exclusion Criteria ...............................................................................................................35
6.
Drug Information................................................................................................................36
6.1.
Carfilzomib (Investigational Agent)...................................................................................36
6.1.1. Drug Shipment....................................................................................................................36
6.1.2. Drug Preparation and Administration.................................................................................37
6.1.3. Storage and Stability...........................................................................................................37
6.1.4. Handling and Disposal........................................................................................................37
6.2.
Rituximab (Rituxan®) ........................................................................................................38
6.3.
Ifosfamide (Ifex®)..............................................................................................................41
6.4.
Carboplatin (Paraplatin®)...................................................................................................41
6.5.
VP-16 (etoposide, VePesid®).............................................................................................41
6.6.
Mesna (Mesnex®) ..............................................................................................................42
6.7.
Neulasta® (Pegfilgrastim, G-CSF, Neupogen, Filgrastim-sndz and biosimilars)..............42
7.
Treatment Plan....................................................................................................................43
7.1.
Preparation and Administration..........................................................................................43
7.2.
General Guidelines .............................................................................................................43
7.3.
Criteria for Retreatment......................................................................................................43
7.4.
Dose Modifications.............................................................................................................44
7.4.1. Definition of Dose-Limiting Toxicity ................................................................................44
7.4.1.1 Non-Hematologic Toxicity................................................................................................44
7.4.1.2 Hematologic Toxicity ........................................................................................................44
7.4.1.3 Criteria for Dose Escalation...............................................................................................44
7.4.2 Treatment Delay .................................................................................................................45
7.4.2.1 Thrombocytopenia and Neutropenia .................................................................................45
7.4.2.1   Cardiac Disorders ............................................................................................................45
7.4.2.2 Gastrointestinal Events ......................................................................................................46
7.4.2.3 Hematologic Toxicity ........................................................................................................46
7.4.2.4 Tumor Lysis Syndrome .....................................................................................................46
7.4.2.5 Infusion Reactions and Adverse Events Experienced within a Day of Dosing.................46
7.4.2.6 Renal Impairment ..............................................................................................................47
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7.4.2.7 Hepatic Impairment ...........................................................................................................47
7.4.2.8 Other Conditions Delaying Treatment...............................................................................47
7.4.2.9 Mechanisms of Action.......................................................................................................47
8
General Concomitant Medication and Supportive Care.....................................................48
8.1
Safety Considerations .........................................................................................................48
8.2
Guidelines for Monitoring, Prophylaxis, and Treatment of Tumor Lysis Syndrome ........49
8.3
Concomitant Medications...................................................................................................50
8.3.1 Required Concomitant Medications ...................................................................................50
8.4
Duration of Treatment ........................................................................................................50
8.5
Treatment Discontinuation .................................................................................................51
9
Study Procedures ................................................................................................................51
9.1
Subject Registration............................................................................................................51
9.2
Pathology ............................................................................................................................56
9.3
Immune Biomarker Blood Sample Collection ...................................................................56
9.4
Pharmacokinetic Blood Sample Collection and Processing (Phase 1 Only)......................56
10
Efficacy Evaluations...........................................................................................................58
10.1
Objectives ...........................................................................................................................58
10.2
Imaging, Laboratory and Pathological Studies...................................................................58
10.3
Modified Cheson Criteria ...................................................................................................58
10.3.1 Complete Response (CR) ...................................................................................................58
10.3.2 Partial Response (PR).........................................................................................................59
10.3.3 Stable Disease (SD) ............................................................................................................59
10.3.4 Progression (PD) or Relapse...............................................................................................60
10.3.5 Duration of Overall Response and/or Progression-Free Survival (in Non-Responders)....60
10.4
Duration of Overall Survival ..............................................................................................61
11
Safety Evaluation................................................................................................................61
11.1
Adverse Events ...................................................................................................................61
11.1.1 Definition............................................................................................................................61
11.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................61
11.1.1.2
Adverse Events Occurring Secondary to Other Events...............................................61
11.1.1.3
Abnormal Laboratory Values......................................................................................62
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11.1.1.4
Preexisting Medical Conditions (Baseline Signs and Symptoms) ..............................62
11.1.2 Grading and Relationship to Drug......................................................................................62
11.1.3 Reporting Adverse Events ..................................................................................................63
11.2
Serious Adverse Events ......................................................................................................63
11.2.1 Definition............................................................................................................................63
11.2.2 Reporting Serious Adverse Events .....................................................................................64
11.3
Investigator Reporting: Notifying the Study Sponsor ........................................................64
11.4
Follow-Up for Serious Adverse Events..............................................................................64
11.5
Unanticipated Problems......................................................................................................65
11.5.1 Definition............................................................................................................................65
11.5.2 Reporting Unanticipated Problems.....................................................................................65
11.6 FDA Reporting ......................................................................................................................65
12
Data and Safety Monitoring................................................................................................66
13
Statistical Methodology......................................................................................................66
13.1
Sample Size Determination ................................................................................................67
13.1.1 Phase I.................................................................................................................................67
13.1.2 Phase Ib...............................................................................................................................67
13.2
Missing Data.......................................................................................................................67
13.3
Descriptive Analyses ..........................................................................................................67
13.4
Phase I.................................................................................................................................68
13.5
Phase Ib (expansion cohort)................................................................................................68
13.5.1 Historical Control ...............................................................................................................68
13.5.2 Phase Ib Decision Rules .....................................................................................................68
13.5.3 Secondary Analyses............................................................................................................69
14
Correlative Studies..............................................................................................................69
14.1
Immune Biomarker Analysis..............................................................................................69
14.1.1 Blood...................................................................................................................................69
14.1.2 Fresh Tissue (Phase I part only) .........................................................................................70
14.2
PK/PD Model Development...............................................................................................70
15
Ethical and Regulatory Standards.......................................................................................71
15.1
Ethical Principles................................................................................................................71
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15.2
Informed Consent ...............................................................................................................72
16
Study Responsibilities ........................................................................................................72
16.1
Data Collection ...................................................................................................................72
16.2
Maintenance of Study Documents......................................................................................73
17
Administrative Rules ..........................................................................................................73
17.1
Revisions to the Protocol....................................................................................................73
17.2
Termination of the Study....................................................................................................73
17.3
Confidentiality ....................................................................................................................74
18
Appendices .........................................................................................................................74
19
References...........................................................................................................................84
IN-TEXT TABLES
Table 1.
CRd: Cohorts 1–5 (Carfilzomib: 15 to 20 mg/m2; LEN: 10 to 25 mg).......................27
Table 2.
Dose Escalation Scheme .............................................................................................44
Table 3.
Study Calendar ............................................................................................................52
Table 4.
Guidelines for Routine Adverse Event Reporting for Phase I Studies (Regardless of 
Expectedness) ................................................................................................................................62
Table 5.
Guidelines for Routine Adverse Event Reporting for Phase Ib Studies (Regardless of 
Expectedness) ................................................................................................................................62
IN-TEXT FIGURES
Figure 1.
Dose-Dependent Effects Carfilzomib & Bortezomib Shown in Raji Family Cells....21
Figure 2.
Effects of Carfilzomib and Bortezomib Observed in ABC and GCB Sensitive and 
Resistant Cells ...............................................................................................................................22
Figure 3.
Various Subtypes of Lymphoma Patient Samples Sensitive to Carfilzomib ..............22
Figure 4.
Carfilzomib Overcomes Rituximab-Resistance in Combination with VP-16.............23
Figure 5.
Carfilzomib Potentiates Carboplatin Anti-Tumor Activity in Both Raji and RL 
Sensitive and Resistant cells..........................................................................................................24
Figure 6.
Treatment Plan Schema...............................................................................................31
APPENDICES
Appendix A.
Ann Arbor Staging System ..................................................................................73
Appendix B.
Karnofsky Performance Status Scores.................................................................75
Appendix C.
Cockcroft-Gault Calculation for Creatinine Clearance........................................76
Appendix D.
  Amgen ISS FAX Transmittal Form…………………………………………….78
Appendix E.      Instructions for network sites…………………………………………………...79
Appendix F.      Roswell Park Shipment Form…………………………………………………..83
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1. BACKGROUND
In 2012 there have been approximately 70,130 new non-Hodgkin’s lymphoma (NHL) cases and 
18,940 deaths in the United States despite available treatment.5 The most common type of B-cell 
NHL is diffuse large B-cell lymphoma (DLBCL), which has an aggressive clinical course. 
Diffuse large B-cell lymphoma accounts for approximately 31% of those diagnosed. State of the 
art treatment for diffuse large B-cell lymphoma depends on the stage of lymphoma with a 
realistic goal of curing these patients with induction therapy. Standard treatment typically 
consists of immunochemotherapy combining monoclonal antibody and combination 
chemotherapy. Radiation therapy may be utilized for CNS, bulky or refractory disease in some 
cases.
DLBCL can be divided into subgroups with distinct biological characteristics and prognosis 
utilizing gene expression profiling (GEP) analysis.2-4 Initial GEP studies have identified 
4 subgroups of primary DLBCL patients with different biology and clinical outcomes: germinal 
center B-cell-like (GCB) activated B-cell-like (ABC), primary mediastinal lymphoma (PML) 
and type 3 DLBCL.3,4
GCB, ABC and PML demonstrate significant differences in terms of prognosis, disease free 
survival and overall survival following systemic chemotherapy or (more recently) chemo-
immunotherapy.2,3,5
GCB-DLBCL appears to be derived at the post-germinal state, primarily driven by deregulation 
of apoptosis by Bcl-6 and has an excellent response to rituximab-based chemo-immunotherapy 
regimens. ABC-DLBCL is driven by high levels of NFB activity that is associated with a poor 
outcome despite chemo-immunotherapy. Finally, PML shares GEP signatures similar to those 
patients with classical Hodgkin’s Lymphomas (HL) and has a good prognosis when compared to 
other DLBCL subtypes. Treatment-related toxicities (i.e., secondary malignancies, organ 
dysfunction, cytopenias, etc.) continue to be a significant problem being addressed in clinical 
trials.
There is a growing need to further characterize resistant DLBCL cells at the molecular level in 
an attempt to: identify biomarkers predictive of response to salvage therapies; better understand 
the mechanisms associated with acquired resistance to immunochemotherapy; and identify and 
develop novel therapeutic strategies against novel targets and/or pathways.
1.1. Front-Line Therapy of Patients with DLBCL
Unless contraindicated by significant and pre-existing co-morbid conditions, the treatment of 
DLBCL should include the use of rituximab and an anthracycline-based multiagent combination 
chemotherapy aimed to achieve a durable complete remission (CR) (i.e., cure). The initial 
treatment is subsequently tailored according to both clinical (e.g., stage) and tumor factors 
(e.g., Ki-67 expression, presence and type of chromosomal translocations, etc.). In general, the 
initial frontline management of DLBCL can be divided according to disease stage in 2 groups: 
localized and advanced stage.
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1.1.1. Multidisciplinary Management of Early Stage DLBCL
Approximately 25% of DLBCL cases present as early stage. Localized DLBCL is defined as 
Ann Arbor Stage I or non-bulky Stage II disease and the management of such patients typically 
consists of an abbreviated course of combined systemic chemo-immunotherapy (e.g., R-CHOP) 
following by involved field radiation therapy (IF-XRT).6,7
In 1998 the Southwestern Oncology Group (SWOG) study 8736 randomly assigned 401 patients 
with non-bulky Stage I or Stage II NHL aggressive B-cell lymphoma, to receive either 3 cycles 
of chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and prednisone 
(CHOP) followed by IF-XRT at 40 cGy to 50 cGy versus 8 cycles of CHOP chemotherapy 
alone.8 Patients managed with combined chemotherapy followed by IF-XRT had a better overall 
survival (OS) (77% and 64%, respectively, p = 0.03) and progression-free survival (PFS) (80% 
and 72%, respectively, p = 0.02) than patients treated with 8 cycles of CHOP alone after five 
years of follow-up.
The use of monoclonal antibodies, particularly rituximab, has changed the treatment paradigm of 
patients with B-cell NHL including DLBCL. Rituximab is a monoclonal antibody targeting the 
CD20 antigen present in normal and the majority of malignant B-cells. The mechanisms by 
which rituximab elucidates its anti-tumor activity includes: antibody-dependent cellular 
cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC) and activation of intracellular 
pathways leading to direct apoptosis. Pre-clinical models had demonstrated that rituximab 
potentiates the effect of several chemotherapeutic agents in B-cell lymphoma.9 In contrast to 
what has been observed in low-grade lymphomas, rituximab monotherapy has limited activity in 
DLBCL.10 On the other hand, the addition of rituximab to standard doses of chemotherapy in 
DLBCL results in improved clinical outcomes without significant additional toxicity.
Few studies addressing the role of rituximab in the management of early stage DLBCL had been 
conducted. The addition of rituximab to combined modality treatment in DLBCL was evaluated 
in a SWOG and reported by Perky et al. The SWOG conducted a phase II clinical trial evaluating 
the addition of rituximab to an abbreviated course of CHOP chemotherapy followed by IF-XRT. 
The study enrolled 60 patients with limited stage DLBCL.11 The PFS and OS were 88% and 
92%, respectively and were considered to be superior to historical (chemotherapy-IF-XRT) 
controls.11 The current literature supports the addition of rituximab to standard chemotherapy 
(e.g. R-CHOP) in the management of early stage DLBCL. The length of therapy and the 
utilization of radiotherapy continue to be a subject of ongoing debate.
1.1.2. Approach of Advanced-Stage DLBCL
The use of systemic chemotherapy to successfully eradicate disseminated DLBCL was first 
described in the early 1970s.12,13 After these original reports, CHOP (given every 21 days, 
i.e., CHOP-21) regimen became the backbone of the standard of care for aggressive lymphomas 
in the US. Multiple attempts to improve survival in DLBCL patients led investigators to evaluate 
more intensive regimens.14 Fisher et al. on behalf of the SWOG reported the results of a large 
clinical trial conducted in US. The study compared CHOP-21 chemotherapy with three intense 
chemotherapy regimens: M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, 
vincristine and prednisone), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, 
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vincristine, prednisone and bleomycin,) and ProMACE/CytaBOM (cyclophosphamide, 
doxorubicin, etoposide, cytarabine, bleomycin, vincristine and prednisone). The study failed to 
demonstrate an improvement in outcome in the “intense” regimens compared to CHOP-21; 
“intense” regimens were associated with more toxicity than CHOP-21. After a follow up of 
6 years the OS and PFS was not statistically significant different between the chemotherapeutic 
regimens tested and therefore CHOP-21 was chosen as the standard-of-care.14
The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted 
by GELA. The GELA group enrolled patients with newly diagnosed aggressive B-cell 
lymphomas over the age of 60 years and randomized them to receive either 8 cycles of CHOP 
versus rituximab plus CHOP at 21 day intervals.15 The study included patients with Stage I to 
Stage IV DLBCL, 59% had 3 or more IPI score risk factors and 80% had Ann Arbor Stage III or 
Stage IV disease. The addition of rituximab to CHOP chemotherapy resulted in higher response 
rates than CHOP alone (83% vs. 69%, respectively, p = 0.005). The PFS and OS at the interim 
analysis (after 18 month period of follow up) were significantly better in the R-CHOP arm 
(p < 0.001 and p = 0.007, respectively). A long term analysis of the study after 5 years of follow 
up confirmed the efficacy of combining rituximab with systemic chemotherapy in terms of PFS 
(54% vs. 30%) and OS (64.5% vs. 45%) (p < 0.0001 and p = 0.0004, respectively) A subset 
analysis demonstrated that, the benefit of rituximab added to CHOP chemotherapy was observed 
across all the different risk categories as determined by IPI risk stratification.15,16
A second study conducted primarily in the United States, was aimed to validate the results from 
the GELA study. Preliminary data from the Eastern Cooperative Oncology Group (ECOG) 
Study 4944 in previously untreated elderly DLBCL randomized to R-CHOP vs. CHOP, and in 
responders to subsequent observation versus rituximab-maintenance showed that the addition of 
rituximab to chemotherapy either during induction treatment or during maintenance improved 
the time to progression (TTP) as compared to patients treated with CHOP chemotherapy alone.17
Similar findings were found in younger patients with DLBCL with 0 to 1 IPI score risk factors. 
Pfreundschuh et al. reported a statistical significant benefit by adding rituximab to CHOP or 
CHOP-like chemotherapy in 824 patients with DLBCL in terms of PFS and OS. After a follow 
up period of 3-years, patients randomized to receive chemotherapy and rituximab had higher 
EFS (79% vs. 59%, p < 0.0001), and had an increased OS (93% vs. 84%; p = 0.0001) compared 
to patients assigned to chemotherapy alone.18
The benefit of adding rituximab to high-intermediate and high-risk DLBCL patients younger 
than 60 years of age has not been formally studied. The use of rituximab in combination with 
CHOP chemotherapy in this group of patients has been extrapolated from the results of the 
GELA and MInT studies. While the addition of rituximab to standard doses of CHOP 
chemotherapy have improved the outcomes of patients with DLBCL, a significant number of 
patients fail to achieve an objective response or relapse after initial response which stresses the 
need for the development of novel therapeutic strategies.
In the front-line setting, three alternative strategies have been or are currently being evaluated in 
DLBCL patients; the concept of dose-dense rituximab (i.e., 12 doses of rituximab delivered 
concomitantly with 6 cycles of CHOP-14); targeting of the ubiquitin proteasome systems with 
bortezomib as a way to potentiate the anti-tumor activity of chemo-immunotherapy; and the use 
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of high dose-chemotherapy and autologous stem cell support (HDC-ASCS) in first remission 
(especially for those patients with high risk-disease).
1.2. New Challenges in the Management of R-CHOP Relapsed/Refractory DLBCL
The PARMA study established the role of HDC-ASCS as consolidation treatment for patients 
with relapsed/refractory DLBCL responding to second-line chemotherapy.19 There is a vast 
number of regimens used in the treatment of patients with relapsed/refractory DLBCL and are 
largely chosen by their relative lack of “cross-resistance” to front-line drugs. The goal of salvage 
regimens is to achieve maximum tumor cytoreduction in preparation for HDC-ASCS. In general, 
when selecting the optimal salvage regimen, regimens with high response rates (especially high 
CR rates), tolerable hematological and non-hematological toxicity, and those that allow effective 
autologous peripheral stem cell collection (PBSC) will be considered.
As rituximab changed the treatment paradigm of patients with DLBCL, it has been postulated 
that the current subset of patients with refractory or relapsed DLBCL represents a different 
patient population to the one studied in the pre-rituximab era. Several investigators questioned if 
response to second-line chemotherapy or if the outcome from HDC-ASCS in patients with 
relapsed/refractory DLBCL previously treated with “R”-CHOP to historical controls was 
different as compared to patients treated prior to the rituximab era.
Dr. Martin, on behalf of the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea 
(GEL/TAMO), reported results from a retrospective analysis in the outcome of patients with 
DLBCL evaluating the influence of the inclusion of upfront rituximab to rituximab plus 
etoposide, methylprednisolone, cytarabine and cisplatin (ESHAP) as salvage therapy.20 Martin 
and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received 
R-ESHAP as second line therapy, 94 patients were previously treated with rituximab-
chemotherapy (R+ group) in the front line setting and 69 patients received only chemotherapy 
alone (R- group). Response rates were higher in patients who were not previously exposed to 
rituximab in a univariate analysis (but not in a multivariate analysis). The overall response and 
complete response rates to R-ESHAP were 67% and 37% in the treatment group versus 81% and 
56% for patients in the R-group (p = 0.045, p = 0.015, respectively).20 In addition, the PFS and 
OS at 3 years were significantly higher for the patients in the R- group (57% and 64%) as 
compared to those patients in the R+ group (38% and 17% [p < 0.0001 and p = 0.0005], 
respectively). Of note: the same percentage of patients in both groups underwent subsequent 
HDC-ASCS. In a multivariate analysis, prior exposure to rituximab was found to be a prognostic 
indicator of worse PFS and OS.20 The results of this retrospective study suggests that DLBCL 
patients who relapse or fail to respond to rituximab-chemotherapy in the front-line setting 
develop more resistant disease and represent an emerging challenge for clinicians. It also stresses 
the need to further study and define the mechanisms and factors associated with 
chemoimmunotherapy resistance.
The need to develop novel salvage chemotherapy regimens after rituximab-CHOP failures was 
further demonstrated by the results of the Phase III collaborative trial in relapsed aggressive 
lymphoma (CORAL) study. This study was aimed to define the most appropriate salvage 
chemotherapy regimen and the role (if any) of rituximab maintenance after HDC-ASCS. In this 
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study, DLBCL patients with relapsed/refractory disease after CHOP or R-CHOP were 
randomized to receive 3 cycles of R-ICE or R-DHAP followed by conditioning chemotherapy 
with carmustine, etoposide, cytarabine and melphalan (BEAM) and ASCS. Subsequently, 
patients were randomized to rituximab maintenance or observation. The study enrolled a total of 
396 patients. The investigators demonstrated that factors affecting event-free survival (EFS), 
include: secondary line age-adjusted international prognostic index (aaIPI) of 0 - 1 (39% vs. 56% 
p = 0.0084), relapse < 12 months after completion of first-line therapy (36% vs. 68%, p < 0.001) 
and prior rituximab exposure in the frontline setting (34% vs. 66%, p < 0.001)21. While no 
significant differences in terms of response rates were observed between patients treated with 
R-ICE or R-DHAP, the overall response rate (ORR) to salvage chemotherapy was lower among 
patients previously treated with R-CHOP (51%) when compared to those patients treated with 
upfront CHOP (83%). Moreover, the CR rate in R-CHOP pre-treated patients to either R-ICE or 
R-DHAP was only 38%.21,22
In summary, the incorporation of upfront rituximab to standard doses of CHOP (R-CHOP-21) 
has resulted in an improved clinical outcome when compared to CHOP-21 alone in patients with 
DLBCL. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy in 
the front line treatment of DLBCL is beyond dispute, it has also caused a new challenge for the 
development of salvage therapies with improved therapeutic outcomes in these patients. In other 
words, R-CHOP has not only improved the survival in patients with DLBCL but also has 
modified the biology and response to subsequent therapy for those patients with refractory or 
relapsed DLBCL.
A group of Roswell Park investigators have demonstrated that the ubiquitin-proteasome system 
(UPS) plays an important role in the acquirement of resistance to rituximab and chemotherapy 
agents in B-cell lymphoma.23,24 It is anticipated that targeting the UPS with novel proteasome 
inhibitors such as carfilzomib may result in higher overall and complete remission rates and 
improved outcomes following high-dose chemotherapy with autologous stem cell transplantation 
(HDC-ASCT) in relapsed/refractory DLBCL patients.
1.3. The Ubiquitin-Proteasome Pathway in the Development, Maintenance and 
Progression of Cancer
Previously, rituximab-chemotherapy resistant cells have an abnormal ubiquitin-proteasome 
system have been noted. The discovery and functional characterization of the ubiquitin-
proteasome pathway as the major system for extra-liposomal protein degradation has delineated 
its importance for regulating the selective proteolysis of key regulatory proteins.25 A significant 
number of proteins that regulate cell cycle, apoptosis, cell proliferation and differentiation are 
now known to undergo processing and functional limitation by entering the ubiquitin-proteasome 
pathway. The degradation of intracellular proteins by the proteasome is a multi-step process in 
which proteins must be “flagged” for recognition and subsequently destroyed by the 
26S proteasome. Targeting of proteins for degradation occurs by a process known as 
ubiquitination and consists of the covalent attachment of multiple monomers of the polypeptide, 
ubiquitin, to a given protein. The ubiquitination of proteins is controlled by three classes of 
enzymes 1) ubiquitin-activating enzymes (E1), 2) ubiquitin-conjugating enzymes (E2), and 
3) ubiquitin-protein ligases (E3).26,27 Rituximab-chemotherapy-resistant cell lines, developed in 
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Roswell Park laboratory, express elevated levels of genes encoding several components of the 
UPS system suggesting enhanced proteasome-mediated protein turnover.28
Cytotoxic effects of proteasome inhibition have long been appreciated, but only more recently 
has this phenomenon been taken advantage of clinically. In addition to a central role in degrading 
misfolded or unfolded proteins, the proteasome has also been implicated in DNA repair and cell 
cycle control.29-31 The mechanisms by which proteasome inhibition kills malignant cells have not 
been fully defined, but likely includes indirect effects on the function or generation of multiple 
gene products, particularly those regulated by the NF-kB pathway. Activity of the transcription 
factor nuclear factor-B (NF-B) is regulated by proteasomal degradation of its cytosolic 
binding partner IB.32 One prevalent theory suggests that active NF-B found in many tumor 
cells supports their survival and that removal of this survival signal via bortezomib-induced 
stabilization of IB favors cell death.33 Indeed, when specific inhibitors of NF-B are used, 
expression of several anti-apoptotic proteins are reduced and tumor cells undergo apoptosis.33,34 
Furthermore, direct inhibition of NF-B with a specific inhibitor or bortezomib sensitized 
rituximab/chemotherapy-resistant B-NHL cell lines to the cytotoxic activity of rituximab.35 
Clinically, bortezomib was found to improve the activity of standard chemotherapeutic agents 
(EPOCH) in relapsed/refractory DLBCL patients with activated B-cell (i.e., ABC-like) gene 
expression profiles which are associated with activation of NF-B, suggesting that bortezomib is 
capable of re-sensitizing NF-B-driven DLBCL cells to chemotherapy.36 These data do not rule 
out the distinct possibility that multiple NF-B independent mechanisms may also contribute to 
the cytotoxic activity of bortezomib and other more potent proteasome inhibitors such as 
carfilzomib.
New treatment strategies utilizing novel agents that can potentially overcome the observed 
resistance pathways in therapy-resistant lymphoma cells are desperately needed. In this regard, 
proteasome inhibitor-based salvage regimens for refractory DLBCL hold great promise. The 
current clinical study proposes to define anti-tumor activity of carfilzomib, a novel proteasome 
inhibitor when combined with R-ICE in patients with relapsed/refractory DLBCL.
1.4. Carfilzomib
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsin-like active site of the 20S proteasome. Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib 
(Velcade®). In addition, when measured against a broad panel of proteases including metalol, 
aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-proteasomal 
proteases when compared to bortezomib.37,38
1.4.1. Toxicology Studies
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by Onyx 
Pharmaceuticals, carfilzomib was administered to rats and monkeys as 2 complete 2-week cycles 
of QD x 5 for 5 days with nine days rest.39,40 Administration to rats at 12 mg/m2, the severely 
toxic dose in 10% of animals (STD10), caused > 90% proteasome inhibition in red blood cells 
1 hour after dosing. Overall, stronger inhibition of the proteasome and longer duration of 
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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.40 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.41
DLTs included effects on the gastrointestinal, renal, pulmonary, and cardiovascular systems and 
appeared to be related to Cmax effects. Of note, neutropenia was not observed; rather, transient 
neutrophilia was seen following acute dosing. Renal, cardiovascular and gastrointestinal 
toxicities were similar to those observed with bortezomib. Finally, cyclical thrombocytopenia, 
likely due to inhibition of platelet budding from megakaryocytes, was similar to that seen with 
bortezomib. Proteasome inhibition in the blood in excess of 90% was achievable at well-
tolerated doses, which contrasts with approximately 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 achieved with bortezomib at 
its MTD on a less intensive schedule.
1.4.2. Carfilzomib Pre-Clinical 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 hours) exposure to 
carfilzomib is associated with potent cytotoxic and pro-apoptotic activity across a broad panel of 
tumor-derived cell lines in culture.37,42 Incubation of hematologic tumor cell lines with 
carfilzomib for as little as 1 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.37,42
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 both 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.37
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A group of Roswell Park investigators (i.e., Department of Medicine Lymphoma/Myeloma 
Laboratory at Roswell Park) evaluated the biological activity of carfilzomib alone or in 
combination with chemotherapeutic agents in rituximab-chemotherapy sensitive (RSCL) or 
resistant (RRCL) cell lines and in tumor cells derived from B-cell lymphoma patients. B-cell 
lymphoma cells were exposed to escalating doses of carfilzomib or bortezomib (1 nM - 7.5 nM) 
alone or in combination with doxorubicin, cisplatin, carboplatin, etoposide, paclitaxel, or 
vincristine for 24, 48, and 72 hours. Cell viability was determined by cell titer glow luminescent 
assay and cell cycle was analyzed by FASCan DNA methodology. In addition, Western blots 
were performed using cell lysates from carfilzomib, bortezomib or control-treated cells to detect 
PARP-cleavage and/or changes in Bcl-2 family members.
Research has found that carfilzomib was more active than bortezomib and exhibited dose-
dependent and time-dependent cytotoxicity against RSCL or RRCL. A 10-fold concentration 
difference between carfilzomib and bortezomib activity was found. See Figure 1.
Figure 1.
Dose-Dependent Effects of Carfilzomib and Bortezomib Shown in Raji 
Family Cells
Raji and Raji therapy-resistant cell lines Raji2R and Raji4RH were exposed to carfilzomib or 
bortezomib at the indicated concentrations in RPMI in 386 well plates for 48 hour and cell 
viability was assessed by cell titer Glo assay. The data are presented as the mean (+ S.D.) of 
3 independent experiments
In addition, the anti-tumor activity of carfilzomib in GCB or ABC DLBCL cell lines will be 
evaluated. Of interest, in both types of cell lines carfilzomib was more potent than bortezomib in 
inducing cell death and a decrease in cell proliferation (Figure 2).
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Figure 2.
Effects of Carfilzomib and Bortezomib Observed in ABC and GCB Sensitive 
and Resistant Cells
Different effects of carfilzomib and bortezomib are observed in ABC and GCB sensitive and 
resistant cells. 2A, 2B, dose-dependent effects of bortezomib were determined on cell viability in 
RL, RL4RH, U2932 and U29324RH. Cells were exposed to bortezomib at the indicated 
concentrations for 48 hours. Cell viability was determined by cell titer Glo assay. 2C, 2D, 
smaller doses of carfilzomib were used (10% of bortezomib concentrations) to treat cells; cell 
viability was calculated after 48 hours. Each dataset presents the mean ± SD of 3 independent 
experiments.
Subsequently, the activity of carfilzomib in a more clinically relevant setting has been evaluated. 
Primary tumor cells were isolated from various patients with B-cell lymphoma (n = 25) and 
exposed to either carfilzomib or bortezomib. In general, carfilzomib was more active than 
bortezomib in primary tumor cells isolated from B-cell lymphoma patients (Figure 3).
Figure 3.
Various Subtypes of Lymphoma Patient Samples Sensitive to Carfilzomib
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Lymphoma cells derived from patients with follicular lymphoma (FL) -3A, diffuse large B-cell 
lymphoma (DLBCL) -3B; and others (Burkitt’s lymphoma, marginal zone lymphoma, mantle 
cell lymphoma, CLL) 3C were exposed to either carfilzomib 5 nM or bortezomib 5 nM. The 
percentage of cell viability was evaluated by Cell titer Glo assay after 48 hours of incubation. 
Asterisks (*) indicate a significant (p < 0.01) difference between carfilzomib treatment patient 
sample and bortezomib group.
In addition, in vitro exposure of RRCL or RSCL to carfilzomib resulted in G2/M phase cell cycle 
arrest. In addition, carfilzomib exposure resulted in the upregulation of Bak and Noxa levels and 
subsequent PARP cleavage in RRCL (Data not show). Finally, carfilzomib demonstrated the 
ability to overcome resistance to chemotherapy in RRCL (Figure 4 and Figure 5).
Figure 4.
Carfilzomib Overcomes Rituximab-Resistance in Combination with VP-16
Raji4RH, RL4RH and U29324RH were pre-exposed to bortezomib (5 nM and 10 nM) (4A, 4B, 
4C) or carfilzomib (0.5 nM, 1 nM, 2.5 nM and 5 nM) (4D, 4E, 4F) for 24 hours and subsequently 
exposed to various doses of VP-16 for another 48 hours. Cell viability was measured and 
calculated. Carfilzomib can achieve the same killing capacity as bortezomib, but at a much low 
dose (10% dosage of bortezomib).
In vitro exposure of rituximab-sensitive or -resistant cell lines to proteasome inhibition 
augmented the cytotoxic activity of several chemotherapy agents proposed to be used in this 
clinical trial (e.g., etoposide and carboplatin). (Figure 4 and Figure 5).
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Figure 5.
Carfilzomib Potentiates Carboplatin Anti-Tumor Activity in Both Raji and 
RL Sensitive and Resistant cells
Raji and RL sensitive and resistant cells were pre-exposed to bortezomib (25 nM) (5A, 5B) or 
carfilzomib (2.5 nM) (5C, 5D) followed with or without carboplatin (430 mM) for another 
48 hours. There are statistically significant differences among Raji and RL sensitive and resistant 
cells treated with the combination of proteasome inhibitor and carboplatin (p < 0.05). 
Carfilzomib can achieve approximately the same killing capacity as bortezomib, but at a much 
low dose (2.5 nM vs. 25 nM).
1.4.3. Phase I Experience with Carfilzomib as a Monotherapy
The results of a Phase I clinical trial, PX-171-002, testing carfilzomib in subjects with 
relapsed/refractory hematologic malignancies, was recently reported.43 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 in the study.
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 
1.2 mg/m2 to 15 mg/m2) of 3 subjects each. At the 20 mg/m2 dose level, 1 of 8 patients had a 
Grade 3 renal failure at Cycle 1, Day 2 which was considered possibly related to study drug and 
lasted for 6 days. The patient continued on study for the remainder of Cycle 1 before having 
disease progression. At the 27 mg/m2 dose level, 1 of 6 subjects experienced a DLT during 
Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing. In 
subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
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constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome 
(TLS) and/or cytokine release. This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion. On the second day, three of 5 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 3 subjects had a rapid decline 
in serum and/or urine M-protein levels; 2 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 patients enrolled in PX-171-002, 20 had MM.43 Four MM patients achieved 
a partial response (PR), 1 of 2 at the 15 mg/m2 dose, 1 of 6 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 1 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 4 NHL and 5 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 2 Phase II studies.
1.4.4. Phase II Experience with Carfilzomib as a Monotherapy
Two Phase II clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 
(N = 46) in relapsed and refractory MM and PX-171-004 (N = 39) in relapsed MM. In both 
studies, patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule. 
In these studies there were 4 cases of suspected or documented TLS prior to institution of the 
prophylaxis guidelines. Since these guidelines were implemented, no further cases of TLS have 
been reported including in > 350 additional patients with relapsed or refractory MM treated in 
ongoing Phase II studies. In both studies, the most common adverse events were fatigue, anemia, 
thrombocytopenia (primarily cyclical), gastrointestinal, and dyspnea. Almost all were Grade 1 or 
Grade 2. There were reported cases of increased in serum creatinine that were primarily 
< Grade 2 and were transient, rapidly reversible, and non-cumulative. A very low rate of 
treatment-emergent peripheral neuropathy, 2.2% Grade 3/4, was observed in PX-171-003-A0 
despite the fact that 78% of patients had Grade 1/2 neuropathy upon study entry.44
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The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these patients that 
entered the study with progressive disease and were refractory to their most recent therapy, often 
including bortezomib and/or an immunomodulatory drug (usually lenalidomide). The median 
time to progression on the PX-171-003-A0 study was 5.1 months with a DOR of 7.4 months 
(mean follow up of 7.6 months).44
A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently been incorporated 
into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical 
benefit of carfilzomib. Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter. The 
study completed enrollment of 266 patients by the end of 2009 and may form the basis for an 
accelerated approval NDA filing in the future. To date, this dosing schedule has been well 
tolerated.43 An independent Safety Oversight Group (SOG) evaluated the safety data from the 40 
of 250 patients to be enrolled on the 20/27 schedules 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 events 
reported to date on PX-171-003-A1.44 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 2 cohorts, with Grade 3 neutropenia in approximately 5% 
without any Grade 4 neutropenia to date.44
In PX-171-004, a first cohort of patients received 20 mg/m2. The subset of patients (N = 54) that 
had not seen bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the 
bortezomib treated patients (N = 33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR).45 
The median TTP was 7.6 and 5.3 months in these 2 groups, respectively. Thus, carfilzomib can 
induce very high levels of response in patients who have not previously been treated with 
bortezomib and, even in bortezomib-treated patients, substantial anti-tumor activity is observed. 
Of note, disease control (PR + MR + SD) was achieved in approximately 65% of patients with 
progressive MM entering the study. Patients on these studies have been treated for > 12 cycles 
with good tolerability and no cumulative toxicity (e.g., bone marrow, severe fatigue, or 
neuropathy) have not been observed.
The protocol was amended to allow patients to increase to 27 mg/m2 in Cycle 2 or later based on 
tolerability, similar to that used in PX-171-003–A1. Further information about the Phase II 
studies is presented in the Investigator’s Brochure.
1.4.5. Experience with Carfilzomib in Combination with Lenalidomide and 
Dexamethasone
PX-171-006 is an ongoing Phase Ib study in patients with relapsed multiple myeloma in which 
carfilzomib is administered in combination with lenalidomide (Revlimid®) and dexamethasone. 
“Low-dose” dexamethasone 40 mg/day is given on Days 1, 8, 15, and 22 in all cases. 
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Carfilzomib is administered IV on Days 1, 2, 8, 9, 15, and 16; lenalidomide is administered PO 
on Days 1 through 21. Enrollment has closed in this study, and no MTD was reached. The 
maximum per protocol doses of carfilzomib (27 mg/m2) with lenalidomide 25 mg and low dose 
dexamethasone are being used.46 After 8 patients tolerated these doses well, an additional 
44 patients were enrolled in an “expansion” cohort at this level, and this regimen is being taken 
into Phase III in study PX-171-009.
To date, 40 patients were treated in Cohorts 1 - 6 and 44 in the Cohort 6 expansion. 
27/32 patients in cohorts 1 - 5 are evaluable for safety and 29/32 for response. Patients were 
heavily pre-treated; 72% received prior BTZ and 87.5% received prior LEN or thalidomide 
(Thal). 47% of patients were refractory to their last therapy (typically lenalidomide + high dose 
dexamethasone; > 84% of patients had a history of neuropathy with 67% BTZ- or Thal-related. 
No treatment emergent fatigue, neuropathy, or thrombotic events ≥ Grade 3 were observed. 
Hematological AEs ≥ Grade 3 (thrombocytopenia [n = 6], anemia [n = 4], and neutropenia 
[n = 6]) were reversible. 4 patients had drug-related SAEs as follows: transient Grade 3 sinus 
bradycardia, Grade 3 upper respiratory tract infection, febrile neutropenia, and Grade 3 diarrhea 
+ Grade 3 urinary infection. ORR and CBR for the 29 evaluable patients are 59% and 72%, 
respectively. Response data is shown in the table below. Initial responses improved with 
continued therapy, (up to 18 cycles). Median duration of response has not been reached (median 
follow-up 5.2 months). No dose-limiting toxicities or deaths attributed to study treatment have 
been observed. Several patients have completed the study (in the lower dose cohorts) after 18 
cycles and are continuing in an extension study. Updated efficacy data are presented in the 
following table:
Table 1.
CRd: Cohorts 1–5 (Carfilzomib: 15 to 20 mg/m2; LEN: 10 to 25 mg)
Response
Relapsed
(n = 16)
Refractory
(n = 13)
Overall
(n = 29)
≥ CR/nCR
5 (31)
1 (8)
6 (21)
≥ VGPR
7 (44)
4 (31)
11 (38)
≥ PR
9 (56)
8 (62)
17 (59)
≥ MR
11 (67)
10 (77)
21 (72)
Together, these results suggest that carfilzomib, lenalidomide, and low-dose dexamethasone 
(CRd) in combination are active and well tolerated and that there are no significant overlapping 
toxicities (in the dose ranges tested). Importantly, lenalidomide-associated neutropenia and 
thrombocytopenia do not appear to be exacerbated by concurrent treatment with carfilzomib, 
even up to 27 mg/m2, suggesting that carfilzomib will combine well with other anti-cancer 
agents.
2. RATIONALE
Current standard salvage chemotherapy regimens (e.g., R-ICE, R-DHAP, etc.) used prior to 
HDC-ASCR in patients with relapsed/refractory DLBCL yield suboptimal outcomes. The ORR 
and CR response rate following salvage therapy with R-ICE or RDHAP is 63% and 38% 
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respectively. Moreover, the 3-year progression-free survival of relapsed/refractory DLBCL 
patients initially treated with R-CHOP and then salvage R-ICE or R-DHAP and HDC-ASCT is 
only 30%. The incorporation of active novel agents into the management of relapsed/refractory 
DLBCL is needed in an attempt to improve clinical outcomes.
A group of Roswell Park investigators has demonstrated that the ubiquitin-proteasome system 
plays an important role in the development of rituximab-chemotherapy resistance in B-cell 
lymphoma. Moreover, targeting the proteasome system with pharmacological inhibitors has 
resulted in significant anti-tumor activity in relapsed/refractory DLBCL. While the combination 
of bortezomib and systemic chemotherapy is currently being studied in patients with 
relapsed/refractory DLBCL, bortezomib is limited by its toxicity profile. Carfilzomib is a more 
potent and better tolerated proteasome inhibitor when compared to bortezomib. The study is 
seeking to determine the maximum tolerable doses of carfilzomib when administered in 
combination with the R-ICE chemotherapy regimen in relapsed/refractory DLBCL patients who 
are ASCT-eligible.
2.1. Dose Rationale
Preliminary data suggest that carfilzomib as a single agent can produce substantial response rates 
in myeloma and B-cell lymphoma subjects across a variety of dosing cohorts. Responses were 
seen over a wide therapeutic window, from 15 mg/m2 to 27 mg/m2. Maximum proteasome 
inhibition was seen at doses 11 mg/m2 and higher in whole blood samples taken 1 hour after the 
first dose. The final analysis of the human pharmacokinetic (PK) data is ongoing but appears to 
be rapid and similar to the results from the animal studies. Carfilzomib is rapidly cleared from 
plasma with an elimination half-life of < 60 minutes at the 20 mg/m2 dose. Large, single arm 
studies of the 27 mg/m2 dose are ongoing and suggest that this dose is very well tolerated with 
patients being treated for > 10 cycles without cumulative toxicities.
By the end of 2009, 269 patients with relapsed and refractory multiple myeloma have been 
enrolled in the PX-171-003-A1 study. The goal of dose escalating to 27 mg/m2 beginning with 
Cycle 2 is to improve ORR, DOR, and TTP. In multiple preclinical studies, the tolerability of 
carfilzomib in rats has been shown to be significantly higher when administered as a 30 minutes 
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 approximately 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 minutes 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 minutes was gastrointestinal bleeding. The reduced toxicity seen with dosing by infusion 
may reflect the reduced Cmax of carfilzomib vs that with bolus dosing.47 Inhibition of the 
pharmacological target of carfilzomib (the chymotrypsin-like activity of the proteasome) was 
equivalent in the bolus and infusion treatment groups.
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In the clinic, the MTD of carfilzomib has not been reached in the multiple myeloma (MM) 
setting, particularly when administered as a 30-minute infusion. 27 mg/m2 of carfilzomib (bolus 
administration over 2 - 10 minutes) is well tolerated in MM patients overall and can be tolerated 
for > 12 cycles in late stage MM patients with substantial comorbidities.
A Phase I dose escalation study (PX-171-007) of single agent carfilzomib administered is 
ongoing and over 65 patients with solid tumors had received therapy in the initial Phase II 
portion of the study at 36 mg/m2 (bolus administration over 2 - 10 minutes). A review of the 
tolerability of 36 mg/m2 carfilzomib in these patients  indicates that this regimen was very well 
tolerated with only one DLT (fatigue) and an overall adverse event profile similar to that seen 
with the 27 mg/m2 carfilzomib experience with bolus dosing (see IB for details). Three patients 
completed > 12 cycles of therapy at 36 mg/m2 with no evidence of cumulative toxicity. There 
were no significant DLTs observed; the majority of discontinuations on the study were due to 
progressive disease. Because of the long-term tolerability carfilzomib, the Phase Ib portion of 
this study was reopened, and a separate arm for multiple myeloma was added.
In the PX-171-007 trial, more recently patients have been treated with carfilzomib given as a 
30-minute infusion in order to potentially minimize Cmax-related infusion events. The protocol 
was amended and does of 20/36 (20 mg/m2 given on Day 1 and Day 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 2 separate cohorts of patients with advanced 
MM and advanced solid tumors; the lower doses were well tolerated. Preliminary tolerability 
information at this dose level (20/56 mg/m2) indicated that it is reasonably well tolerated with 
minimal infusion reactions. In some cases at 20/56 mg/m2, dexamethasone was increased from 
4 mg/dose to 8 mg with the 56 mg/m2 doses in order to reduce fevers and hypotension. As of 
March 20, 2010, 7 patients have received 20/56 mg/m2 and are tolerating it. Patients with 
advanced, refractory MM being treated at 36 mg/m2 and 45 mg/m2 have shown very good 
tolerability (> 6 months in some cases) with documented minimal and partial responses in these 
heavily pretreated patients. These data indicate that carfilzomib 30-minute infusion can be given 
at very high levels, with > 95% inhibition of blood proteasome levels achievable and with (at 
least) acute tolerability. All protocols using ≥ 36 mg/m2 carfilzomib are now administering the 
drug as a 30-minute infusion.
In addition to the above observations, a Phase I study of carfilzomib in patients with relapsed and 
refractory multiple myeloma was reported in abstract form at the 2009 American Society of 
Hematology meeting which demonstrated that carfilzomib can be safely administered to patients 
with substantial renal impairment (CrCL < 30, including patients on dialysis) without dose 
adjustment.48 These data indicate that carfilzomib does not exacerbate underlying renal 
dysfunction, and confirm the “pre-renal” etiology of the BUN/creatinine elevations observed 
with IV bolus carfilzomib.
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3. OBJECTIVES
3.1. Phase I Primary Objectives

To estimate the maximum tolerated dose (MTD) and examine the dose-limiting 
toxicities of carfilzomib when administered in combination with rituximab, ifosfamide, 
carboplatin, and etoposide (C-R-ICE) in patients with relapsed/refractory DLBCL.

To assess the toxicity of dose regimen using the CTEP NCI Common Terminology 
Criteria for Adverse Events (CTCAE Version 4.0).
3.2. Phase Ib Primary Objectives (Expansion cohort)

To evaluate the safety of carfilzomib (given at maximum tolerated dose [MTD] as 
determined in Phase I of this study) in combination with R-ICE salvage therapy in 
relapsed/refractory DLBCL patients.

To achieve an overall response rate (CR and PR) of 70% after 3 cycles of C-R-ICE in 
patients between the ages of 18 to 75 with relapsed/refractory CD20-positive DLBCL 
previously treated with rituximab-based immunochemotherapy (e.g., R-CHOP, R-
EPOCH, R-HyperCVAD, etc.) induction.
3.3. Secondary Objectives

To determine the feasibility of successful mobilization of autologous stem cells 
(i.e., minimum of 2 x 106 CD34+ cells/kg should be collected) to be used for ASCT (if 
applicable).

To determine toxicities associated with C-R-ICE salvage therapy.

To determine the TTP, PFS, and OS followed by ASCT (if applicable); Disease-free 
survival in CR patients.

To 
determine 
the 
pharmacokinetics/pharmacodynamics 
relationship 
between 
carfilzomib’s degree of proteasome inhibition and response rate along with the time 
course of thrombocytopenia.

To 
study 
differences 
in 
clinical 
outcomes 
between 
GCB 
and 
non-GCB 
relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE.
Correlative translational research studies to include: phenotypic/genotypic analysis and 
functional activity (i.e., ADCC and CMC) of patient’s peripheral blood mononuclear "effector" 
cells (PBMC), as well as ex vivo analysis of sensitivity of primary tumor cells to various 
combinations of carfilzomib versus Bortezomib +/- rituximab;, enzymatic assay for 
chymotrypsin-like activity to determine the degree of proteasome inhibition in primary DLBCL 
patient samples and patient PBMC specimens; explorative analysis to identify potential factors 
predictive of response to therapy will be performed (as part of an NIH-supported R01 grant: R01 
CA136907-0A1; PI: Francisco J. Hernandez-Ilizaliturri, MD).
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4. METHODOLOGY
4.1. Study Design
This is an open-label, non-randomized, multicenter, dose-escalation Phase I, followed by 
Phase Ib expansion study of carfilzomib in combination with R-ICE regimen in 
relapsed/refractory DLBCL patients. Based on the results of the Phase I portion of the study, the 
Phase Ib dose will be at Dose Level 6. The study schema is depicted in Figure 6.
Figure 6.
Treatment Plan Schema
Subjects will be treated on an inpatient and outpatient basis. All subjects will meet the inclusion 
and exclusion criteria summarized in Section 5.1 and Section 5.2 prior to enrollment in this 
study.
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4.2. Target Accrual and Study Duration
A maximum of 21 patients for Phase I and 9 patients for the Phase Ib expansion part of this trial 
will be enrolled at Roswell Park and Network Sites (For Phase Ib only). The number of subjects 
required is a function of a currently unknown dose-toxicity relationship. Accrual is expected to 
take up to 10 years.
5. SUBJECT SELECTION
5.1. Inclusion Criteria
To be included in this study, subjects must meet the following criteria:
5.1.1
Disease Specific

Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell 
lymphoma.  Network sites must submit slides to Roswell Park for Central Review and 
confirmation.

Ann Arbor Stage I – Stage IV DLBCL at the time of relapsed/refractory disease to be 
eligible.

Measurable or assessable disease is required. Measurable tumor size (at least one node 
measuring 2.25 cm2 in bidimensional measurement) per CT scan, other radiological 
study, and/or physical exam.
5.1.2
Prior Treatment

Patients must have received at least 1 prior rituximab-based immunochemotherapy 
(e.g., R-CHOP, R-EPOCH, etc.).

≥ 2 weeks since major surgery.

Patients must not have any significant toxicity associated with prior surgery, radiation 
therapy, chemotherapy, or immunotherapy, per PI discretion 
5.1.3
Demographic

Age ≥ 18 years and < 75 years of age.

Life expectancy ≥ 3 months.

Karnofsky Score (KS) ≥50 (Appendix B).
5.1.4
Laboratory

Adequate hepatic function, with serum ALT/AST ≤ 3.5 times the upper limit of normal 
in the absence of a history of Gilbert's disease (or pattern consistent with Gilbert’s), 
within 14 days prior to starting therapy.
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
Adequate bone marrow reserve (If patient has cytopenias due to bone marrow 
involvement, these requirements are not applicable):
o
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to starting 
therapy.
o
Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to starting therapy (subjects 
may be receiving red blood cell [RBC] transfusions in accordance with 
institutional guidelines).
o
Platelet count ≥ 50 × 109/L (≥ 20 × 109/L if lymphoma involvement in the pre-
treatment bone marrow is found) within 14 days prior to starting therapy 

Patients must have a serum creatinine of ≤ 1.5 mg/dL; if creatinine > 1.5 mg/dL 
creatinine clearance must be > 60 mL/min within 7 days prior to treatment either 
measured or calculated using a standard Cockcroft and Gault formula. Refer to 
Appendix C.
5.1.5
Medical/Ethical

Written informed consent in accordance with federal, local, and institutional guidelines. 

Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and 
to practice contraception. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately.

Male subjects must agree to practice contraception.

No known hypersensitivity to murine products. 

Patients must have normal baseline cardiac function based upon echocardiogram or 
gated blood pool scan (MUGA) with an ejection fraction ≥ 50%.

Patients who test positive for Hepatitis C Antibody are eligible provided all of the 
following 
criteria 
are 
met: 
a) bilirubin 
≤ 2 x upper 
limit 
of 
normal; 
b) 
ALT/AST ≤ 3 x upper limit of normal; and c) clinical evaluation to rule out cirrhosis.

Specific guidelines will be follow regarding inclusion of relapsed/refractory DLBCL 
based on Hepatitis B serological testing as follow:
o
HBsAg negative, HBcAb negative, HBsAb positive patients are eligible.
o
Patients who test positive for HBsAg are ineligible (regardless of other 
Hepatitis B serologies).
o
Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb 
status) should have a HBV DNA testing done and protocol eligibility 
determined as follow:

If HBV DNA is positive, the subject will be excluded from the study.
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
If HBV DNA is negative, the subject may be included but must undergo 
at least every 2 months HBV DNA PCR testing from the start of 
treatment throughout the duration the treatment course. 
5.2. Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
5.3. Exclusion Criteria
Subjects will be excluded from this study for the following:

Patients with NHL other than DLBCL; including “transformed” DLBCL.

Known to be seropositive for HIV. An HIV test is not required for entry on this 
protocol, but is required if the patient is perceived to be at risk.

Positive serology for HBV defined as a positive test for HBsAg. In addition, if negative 
for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be 
performed and if positive the subject will be excluded.

Patients with symptomatic brain involvement.

Peripheral neuropathy of Grade 2 or greater severity as defined by the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0. Patients with Grade 2 or higher (NCI-CTC) neuropathy.

Myocardial infarct within 6 months before enrollment, New York Heart Association 
(NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled 
ventricular 
arrhythmias, 
clinically 
significant 
pericardial 
disease, 
or 
electrocardiographic evidence of acute ischemia.

Uncontrolled intercurrent illness including, but not limited to, active infection, poorly 
controlled hypertension, diabetes mellitus or other serious medical or psychiatric 
conditions that could interfere with adherence to or completion of this study.

Pregnant or breastfeeding.

Patient has received other investigational drugs within 4 weeks before enrollment.

Chemotherapy within3 weeks of the first scheduled study treatment.

Less than 2-year disease free from another primary malignancy (other than squamous 
or basal cell carcinoma of the skin, “in-situ” carcinoma of the cervix or breast, 
superficial bladder carcinoma, or previously treated localized prostate cancer with 
normal PSA levels). Patients are not considered to have a “currently active” 
malignancy if they have completed anti-cancer therapy, are considered by their 
physician to be at less than 30% risk of relapse and at least 2 years have lapsed.

Major surgery, other than diagnostic surgery, within 2 weeks.
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
Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize 
carfilzomib).

Medical condition requiring chronic use of high dose systemic corticosteroids 
(i.e., doses of prednisone higher than 10 mg/day or equivalent).

Prior HDC-ASCT.

Active CNS disease defined as symptomatic meningeal lymphoma or known CNS 
parenchymal lymphoma. A lumbar puncture demonstrating DLBCL at the time of 
registration to this study is not exclusion for study enrollment.
6. DRUG INFORMATION
6.1. Carfilzomib (Investigational Agent)
Generic Name: Carfilzomib is the generic name; formerly referred to as PR-171.
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.
Molecular Formula: C40H57N5O7
Molecular Weight: 719.9
Amgen, Inc. will supply non-commercial carfilzomib to the investigator. Carfilzomib for 
injection (formerly referred to as PR-171 for injection) is supplied as a lyophilized parenteral 
drug product in 45 mg and 60 mg single-use vials. Prior to administration, the lyophilized 
product is aseptically reconstituted with sterile water for injection. Upon reconstitution, 
carfilzomib for injection consists of 2 mg/mL carfilzomib, 100 mg/mL sulfob tylether beta-
cyclodextrin (SBE-β-CD), and 1.9 mg/mL citrate buffer (pH 3 to 4).
Preparation: Remove the vial from the refrigerator just prior to use. Aseptically reconstitute 
each vial by slowly injecting 29 mL of sterile water for injection, 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 the solution to rest in the vial for about 2 to 5 minutes, 
until foaming subsides. The reconstituted solution contains carfilzomib 2 mg/mL. After 
reconstitution, carfilzomib is ready for IV administration. When administering in an IV bag, 
withdraw the calculated dose from the vial and dilute into dextrose 5% injection 50 mL 
D5W bag. The reconstituted product should be a clear, colorless solution. If any discoloration or 
particulate matter is observed, do not use the reconstituted product.
6.1.1. Drug Shipment
Carfilzomib will be provided by Amgen, Inc. The site will document the date of receipt and 
condition of the shipment. The investigational pharmacist or designee will retain drug-shipment 
records.
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6.1.2. Drug Preparation and Administration
Carfilzomib for injection is supplied as a lyophilized parenteral product in single-use vials. The 
lyophilized product is reconstituted with water for injection to a final carfilzomib concentration 
of 2 mg/mL prior to administration. The dose will be calculated using the subject’s actual BSA at 
baseline. Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA.
IV hydration will be given immediately prior to carfilzomib during Cycle 1. This will consist of 
250 mL to 500 mL normal saline or other appropriate IV fluid. If lactate dehydrogenase (LDH) 
or uric acid is elevated (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.
If the subject has a dedicated line for carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration.
Carfilzomib will be given as an IV infusion over approximately 10 minutes. For doses 
> 27 mg/m2, carfilzomib should be infused over 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) will be given. Subjects 
should be monitored periodically during this period for evidence of fluid overload.
6.1.3. Storage and Stability
Carfilzomib for injection is stored refrigerated at 2°C to 8°C. After addition of the appropriate 
amount of water for injection and vigorous mixing, the solution is administered as an IV 
infusion. Please note: the use of closed-system drug-transfer devices, where multiple stopper 
punctures in close proximity to one another can occur, is not recommended as it could result in 
coring.
The reconstituted solution in its original vial can be stored in a refrigerator controlled at 2°C to 
8°C (recommended), or at room temperature (15°C to 30°C) until use; and the reconstituted 
solution should not be frozen. Reconstituted carfilzomib for injection is a clear, colorless to 
slightly yellow solution, and is essentially free of visible particulates.
Parenteral drug products should be visually inspected for particulate matter and discoloration 
prior to administration, whenever solution and container permit. If particulate matter or 
discoloration is observed, the reconstituted product should not be used.
6.1.4. Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Amgen, Inc., exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
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Records of product lot numbers and dates received will be entered on a product accountability 
form. It is the Investigator’s responsibility to ensure that an accurate record of investigational 
drug issued and returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices at the site after 
properly accounting for the dispensing. Partially used vials of study drug will not be re-used for 
other subjects. Expired product and/or unused vials will be inventoried by the study monitor.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
6.2. Rituximab (Rituxan®)
Rituximab is a chimeric monoclonal antibody. Rituximab binds to the CD20 antigen expressed 
on benign and malignant B-cells and causes cell death by complement mediated lysis, induction 
of apoptosis and by antibody dependent cellular cytotoxicity (ADCC).
Formulation: Rituximab is a genetically engineered, chimeric, murine/human monoclonal 
antibody directed against the CD20 antigen found on the surface of normal and malignant pre-B 
and mature B cells. The antibody is an IgG1 κ immunoglobulin containing murine light-and 
heavy-chain variable region sequences and human constant region sequences. Rituximab is 
composed of two heavy chains of 451 amino acids and 2 light chains of 213 amino acids (based 
on cDNA analysis) and has an approximate molecular mass of 145 kD. Rituximab has a binding 
affinity for the CD20 antigen of approximately 8nM. Rituximab is supplied as 100 mg and 
500 mg sterile, preservative-free, single-use vials.
Supplier: Commercially available and will not be provided for this study.
Preparation: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Do not 
infuse rituximab concomitantly with another IV solution or other IV medications. The 
appropriate dose is withdrawn and diluted to a final concentration of 1 - 4 mg/mL in either 0.9% 
sodium chloride or 5% dextrose solution. The solution is then stable at 2° to 8°C for 24 hours 
and at room temperature for an additional 12 hours.
Storage: Vials can be stored at 2˚C to 8˚C. They should be protected from sunlight.
Administration: The first infusion should be administered at an initial rate of 50 mg/hr. If 
hypersensitivity or infusion-related events do not occur, the rate may be increased by 50 mg/hr 
every 30 minutes up to a maximum of 400 mg/hr. Subsequent infusions may be started at 
100 mg/hr and the rate increased by 100 mg/hr at every 30 minutes to a maximum of 400 mg/hr, 
as tolerated. Rituximab may also be infused per institutional guidelines at the discretion of the 
PI.   Patients will be premedicated with acetaminophen 650-mg po and diphenhydramine 50 mg 
IV 30 minutes prior to beginning the rituximab infusion. For severe reactions, the infusion will 
be stopped and can be resumed at 50% of the prior rate once the reactions are treated and 
symptoms resolved.
Toxicity:

Common: Fever, chills, fatigue, headache; less common: nausea, vomiting, rhinitis, 
pruritus, hypotension; rare: neutropenia, thrombocytopenia, asthenia, arthritis, vasculitis, 
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lupus-like syndrome, pleuritis, bronchiolitis obliterans, uveitis, optic neuritis, and skin 
reactions such as toxic epidermal necrolysis and pemphigus.

Fatal Infusion Reactions: Severe and fatal cardiopulmonary events, including 
angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, and cardiogenic shock, have been reported. These severe 
reactions typically occurred during the first infusion with time to onset of 
30 - 120 minutes.

Cardiac Events: Patients with preexisting cardiac conditions, including arrhythmia and 
angina, have had recurrences of these cardiac events during rituximab infusions.

Tumor Lysis Syndrome (TLS): TLS has been reported and is characterized in patients 
with a high number of circulating malignant cells (≥ 25,000 µL) by rapid reduction in 
tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and 
hyperphosphatemia.

Renal Events: Rituximab has been associated with severe renal toxicity including acute 
renal failure requiring dialysis, and in some cases has led to death. Renal toxicity has 
occurred in patients with high numbers of circulating malignant cells (≥ 25,000/mm2) or 
high tumor burden who experience tumor lysis syndrome and in patients administered 
concomitant cisplatin.

Mucocutaneous Reactions: Severe bullous skin reactions, including fatal cases of toxic 
epidermal necrolysis and paraneoplastic pemphigus, have been reported in patients 
treated with rituximab. The onset of reaction has varied from 1 to 13 weeks following 
rituximab exposure.

Hematologic Events: In clinical trials, Grade 3 and Grade 4 cytopenias were reported in 
48% of patients treated with RITUXIMAB; these include: lymphopenia (40%), 
neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The 
median duration of lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia 
was 13 days (range, 2 to 116 days). A single occurrence of transient aplastic anemia 
(pure red cell aplasia) and two occurrences of hemolytic anemia following 
RITUXIMAB therapy were reported.
In addition, there have been a limited number of post-marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 
40 days after the last dose of RITUXIMAB) in patients with hematologic malignancies. 
In reported cases of late onset neutropenia (NCI-CTC Grade 3 and Grade 4), the median 
duration of neutropenia was 10 days (range 3 to 148 days). Documented resolution of 
the neutropenia was described in approximately one-half of the reported cases; of those 
with documented recovery, approximately half received growth factor support. In the 
remaining cases, information on resolution was not provided. More than half of the 
reported cases of delayed onset neutropenia occurred in patients who had undergone 
prior autologous bone marrow transplantation. In an adequately designed, controlled, 
clinical trial, the reported incidence of NCI-CTC, Grade 3 and Grade 4 neutropenia was 
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higher in patients receiving RITUXIMAB in combination with fludarabine as compared 
to those receiving fludarabine alone (76% [39/51] vs. 39% [21/53]).

Infectious Events: Rituxan induced B-cell depletion in 70% to 80% of patients with 
NHL and was associated with decreased serum immunoglobulins in a minority of 
patients; the lymphopenia lasted a median of 14 days (range, 1 - 588 days). Infectious 
events occurred in 31% of patients: 19% of patients had bacterial infections, 10% had 
viral infections, 1% had fungal infections, and 6% were unknown infections. Serious 
infectious events (Grade 3 or Grade 4), including sepsis, occurred in 2% of patients.

Other Serious Viral Infections: The following additional serious viral infections, either 
new, reactivated or exacerbated, have been identified in clinical studies or postmarketing 
reports. The majority of patients received Rituxan in combination with chemotherapy or 
as part of a hematopoietic stem cell transplant. These viral infections included JC virus 
(progressive multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex 
virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some 
cases, the viral infections occurred up to one year following discontinuation of Rituxan 
and have resulted in death.
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported in some patients with hematologic malignancies treated with 
rituximab. The majority of patients received rituximab in combination with 
chemotherapy. The median time to the diagnosis of hepatitis was approximately 
4 months after the initiation of rituximab and approximately one month after the last 
dose.
PML is a rare and demyelinating disease of the brain caused by infection with the JC 
virus that usually leads to death or severe disability. JC virus infection resulting in PML 
and death has been reported rarely in patients with hematologic malignancies receiving 
rituximab. The majority of these patients had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Cases of PML resulting 
in death have also been reported in patients with systemic lupus erythematosus (SLE) 
treated with rituximab. These patients with SLE had longstanding disease, history of 
prior immunosuppressant therapy, and were diagnosed with PML within 12 months of 
their last infusion of rituximab.
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should 
be considered as clinically indicated. In patients who develop PML, rituximab should be 
discontinued and reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered.

Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and 
perforation, in some cases leading to death, were observed in patients receiving Rituxan 
in combination with chemotherapy for DLBCL. In post-marketing reports, which 
include both patients with low-grade or follicular NHL and DLBCL, the mean time to 
onset of symptoms was 6 days (range 1 - 77) in patients with documented gastro-
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intestinal perforation. Complaints of abdominal pain, especially early in the course of 
treatment, should prompt a thorough diagnostic evaluation and appropriate treatment.

Additional Safety Signals: The following serious adverse events have been reported to 
occur in patients following completion of rituximab infusions: arthritis, disorders of 
blood vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders 
(uveitis and optic neuritis), lung disorders including pleuritis and scarring of the lung 
(bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac failure.
6.3. Ifosfamide (Ifex®)
Supplier: Commercially available and will not be provided for this study.
Mechanism of Action: Ifosfamide is activated in the liver by microsomal enzymes and the 
subsequent ifosfamide mustard causes direct alkylation of DNA.
Formulation: Ifosfamide is supplied in single dose vials for constitution and administration by 
IV infusion. Each contains 1 gram or 3 grams of sterile ifosfamide.
Storage: The dry powder may be stored at room temperature.
Preparation: Injections are prepared by adding sterile water to the vial. The 1-gram dose is 
mixed with 20 mL and the 3-gram dose with 60 mL for a final concentration of 50 mg/mL.
Toxicity: Alopecia, nausea and vomiting, hematuria, gross hematuria, CNS toxicity, infection, 
renal dysfunction, allergic reactions and at high doses, cardiotoxicity.
6.4. Carboplatin (Paraplatin®)
Supplier: Commercially available and will not be provided for this study.
Mechanism of Action: Carboplatin binds to DNA and causes cross-linking with a non-cell cycle 
dependent tumor cell lysis. It inhibits DNA synthesis by altering the template via the formation 
of intrastrand cross-links.
Formulation: Carboplatin is available in 10 mg/mL solution in 50, 150, 450, 600 mg vials.
Storage: Unopened vials are stable for the life indicated on the insert if protected from light.
Preparation: Per Institute standard.
Toxicity: Myelosuppression, nausea, vomiting, peripheral neuropathy, ototoxicity, hepatic 
toxicity, electrolyte abnormalities, hypomagnesemia, hypocalcemia, and allergic reactions.
6.5. VP-16 (etoposide, VePesid®)
Supplier: Commercially available and will not be provided for this study.
Mechanism of Action: Induction of an irreversible blockade of cells in the premitotic phases of 
the cell cycle leading to accumulation of cells in late S or G2 phases. This mechanism is 
secondary to interference of the scissors-reunion reaction of the enzyme topoisomerase II.
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Formulation: VP-16 injection is available in 100-mg (5-mL) sterile multiple-dose vials. The pH 
is 3-4. Each mL contains 20-mg etoposide, 2-mg citric acid, 30-mg benzyl alcohol, 80-mg 
polysorbate 80, 650-mg polyethylene glycol 300 and 30.5% alcohol.
Storage: Unopened vials of VP-16 are stable for 24 months at room temperature. Vials are 
diluted as recommended to a concentration of 0.2 mg/mL or 0.4 mg/mL and are stable for 
96 hours and 48 hours respectively, at room temperature under normal light in both plastic and 
glass containers.
Preparation: As per Institute standard intravenous infusion over2 hours.
Toxicity: Leukopenia, thrombocytopenia, alopecia, nausea, vomiting, headache, fever, 
hypotension, anorexia, and allergic reactions.
6.6. Mesna (Mesnex®)
Supplier: Commercially available and will not be provided for this study.
Mechanism of Action: Mesna was developed as a prophylactic agent to inhibit hemorrhagic 
cystitis induced by ifosfamide and is analogous to the cysteine-cystine system; mesna is rapidly 
metabolized to mesna disulfide and acts as a free radical scavenger.
Formulation: Mesna is a sterile preservative free aqueous solution of clear, colorless appearance 
in clear glass vials for IV administration. Mesna injection contains 100 mg/mL Mesna, 
0.25 mg/mL acetate disodium, and sodium hydroxide to maintain pH 6.5-8.5.
Storage: Diluted solutions are chemically and physically stable for 24 hours at room 
temperature. It is recommended that solutions be refrigerated and used within 6 hours.
Preparation: For IV administration the drug is diluted in sterile solution to make a final 
concentration as per Institute standard.
Toxicity: Nausea, vomiting, diarrhea
6.7. Neulasta® (Pegfilgrastim, G-CSF, Neupogen, Filgrastim-sndz and biosimilars)
Supplier: Commercially available and will not be provided for this study.
Mechanism of action: Pegfilgrastim is a human protein, which is involved in the promotion of 
the growth and maturation of granulocytic progenitors and the stimulation of functional activity. 
It is a covalent conjugate of recombinant methionyl human G-CSF (Filgrastim) and 
monomethoxypolyethylene glycol
Formulation: Available as a pegylated recombinant DNA product supplied as 0.6 mL prefilled 
syringe containing clear colorless sterile protein solution.
Storage: It can be stored at 2°C - 8°C and is stable for at least 30 months.
Toxicity: Bone pain, exacerbation of preexisting autoimmune disorders, transient and reversible 
changes in alkaline phosphatase, uric acid and LDH, nausea, fatigue, alopecia, diarrhea, 
vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, 
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myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, 
dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever
7. TREATMENT PLAN
7.1. Preparation and Administration
Treatment will be administered in an outpatient and inpatient basis. Appropriate dose 
modifications are described in Section 7.4. No other investigational or commercial drugs or 
therapies other that those described below may be administered with the intent to treat the 
patient.
7.2. General Guidelines
Prior to initiating therapy, placement of mediport or a multi-lumen indwelling intravenous 
catheter is required. All patients will be given allopurinol 300 mg/day PO starting at least one 
day prior to Treatment 1 (Day 0) and then 300 mg/day PO for Day 1 through Day 10 of the first 
cycle. Allopurinol length of therapy may be changed at discretion of the investigator (e.g., the 
presence of tumor lysis syndrome). If patient cannot receive Allopurinol for any reason, a 
different drug may be used for the prevention of tumor lysis syndrome at the discretion of the PI. 
7.3. Criteria for Retreatment
The following laboratory parameters must be met before starting Cycles 2 and Cycle 3:

Begin subsequent cycles no sooner than Day 22 but no later than Day 36 (If a subject is 
delayed beyond Day 36, contact the Principle Investigator or designee from Roswell 
Park)

ANC ≥ 1000/μL without G-CSF

Platelets ≥ 50,000/μL

Serum creatinine ≤ 2.0 mg/dL

Total bilirubin ≤ 2.0 mg/dL (unless due to disease involvement with DLBCL or 
Gilbert’s syndrome). 
Serum chemistry values, including creatinine, must be obtained (within 24 hours) and reviewed 
prior to each dose of carfilzomib. Carfilzomib must be held for subjects with a 
CrCL < 30 mL/min at any time during study participation. Subjects with active or suspected 
infection of any kind that required systemic treatment should not be dosed with carfilzomib until 
the infection has resolved and if being treated with anti-infective, the course of antibiotics has 
been completed. 
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7.4. Dose Modifications
7.4.1. Definition of Dose-Limiting Toxicity
For this protocol, a DLT will be defined by the occurrence of the following toxicity, related to 
study drug, within cycle 1 of treatment.  Patients that experience a DLT will be continued on 
treatment, per PI discretion, at one level of dose reduction.  

Any ≥ Grade 3 non-hematologic adverse event attributed (definitely, probably, or 
possibly) during C-R-ICE therapy and meeting the following criteria and for 
hematologic toxicity see Section 0.
7.4.1.1
Non-Hematologic Toxicity
For non-hematologic toxicities, DLT will be defined as any CTCAE v4.0 Grade 3 or greater 
toxicity, except for:

Grade 3 or Grade 4 nausea and vomiting lasting less than 72 hours after the last dose of 
chemotherapy with use of standard anti-emetic therapy.

Grade 3 non-hematologic laboratory abnormalities that resolve to Grade 1 or baseline 
(if the patient entered the study with existing toxicity) within 14 days.

In the event that Grade 3 or Grade 4 adverse events are obviously unrelated to study 
drug and thus not DLT, the principal investigator will determine whether dose 
escalation or cohort expansion is required.
7.4.1.2
Hematologic Toxicity
DLT for hematologic toxicity, using CTCAE v4.0, will be defined as:

Any hematologic toxicity that causes a dose-delay of > 2 weeks (i.e., > Day + 36) of 
the intended next dose will also be considered at DLT.
7.4.1.3
Criteria for Dose Escalation
Dose escalation will proceed within each cohort according to the following scheme in Table 2.
Patients who do not have a DLT and who do not complete Cycle 1 of treatment or more if 
appropriate will be replaced in the study.
Management and dose modifications associated with the above AEs are outlined in Section 7.4.
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Table 2.
Dose Escalation Scheme
Number of Patients with a 
Dose-Limiting Toxicity at 
a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter 3 patients at the next dose level.  If there are no dose-limiting toxicities found 
after completing all dose levels, an additional 3 patients will be enrolled at the 
maximally administered dose.  If this dose level is determined to be a safe dose 
(≤1out of 6 dose-limiting toxicities), it will then be used in the expansion phase.
≥ 2
Dose escalation will be stopped. This dose level will be declared the maximally 
administered dose (highest dose administered). Three additional patients will be 
entered at the next lowest dose level if only 3 patients were treated previously at that 
dose.
1 out of 3
Enter at least 3 more patients at this dose level. If 0 of these 3 patients experience a 
dose-limiting toxicity, proceed to the next dose level. If 1 or more of this group 
suffer a dose-limiting toxicity, then dose escalation is stopped, and this dose is 
declared the maximally administered dose. Three additional patients will be entered 
at the next lowest dose level if only 3 patients were treated previously at that dose.
≤ 1 out of 6 at highest dose 
level  
This is generally the recommended Phase Ib dose. At least 6 patients must be entered 
at the recommended Phase Ib dose.
7.4.2
Treatment Delay Thrombocytopenia and Neutropenia
Carfilzomib is associated with thrombocytopenia. The thrombocytopenia pattern is cyclic with 
nadirs following the second dose each week and typically recovering prior to the initiation of the 
next treatment, similar to that observed with bortezomib. The severity of thrombocytopenia is 
related to the pretreatment platelet counts. Transfusions may be considered. The incidence of 
significant bleeding is < 5%. Platelet counts should be monitored at a minimum prior to each 
cycle of treatment and more frequently if baseline counts are > Grade 1. Severe neutropenia has 
been reported and may occur during treatment but is uncommon. Carfilzomib should be 
administered with caution to patients with ANC < 1000/mm3 and the drug should be held for 
ANC < 500/mm3. Febrile neutropenia is rare and carfilzomib should be held until the AE has 
resolved. In addition, patients with active infections or who are completing treatment for 
systemic infections should not receive carfilzomib until the infection has resolved. 
            7.4.2.1   Cardiac Disorders
Acute development or exacerbation of congestive heart failure and new onset of decreased left 
ventricular function have been reported, including reports in patients with no risk factors for 
decreased left ventricular ejection fraction. The incidence of heart failure events (acute 
pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary 
edema) is less than 8%. Patients with risk factors for or evidence of existing heart disease should 
be closely monitored throughout their treatment with carfilzomib. Carfilzomib should be held if 
CHF develops or appears to be exacerbated by treatment and may be resumed once the 
symptoms resolve. Consideration should be given to a reduction in dosage with gradual increase 
to full dose only if well tolerated. Ischemic heart disease and arrhythmias have also occurred. 
Dyspnea may occur in association with cardiac disorders. Patients who experience dyspnea 
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should be evaluated for the presence of associated conditions and management should be tailored 
to the appropriate treatment for the underlying disorder. The effect of carfilzomib on cardiac 
repolarization using the QTcF interval and the PK-PDn relationships shows no clear signal of 
any dose related effect. Serious cardiac reactions and even death may occur following the 
administration of carfilzomib.
7.4.2.2
Gastrointestinal Events
Carfilzomib 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. Routine premedication with antinausea or antidiarrheal agents is not 
required. Carfilzomib should be held if these events persist after symptomatic treatment, are 
Grade 3 or greater and determined by the Investigator to be related to the Carfilzomib.
7.4.2.3
Hematologic Toxicity
Typically, there is no dosages adjustment related to hematological toxicity with the R-ICE 
regimen as described in this study. C-R-ICE will be planned to be given on a q 21 - 28 day cycle. 
C-R-ICE will be postponed until neutrophil counts reach ≥1 x 109/L and platelet 
counts ≥50 x 109/L.
7.4.2.4
Tumor Lysis Syndrome
Suspected or documented TLS or multiorgan failures have been observed in some patients 
treated with carfilzomib in the Phase II studies prior to the institution of TLS prophylaxis 
guidelines. Patients with high tumor burden or compromised renal function may be at elevated 
risk, and should be closely monitored, and uric acid levels normalized prior to initiation of 
treatment, if appropriate. Adequate oral and IV hydration and premedication with 
dexamethasone 4 mg PO or IV are required prior to initiation of therapy with carfilzomib, at 
least in Cycle 1. If TLS occurs, carfilzomib should be held until the event has resolved. 
Prophylaxis should be reinstituted and the patient should be monitored carefully. Additional 
safety measures are described in detail in the protocols.
7.4.2.5
Infusion Reactions and Adverse Events Experienced within a Day of 
Dosing
True infusion reactions have been reported but are rare. Should an infusion reaction occur, 
treatment with glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators, and 
acetaminophen should be available for immediate use and instituted as medically indicated. 
Adverse events have been observed with carfilzomib that include fever, chills, dyspnea, and/or 
rigors occurring in the evening following the first day of infusion during the first cycle of 
therapy, which may be the clinical sequelae of rapid tumor lysis or cytokine release; this has 
been associated with an increase of creatinine on the second day. Cytokine release has been 
documented in animals treated with carfilzomib. Management guidelines were instituted which 
included premedication with dexamethasone (4 mg PO on Days 1, 2, 8, and 9 or equivalent) and 
starting patients at a 20 mg/m2 dose for a minimum of 2 days before dose escalation. These 
management guidelines and stepped-up dosing were generally effective at alleviating AEs 
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experienced within the first day of dosing in further studies. If fevers or chills persist after the 
first cycle, continued premedication with dexamethasone is recommended.
7.4.2.6
Renal Impairment
Grade 1 and Grade 2 reversible increases in creatinine were reported. Renal failure has been 
reported less frequently. It is not known if there is a clear association between renal failure and 
carfilzomib. Many cases of renal failure were confounded by documented or suspected TLS, 
sepsis/infections, light-chain disease, and disease progression. Renal function should be 
monitored prior to each dose in Cycle 1 and Cycle 2 and in patients experiencing increases in 
creatinine ≥ Grade 2. Carfilzomib has been characterized in patients with CrCL < 15 mL/min or 
creatinine ≥ 2.5 mg/dL. Studies in patients with very severe renal dysfunction and those 
receiving hemodialysis demonstrated there were no major differences in the observed safety 
findings among patients with renal dysfunction compared to those with normal renal function.
7.4.2.7
Hepatic Impairment
Three cases of hepatic failure (including 2 cases that were precursors to the patients’ death due to 
end-stage progression of their MM) and 1 case of veno-occlusive has been reported with the use 
of carfilzomib (refer to Carfilzomib Investigator’s Brochure). Non-serious and serious 
(Grade 1 - 3) transaminitis have been reported infrequently. Carfilzomib dosage should be held 
in patients who experience a liver abnormality ≥ Grade 3. If the event resolves within 2 weeks, 
carfilzomib may be restarted at a reduced dose and monitored carefully. The use of carfilzomib 
has not been characterized in patients with hepatic impairment.
7.4.2.8
Other Conditions Delaying Treatment
If posterior reversible encephalopathy syndrome (PRES) is suspected, carfilzomib should be 
held.  The patient should then be evaluated with MRI and for onset of visual or neurological 
symptoms suggestive of PRES.  If PRES is confirmed, carfilzomib should be permanently 
discontinued.  If a diagnosis of PRES is excluded, carfilzomib may be restarted per the discretion 
of the PI.
Carfilzomib should be held if thrombotic microangiopathy (TMA) is suspected and patient 
should be managed per institutional standard of care, which may include plasma exchange, if 
appropriate.  If TMA is confirmed, carfilzomib should be permanently discontinued.  If TMA is 
ruled out, then carfilzomib may be restarted per the discretion of the PI.
If the patient experiences a hypertensive crisis, carfilzomib should be held until the resolution of 
the event to the patient’s baseline.  Carfilzomib may then be restarted at 1 dose decrement.
7.4.2.9
Mechanisms of Action
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that binds selectively and 
irreversibly to the N-terminal threonine containing active sites of the 20S proteasome and 
displays little to no activity against other classes of proteases. In vitro, carfilzomib has been 
shown to have antiproliferative and proapoptotic activities across a range of solid and 
hematologic tumor cells, including cells that are resistant to bortezomib. Carfilzomib does not 
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induce neurite degeneration in differentiated neuronal cell lines sensitive to an equimolar 
concentration of bortezomib. In vivo, carfilzomib results in rapid and sustained inhibition of 
proteasome activity in blood and tissues and delays tumor growth in MM, hematologic, and solid 
tumor animal models, including bortezomib-insensitive human tumor xenograft models.
8
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE
8.1
Safety Considerations
Based upon the experience in the Phase I and Phase II clinical studies with carfilzomib, 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 sequelae of rapid tumor lysis 
and/or cytokine release.

Should a “first dose” effect occur at any point during Cycle 1 or Cycle 2, treatment 
with high dose glucocorticoids (e.g., methylprednisolone 50 mg - 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 4 mg PO/IV will be administered prior to all carfilzomib doses.

Acyclovir or similar should be given to all subjects with a history of herpes simplex or 
zoster, per institutional prophylaxis guidelines, unless contraindicated.

CrCL changes are mostly transient, reversible, and non-cumulative. All subjects should 
be well hydrated. Clinically significant electrolyte abnormalities should be corrected 
prior to dosing with carfilzomib. Renal function must be monitored closely during 
treatment with carfilzomib. Serum chemistry values, including creatinine, must be 
obtained (within 24 hours) and reviewed prior to each dose of carfilzomib. Carfilzomib 
must be held for subjects with a CrCL < 30 mL/min at any time during study 
participation.

Subjects with active or suspected infection of any kind that required systemic treatment 
should not be dosed with carfilzomib until the infection has resolved and if being 
treated with anti-infective, the course of antibiotics has been completed. 

Thrombocytopenia has been transient and typically resolves during the week between 
treatments. For platelet counts ≤ 50,000/mm3, carfilzomib dosing must be held before 
proceeding to the next cycle of C-R-ICE.

Subjects should have anemia corrected in accordance with the Institutional guidelines.

Carfilzomib 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.
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8.2
Guidelines for Monitoring, Prophylaxis, and Treatment of Tumor Lysis Syndrome

Tumor Lysis Syndrome (TLS), which may be associated with multiorgan failure, has 
been observed in treatment Cycle 1 and Cycle 2 in some patients with MM who have 
been treated with carfilzomib.
The following safety measures are mandatory for all subjects:

In addition, subjects with high tumor burden or rapidly progressing DLBCL or 
compromised renal function (CrCL < 50 mL/min) should be considered to be at 
particularly high risk.
Hydration and Fluid Monitoring

Oral hydration: All subjects must be well hydrated (i.e., volume replete). Begin oral 
hydration equal to approximately 30 mL/kg/day (approximately 6 – 8 cups of liquid per 
day), starting 48 hours prior to the planned first dose of carfilzomib. Compliance must 
be reviewed with the subject and documented by the site personnel prior to initiating 
treatment with carfilzomib; treatment is to be delayed or withheld if oral hydration is 
not deemed to be satisfactory.

Intravenous Fluids: 250 - 500 mL of IV normal saline (or other appropriate IV fluid 
formulation) must be given before and after each carfilzomib dose during Cycle 1. If 
lactate dehydrogenase (LDH) or uric acid is elevated at Cycle 2, Day 1, then the 
recommended IV hydration should be repeated for 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.

In subjects considered to be still at risk for TLS at completion of Cycle 1, hydration 
should be continued in Cycle 2, if clinically indicated. Patients in whom this program 
of oral and IV fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, 
cardiac, or renal impairment, will not be eligible to participate in the clinical trial.
Laboratory Monitoring

Appropriate chemistries, including creatinine, and complete blood counts (CBC) with 
platelet count should be obtained and reviewed prior to carfilzomib dosing on day 1 of 
each cycle. Results of laboratory studies must be reviewed and deemed acceptable prior 
to administering the carfilzomib dose. Subjects with laboratory abnormalities consistent 
with lysis of tumor cells (e.g., serum creatinine ≥ 50% increase, LDH ≥ 2-fold increase, 
uric acid ≥ 50% increase, phosphate ≥ 50% increase from baseline, potassium ≥ 30% 
increase, calcium ≥ 20% decrease) prior to dosing should not receive the scheduled 
dose. Subjects with such abnormalities should be re-evaluated again within the next 
24 hours (or sooner, if clinically indicated) and then periodically as clinically indicated.
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Clinical Monitoring

Inform subjects of signs and symptoms that may be indicative of TLS, such as fevers, 
chills/rigors, dyspnea, nausea, vomiting, muscle tetany, weakness, or cramping, 
seizures, and decreased urine output. Advise subjects to report such symptoms 
immediately and seek medical attention.
Management of Tumor Lysis Syndrome

If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring should be 
instituted. Correct electrolyte abnormalities, monitor renal function and fluid balance, 
and administer therapeutic and supportive care, including dialysis, as clinically 
indicated.
8.3
Concomitant Medications
Concomitant medication is defined as any prescription or over-the-counter preparation including 
vitamins and supplements. Concomitant medications will not be collected at this time. 
8.3.1
Required Concomitant Medications

Female subjects of child-bearing potential must agree to use dual methods of 
contraception for the duration of the study and for at least 30 days after the last dose of 
carfilzomib. 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.  Male 
subjects must also refrain from donating sperm for at least 90 days after the last dose of 
carfilzomib.

Subjects should receive antibiotic prophylaxis with ciprofloxacin or other 
fluoroquinolone 
(or 
trimethoprim/sulfamethoxazole 
if 
fluoroquinoles 
are 
contraindicated). In addition, subjects should receive acyclovir or similar (famciclovir, 
valacyclovir) anti-varicella (anti-herpes) agent prophylaxis.

Subjects should receive adequate granulocyte colony stimulating factor support on 
Day 8 of treatment.

All subjects must receive prophylaxis with hydration as typically used for R-ICE per 
institutional guidelines.

Subjects may be pretreated for nausea and vomiting with appropriate anti-emetics.

Patients may receive transfusion support as per institutional guidelines.
8.4
Duration of Treatment
Subjects may remain on study for a maximum of 3 cycles.
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8.5
Treatment Discontinuation
Upon treatment discontinuation all end of study evaluations and tests will be conducted. All 
subjects who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the subject’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Treatment-related toxicity

Toxicity unrelated to treatment

Investigator judgment
o
The Investigator may withdraw a subject if, in his/her judgment, it is in the 
subject’s best interest to do so.

Noncompliance

Subject voluntary withdrawal
o
A subject may withdraw from the study at any time, for any reason. If a subject 
discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.

Early withdrawal of subject(s)

Sponsor decision.
Subjects who are unavailable for follow-up evaluations should be classified as lost to follow-up 
for 1 of the following reasons:

Lost to follow-up: For a subject to be considered lost to follow-up, the investigator 
must make 2 attempts to re-establish contact with the subject. The attempts to re-
establish subject contact must be documented (e.g., certified letter).

Death: Date and cause of death will be recorded for those subjects who die within 
30 days after last dose of study drug (telephone contact is acceptable).
9
STUDY PROCEDURES
9.1
Subject Registration
All data management will be conducted at Roswell Park. Eligible patients will be entered on 
study centrally at the institute by the Study Coordinator. Following registration, patients should 
begin protocol treatment within 14 days or sooner if clinically necessary. Issues that would cause 
treatment delays should be discussed with the Principal Investigator at Roswell Park (or 
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designee). If a patient does not begin protocol therapy within 14 days following registration, the 
patient’s registration on the study may be canceled. The Study Coordinator should be notified of 
cancellations as soon as possible.
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Table 3.
Study Calendar
Tests and Observations
Prior to 
Study1
Day 1 of 
Each Cycle2
At Time of 
Restaging3
Collect Stem 
Cell  and
ASCT  Data 
(if 
applicable)20
Collect Post 
ASCTDay 
+100Data20
Post
Treatment
Follow-Up4
History and Physical Exam
X
X
X
Pulse, Blood Pressure
X
X
X
Height/Weight/Body Surface Area5
X
X
Performance Status
X
X
X
Drug Toxicity Assessment
X
X7
Laboratory Studies
CBC, Differential, Platelets
X
X8
X
Serum Creatinine, BUN
X
X9
X
Creatinine Clearance (Appendix C)
X
X9
Serum Electrolytes
X
X9
X
Ca++ , Potassium
X
X9
X
ALT, AST, Alkaline Phosphatase, Bilirubin
X
X9
X
Phosphorus
X
X9
LDH and Uric Acid
X
X9
X
EKG
X
MUGA or ECHO
X
HBsAg, HBcAb10
X
HBV DNA, Qualitative
X10
HCV Ab
X11
HIV (If risk factors present)
X
Beta-2-microglobuline (B2M)
X
Albumin
X
X
X

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Serum or Urine-HCG (female patients)
X12
   
Staging
Lumbar Puncture
X7
X13
X13
CT Scan (Chest/Abdomen/Pelvis) and/or PET
X6
X
        X 23
Bone Marrow Aspiration and Biopsy
 X21
   X14
X14
Histologic Review
X22
X15
Cytogenetics (e.g., Bcl-2 or c-MYc studies)
X
X15
Sample Submission and Correlative Studies
Lymph Node Biopsy
     X16,17
Immune Biomarker Samples
         X18
Pharmacokinetic /Pharmacodynamic Samples24
  X19
Adverse Events
X
X
X
X7
1
To be completed within28 days prior to enrollment
2
Within 48 hours prior to Day 1 of each induction treatment cycle.
3
Prior to study, at time of restaging; between Cycle 2 Day 15 to Cycle 2 Day 28 following Cycle 3 but before ASCT and at the end of treatment 
evaluation, then every 4 months (±2 weeks) for 1 year, then every 6 months (±2 weeks) for 2 years, then once a year (±2 weeks) for 2 years for 
a total of 5 years, then as clinically indicated.  The follow up period will begin at the end of study evaluation visit for patients that became 
ineligible for transplant for any reason but did not meet criteria for disease progression.  The follow up period for patients that go on to 
transplant will begin at the Day +100 bone marrow biopsy. 
4
At least every 4 months (± 1 week) for 1 year, then every 6 months (± 1 week) for 2 years, then once a year (± 2 weeks) for 2 years for a total 
of 5 years from study entry, then as clinically indicated.  The follow up period will start at the Day 100 bone marrow biopsy in patients that 
received a transplant.  Patients that progress will be followed for survival status only on a yearly basis.
5
If there is a greater than 10% difference in weight from baseline, then recalculate the BSA prior to each treatment; otherwise the actual dose 
given does not need to change.
6
 CT Scan to be completed within 28 days prior to enrollment
7
When clinically appropriate.
8
CBC with differential and platelet counts will be monitored 3 times per week in between cycles of C-R-ICE until count recovery.
9
Days  1, 2, 8, and 9
10
All patients must be screened for hepatitis B infection (HBsAg/HBcAb) before starting treatment. Patients tested positive for HBV surface 
antigen are ineligible. Patients tested HBsAg negative/HBcAb positive should have qualitative HBV DNA PCR testing. If HBV DNA is 
positive the subject is excluded. If HBV DNA is negative, subject may be included but must undergo at least every 2 months HBV DNA PCR 

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testing from the start of treatment throughout the duration the treatment course. Monitoring during the on treatment periods is required at least 
every 2 months and during follow-up at a minimum of every 2 - 3 months up to 6 months after the last dose. Prophylactic antiviral may be 
initiated at the discretion of the investigator.
11
All patients must be screened for HCV infection before starting treatment. Patients who test positive for HCV antibody (Ab) evaluation of 
LFT’s and clinical evaluation to rule out cirrhosis.
12
To be completed within 7 days prior to enrollment.
13
Repeat as medically indicated if positive at baseline.
14
Document absence of disease at least once in CR if previously involved.
15
At the time of relapsed/refractory disease diagnosis.
16
If the patient is undergoing a pre-treatment fresh biopsy - collect tissue with a goal of at least 0.5 g (in saline or media (RPMI 1640) provided to 
pathology by Roswell Park Department of Medicine Lymphoma/Myeloma Laboratory; fresh tissue will not be collected from Network Sites
17
Repeat diagnostic lymph node/tumor biopsy if initial biopsy was not diagnostic. Do not repeat due to less than 0.5g of tissue being collected.
18
Refer to Section 9.3.  To be drawn the day of the tissue biopsy.  
19
Refer to Section 9.4  PK [pharmacokinetics] and 14.2 PD pharmacodynamics)[proteasome inhibition]Cycle 1 only 
20
As per BMT services
21
 BM biopsy and aspiration to be completed within 28 days prior to enrollment 
22
If biopsy is completed at an outside facility or Network Site, a tissue block or slides will be submitted to the Roswell Park Pathology 
Department for central pathology review. In addition immunohistochemistry (IHC) for CD20, Ki67, CD10, Bcl-2, Bcl-6, and MUM-1 staining 
will be performed.  Cell of origin will be determined according to the Han’s algorithm as previously described.  Samples may only be shipped 
to Roswell Park Monday-Thursday.  
23
For patients within the first 3 years of follow up, CT scans will be ordered every other visit.  Patients on annual follow up will receive a CT 
scan at every study visit until the end of year 5, then CT scans will be ordered as clinically indicated
24
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9.2
Pathology
If a patient was confirmed at Roswell Park or an outside institute for CD20-positive DLBCL, 
then the diagnosis will be confirmed by centrally reviewing the available pathology material or 
the outside material utilized for this purpose. If confirmation is needed on outside material, a 
representative block or 15 unstained 4 µm sections on 15 charged slides will be requested for this 
purpose.
Immunohistochemistry (IHC) will be utilized, if not already performed, to confirm the diagnosis 
of DLBCL and subtype it as Germinal Center (GC) or non-GC-like based on variable expression 
of CD10, BCL6, and MUM1 (based on Hans algorithm). Additional IHC markers that could be 
used, most of which are part of routine standard of care work up, include but not restricted to 
CD20, BCL1 (to exclude mantle cell lymphoma), BCL2, and ki-67.
A fresh lymph node/tumor biopsy needs to be repeated only for diagnostic purposes or if the 
patient has received additional chemotherapy after their previous biopsy. Fresh tissue or paraffin 
imbedded/unstained slides (N=15) (For Network Institutions) will be submitted to the 
department of pathology for standard and research protocol work-up. The tissue will be divided 
into standard of care diagnostic tissue (for H-E and IHC work-up, among others if needed such 
as flow cytometry immunophenotypic analyses and cytogenetics) and fresh tissue sent to 
Roswell Park Department of Medicine Lymphoma/Myeloma Laboratory (if sufficient tissue). 
Contact Cory Mavis at 716-868-5333 or 716-845-3464 for additional information. 
Outside material should be sent to Dr. Vishala Neppalli, Pathology Department, Roswell Park 
Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo NY 14263.
9.3
Immune Biomarker Blood Sample Collection
If the patient is undergoing a fresh lymph node/tumor biopsy, the following samples will be 
collected. Samples of blood will be collected using (5) 10 mL green-top heparinized tubes 
(1 tube for phenotype in flow cytometry, and 4 tubes for CMC/ADCC), (1) gold-tube (for CMC), 
and (1) 10 mL lavender-top tube (for genotypic analysis). Samples will be collected on the same 
day as the lymph node biopsy. Network Sites will collect immune biomarker samples on day of 
tumor biopsy if it is after the informed consent.  Fresh tissue will not be collected from Network 
Sites.
One green top tube will be sent to the flow cytometry department and the remainder of the 
samples will be sent to Roswell Park Department of Medicine Lymphoma/Myeloma Laboratory 
for processing: Tube station #621 in Roswell Park Cancer Cell Center.
For additional information regarding the handling of samples please contact Cory Mavis at 
716-868-5333 or 716-845-3464.
Refer to Section 14.1 for analysis details.
9.4
Pharmacokinetic Blood Sample Collection and Processing (Phase 1 Only)
Whole blood samples for the pharmacokinetic analysis of carfilzomib levels will be collected via 
venipuncture using 4 mL green-top heparinized tubes.
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PK samples will be collected pre-dose, just prior to the end of the infusion; and at 15 minutes, 
30 minutes, 1, 2, 4, 6 hours post infusion on Cycle 1, Day 1, then at 24 hours post Cycle 1 
infusion on Cycle 1, Day 2 (prior to Day 2 infusion).
PK samples will be sent to procurement lab.  PD samples will be sent to Roswell Park 
Department of Medicine Lymphoma/Myeloma Laboratory for processing: Tube station #621 in 
Roswell Park Cancer Cell Center.
Plasma will be separated from the whole blood within 30 minutes following the extraction. The 
screw cap polypropylene cryogenic tube will be labeled with the subject’s initials, subject’s 
study number, clinical study number, protocol time point, dose, and protocol day. The samples 
will be frozen at -70°C or below until analyzed. After hours, samples will be processed in Lab 
Medicine.
The concentrations of carfilzomib in plasma will be determined using a validated LC/MS/MS 
method. Drug extraction will consist of protein precipitation with acetonitrile. The analytes will 
be separated on a C18 column with mobile phase consisting of acetonitrile, water and 0.1% 
formic acid. The method will be cross-validated before applying to the specimens for 
quantification. Quality assurance will be maintained by injecting quality control samples each 
time the samples are assayed.
Samples will be analyzed in Roswell Park Bioanalytics, Metabolomics & Pharmacokinetics Core 
Facility.
Roswell Park 
Bioanalytics, Metabolomics & Pharmacokinetics Core Facility
Center for Genetics and Pharmacology, Room L1-140
Refer to Study Number– I 240813
Elm & Carlton Streets
Buffalo, New York 14263
PKPDCore@RoswellPark.org 
For additional information regarding the handling of pharmacokinetic samples please contact 
Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics Core Facility laboratory at 
716-845-3303 (Tel) or 716-845-1579 (Fax).
Refer to Section 14.2 for analysis details.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/ shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
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10 EFFICACY EVALUATIONS
10.1 Objectives
One of the secondary objectives of this clinical study is to evaluate the overall response rate and 
complete response rate to C-R-ICE in rel/ref DLBCL. It is important to evaluate response to 
therapy using standardized response criteria utilized in previous clinical studies in DLBCL 
patients so direct comparisons can be performed with historical controls (i.e., R-ICE). For this 
reason response to therapy will be evaluated using the response criteria reported by Cheson 
published in 2007 which incorporate whole body PET scan in addition to CT scanning.
10.2 Imaging, Laboratory and Pathological Studies
Imaging, laboratory and pathological studies will be conducted for staging and response 
evaluation at baseline, between Cycle 2 Day 15 and Cycle 2 Day 28, and at the end of study 
evaluation following Cycle 3. Response to treatment will be evaluated according to the 
International Working Group Response criteria as reported by the revised Cheson criteria 
(Section 10.3).
10.3 Modified Cheson Criteria
10.3.1 Complete Response (CR)

Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy.

Typically FDG-avid lymphoma: in patients with PET scan positive before 
therapy, a post-treatment residual mass of any size is permitted as long as it is 
PET negative.

Variably FDG-avid lymphomas/FDG avidity unknown: in patients with a 
negative pretreatment PET scan, all lymph nodes and nodal masses must have 
regressed on CT to normal size (1.5 cm in their greatest transverse diameter for 
nodes 1.5 cm before therapy). Previously involved nodes that were 
1.1 cm to 1.5 cm in their long axis and more than 1.0 cm in their short axis before 
treatment must have decreased to 1.0 cm in their short axis after treatment.

The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is 
not always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma.

If the bone marrow was involved by lymphoma before treatment the infiltrate 
must have cleared on repeat bone marrow biopsy.
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
The bone marrow biopsy sample on which this determination is made must be 
adequate (with a goal of 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is 
negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome.
10.3.2 Partial Response (PR)

A decrease of ≥ 50% in the in the sum of the products of their greatest transverse 
diameters (SPD) of the 6 largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to the following features: a) they should be 
clearly measurable in at least two perpendicular measurements; b) they should be 
from as disparate regions of the body as possible; and c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved.

No increase in the size of other nodes, liver, or spleen.

Spleen and hepatic nodules must regress by at least 50% in SPD.

With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease.

Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive the cell type should 
be specified in the report (e.g., large-cell lymphoma).

Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders.

When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients should be 
considered partial responders.

No new sites of disease should be observed.

Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if 
the PET scan was positive before therapy, the post-treatment PET should be 
positive in at least one previously involved site.

Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria 
should be used.
10.3.3 Stable Disease (SD)

A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
Relapsed Disease [after CR]/Progressive Disease [after PR, SD]).
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
Typically FGD-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET.

Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan. 
10.3.4 Progression (PD) or Relapse

Lymph nodes should be considered abnormal if the long axis in more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 cm to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1 cm. Lymph 
nodes 1 cm x 1 cm will not be considered as abnormal for relapse or progressive 
disease.

Appearance of any new lesion more than 1.5 cm in any axis during or at the end 
of therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. In patients with no prior history 
of pulmonary lymphoma, new lung nodules identified by CT are mostly benign. 
Thus, a therapeutic decision should not be made solely on the basis of the PET 
without histologic confirmation.

At least a 50% increase from nadir in the SPD of any previously involved nodes, 
or in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules). To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1 cm must increase by 50% and to a size of 1.5 cm or 
more than 1.5 cm in the long axis.

At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis.

Lesions should be PET positive if observed in a typical FDG avid lymphoma or 
the lesion was PET positive before therapy unless the lesion is too small to be 
detected with current PET systems (1.5 cm in its long axis by CT).
10.3.5 Duration of Overall Response and/or Progression-Free Survival (in Non-
Responders)

The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).

The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented.

Duration of Stable Disease
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
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started.
10.4 Duration of Overall Survival
Duration of Overall Survival is measured from the start of treatment until death for any reason 
(cause of death will be documented whenever possible).  Patients that progress at any time will 
be followed for survival only, on a yearly basis either by review of medical records or a phone 
call.  
11 SAFETY EVALUATION
11.1 Adverse Events
11.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
11.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
11.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
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11.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
11.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
11.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 
of 
the 
CTCAE 
is 
identified 
and 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. AEs not covered by 
specific criteria should be reported with common medical terminology and graded according to 
definitions provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the patient’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the patient.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the patient’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the patient’s 
clinical state, other therapeutic interventions or concomitant drugs.
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
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event 
cannot be reasonably explained by other factors such as the patient’s clinical state, 
therapeutic interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be 
reasonably explained by other factors such as the patient’s condition, therapeutic 
interventions or concomitant drugs; AND occurs immediately following study drug 
administration, improves upon stopping the drug, or reappears on re-exposure.
11.1.3 Reporting Adverse Events
Table 4.
Guidelines for Routine Adverse Event Reporting for Phase I Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Table 5.
Guidelines for Routine Adverse Event Reporting for Phase Ib Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
All new routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, stabilized, death, or a new treatment is started, 
whichever comes first, will be reported.
11.2 Serious Adverse Events
11.2.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.
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
A life-threatening adverse event (experience). Any AE that places a patient or patient, in 
the view of the Investigator or sponsor, at immediate risk of death from the reaction as it 
occurred. It does NOT include an AE that, had it occurred in a more severe form, might 
have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
patient or patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
11.2.2 Reporting Serious Adverse Events
All new SAEs occurring from the date the patient signs the study consent until 30 days after the 
last intervention or a new treatment is started, whichever comes first, will be reported. SAE’s 
occurring after this time that the investigator determines to be possibly, probably or definitely 
related to the study intervention, should be reported.
The Roswell Park SAE Source Form is to be completed with all available information, including 
a brief narrative describing the SAE and any other relevant information. The site Investigator or 
designated research personnel will report all SAEs, whether related or unrelated, to the 
investigational agent(s) to the IRB in accordance with their local institutional guidelines.
SAE’s identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 11.5 for details on reporting Unanticipated Problems.
Amgen should receive copies of all safety reports submitted to the FDA, or any regulatory 
agency, IRB or IEC, within 24 hours of such submission.  Such notifications should be submitted 
as MedWatch reports using the attached SAE fax cover letter and faxed to 1-888-814-8653.  
Note the fax cover must contain both Amgen and Onyx study numbers, as reflected in the 
attached form (Appendix D).
11.3 Investigator Reporting: Notifying the Study Sponsor
Notify the study sponsor: SAEs should be reported to Amgen by fax to: +1 (888) 814-8653.
11.4 Follow-Up for Serious Adverse Events
All SAEs will be followed until resolution, stabilization, death, or the start of new treatment. 
New information will be reported when it is received.
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11.5 Unanticipated Problems
11.5.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of patient privacy or 
confidentiality of data.
b) The characteristics of the patient population being studied.

Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research).

Suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 11.2.
11.5.2 Reporting Unanticipated Problems
The Unanticipated Problem Form will be submitted to CRS Compliance Office within 1 business 
day of becoming aware of the Unanticipated Problem.
When becoming aware of new information about the Unanticipated Problem, submit this updated 
information to CRS Compliance with an updated Unanticipated Problem Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
11.6 FDA Reporting
When Roswell Park is the IND holder the following describes the FDA reporting requirements 
by timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
Related or possibly related to the use of the study drug;
Unexpected; and Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
Related or possibly related to the use of the study drug;
Unexpected; and Serious but not fatal or life-threatening.
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Or meets ANY of the following criteria:
A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).
Any findings from other studies, including epidemiological studies, pooled analysis of multiple 
studies, or other clinical studies conducted with the study drug that suggest a significant risk in 
humans exposed to the drug.
Any findings from animal or in vitro testing that suggest a significant risk for human patients 
including reports of mutagenicity, teratogenicity, or carcinogenicity or reports of significant 
organ toxicity at or near the expected human exposure.
Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance 
Office via email to: CRSCompliance@RoswellPark.org.
12 DATA AND SAFETY MONITORING
Phase I studies will be reviewed at the scheduled Roswell Park Phase I meetings and the minutes 
are forwarded to the IRB for review.
The Roswell Park Data and Safety Monitoring Board will assess the progress of the study, the 
safety data, and critical efficacy endpoints. The DSMB will review the study annually and will 
make recommendations that include but not limited to; (a) continuation of the study, 
(b) modifications to the design (c) or termination of the study.
13 STATISTICAL METHODOLOGY
This is single-center, open-label, prospective Phase I/Ib clinical trial evaluating the safety, 
efficacy, and pharmacokinetics/pharmacodynamics of carfilzomib and standard R-ICE 
combination therapy in adult patients with relapsed/refractory diffuse large B-cell lymphoma. 
The statistical design is based on a dose-finding algorithm to determine the maximal tolerated 
dose (MTD) of the study regimen and an assessment of the efficacy of the treatment for patients 
as compared to an external standard, i.e., R-ICE historical control. All enrolled patients will 
receive the study drug and initiation of the treatment should take place as soon as possible 
following study enrollment. A maximum total of up to 21 evaluable patients will be enrolled in 
the Phase I of this study, and a total of 9 evaluable patients will be enrolled in the Phase Ib 
portion of the study. An evaluable subject is defined as a subject who meets eligibility 
requirements and who does not discontinue prior to end of Cycle 1 for reasons other than DLTs 
for Phase I or who completes at least 1 cycle of planned therapy for Phase Ib. If a subject signs 
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an Informed Consent and does not receive treatment, the subject will not be classified as 
evaluable and will be replaced. Unevaluable patients will be replaced. Analyses will be 
performed with a focus on estimation of specific clinically important parameters for use in the 
planning of larger subsequent comparative trials designed to fully assess efficacy and safety.
13.1 Sample Size Determination
13.1.1 Phase I
The actual sample size for the Phase I population depends on the unknown dose-toxicity profile 
of the treatment and the sample size is 21.
13.1.2 Phase Ib
The sample size calculation for the Phase Ib population is based on testing the hypotheses
concerning the proportion of the population who experience an objective response (i.e., CR or
PR) described above. This design requires a total of up to 30 patients in order to achieve
approximately 80.1% power to detect differences of 20 percentage points (50% versus 70%).
Based on the excellent response observed in the patients treated in the Phase I portion (ORR 
90%) and budget changes, the sample size for the Phase Ib portion was reduced. The phase Ib 
portion will include 9 additional patients. The efficacy analysis will include evaluable patients in 
the Phase I and Phase Ib portions combined (sample size up to 45). The sample size calculation 
for the efficacy analyses is based on testing the hypotheses concerning the proportion of the 
population who experience an objective response (i.e., CR or PR) described above. This design 
requires a total of up to 30 patients in order to achieve approximately 80.1% power to detect 
differences of 20 percentage points (50% versus 70%).
13.2 Missing Data
The amount and nature of missing data will be characterized and no method of imputation will 
be used for missing data. A summary of missing data will be provided according to the number 
of subjects, the time points where the data are missing, and clinical center. For each clinical 
center, the number and percent of subjects with no missing data will be presented in tabular 
form.
13.3 Descriptive Analyses
Measured outcome variables will be summarized overall and by relevant demographic and 
baseline variables. Descriptive statistics such as frequencies and relative frequencies will be 
computed for all categorical variables. Numeric variables will be summarized using simple 
descriptive statistics such as the mean, standard deviation and range. A variety of graphical 
techniques will also be used to display data, ex. histograms, boxplots, scatterplots, etc.
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13.4 Phase I
The primary objective of the Phase I part of this study is to determine the MTD of the proposed 
regimen defined as the dose of carfilzomib added to standard R-ICE chemotherapy which, if 
exceeded, would put the patient at an undesirable risk of medically unacceptable, DLTs 
experienced during treatment with C-R-ICE within the treated patient population. The definition 
of a DLT is in Section 7.4.1.
The basic design of the Phase I trial will utilize a standard 3+3 dose-finding scheme which is a 
special case of the A + B design described by Lin and Shih (2001). Rationale behind the design 
is nested in the assumption that both the probabilities of toxicity and efficacious response are 
continuous monotonic non-decreasing functions of the dose.
13.5 Phase Ib (expansion cohort)
The objective of the Phase Ib component is examination of the efficacy and toxicity of the 
addition of carfilzomib to R-ICE at the MTD dose.
The primary objective of the Phase Ib component is to assess the efficacy of the study treatment 
arm as compared to historical control. The primary efficacy endpoint will be best overall 
response rate (PR+CR) within following 3 cycles of C-R-ICE therapy (as demonstrated by whole 
body PET-CT and dedicated CT scans following Cycle 3 of therapy).  
The efficacy analysis will include patients treated in the Phase I and Phase Ib part of the study. 
This change in the protocol was decided based on the excellent ORR observed in the first 15 
patients treated in the Phase part of the study and changes in the protocol budget. 
13.5.1 Historical Control
Patients in this population defined by the eligibility criteria receive standard-of-care which 
consist of blood product support as needed and growth factor support with each cycle. Based on 
provided historical information, the overall response rate in this patient population receiving 
standard-of-care is 50%. It is anticipated that treatment with carfilzomib added to standard 
R-ICE will increase the overall response rate beyond the clinically significant rate of 70%.
13.5.2 Phase Ib Decision Rules
Let 
 represent the proportion of the evaluable population of interest who experience an overall 

response within 3 weeks after completion of therapy (i.e., 3 cycles) at the carfilzomib MTD. If 
the response rate of less than 50% is considered unacceptable. A response rate of more than 70% 
is considered promising and evidence of such will deem the treatment worthy of further study. 
The null and alternative hypotheses corresponding to the design are
0 :
50%,
:
50%.
a
H
H




A total of up to 30 evaluable patients will be accrued in the Phase I and Phase Ib portions of the 
study. The evaluable population is defined as patients who meet eligibility requirements and 
complete at least 1 cycle of therapy. Unevaluable patients will be replaced.
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With this re-design, the probability is 4.8% of falsely concluding that the proportion of those 
who experience an overall response exceeds 50% and 80.1% is the probability of correctly 
concluding efficacy when the overall response rate is 70%.
In the event that the actual first stage sample size is not as planned, the adjustment of the first-
stage stopping rule will be based on the approximate minimax rule proposed in Green and 
Dahlberg (1992): Stop the trial if the number of responses is α or less, where a is the largest 
value for which power properties would be maintained given the attained first-stage sample size, 
assuming the planned final sample size is achieved and one applies the planned final boundary. If 
the planned second stage sample size is not attained, the bound will be adjusted so to preserve 
Type I error.
13.5.3 Secondary Analyses
Both efficacy and toxicity rates will be estimated using simple relative frequencies. The 
corresponding 95% confidence intervals for the estimated probabilities will be computed using 
the method proposed in Clopper and Pearson (1934). The relationship between binary outcomes 
and collected demographic and baseline variables will be statistically assessed using logistic 
regression in an exploratory fashion. Maximum likelihood estimation will be utilized in the 
model fitting procedures as implemented by SAS PROC LOGISTIC. Wald tests of the model 
effects will be performed to assess statistical significance; see SAS documentation for details. 
See Hosmer and Lemeshow (2000) for a discussion of such techniques. Alternative parametric 
models will be considered if model fit is found to be inadequate.
The estimated distributions of overall and progression free survival will be obtained using the 
Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. 
Corresponding confidence intervals using the methodology of Brookmeyer and Crowley (1982) 
will be computed. It is assumed a priori that any drop out times will be non-informative in terms 
of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric 
demographic/baseline variables will be compared in regards to time-to-event distributions using 
the log-rank test. Cox proportional hazards model regression will be utilized for multivariate 
analyses.
All tests will be two-sided and tested at a 0.05 nominal significance level. Standard diagnostic 
plots will be used to assess model fit and transformations of variables may be considered in order 
to meet statistical assumptions.
The analysis will be performed using the SAS® statistical software system.
14 CORRELATIVE STUDIES
14.1 Immune Biomarker Analysis
14.1.1 Blood

Phenotypic Studies by direct flow cytometric analysis of neutrophils, NK and 
monocytes for the expression of CD11b/CD18; CD32, CD33, CD62, CD64, CD69, and 
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CD56 vFunctional Assays in vitro. (1) 10 ml green top – same day as lymph node 
biopsy

Antibody-dependent cellular cytotoxicity (ADCC) assays: The capacity to lyse 
autologous tumor cells in the presence of RITUXAN by peripheral blood mononuclear 
cells of each patient will be studied by standardized assays, including appropriate 
controls. (4) 10 ml green tops – same day as lymph node biopsy

Complement mediated cytotoxicity (CMC) assays: The capacity to lyse autologous 
tumor cells in the presence of RITUXAN by serum from each patient will be studied by 
standardized assays, including appropriate controls. (1) gold top – same day as lymph 
node biopsy

Genotypic Analysis: Polymorphisms in the IgG Fc receptor FcγIIIa gene will be 
performed using a nested PCR followed by allele-specific restriction enzyme digestion  
performed in Roswell Park Department of Medicine Lymphoma/Myeloma 
Laboratory.(1) 10 ml lavender top – same day as lymph node biopsy 

Assay for proteasome inhibition of patient-derived primary DBLCL cells and PBMCs 
will be performed using an enzymatic assay for chymotrypsin-like activity. (1) 10 ml 
green top with each designated time point in Cycle 1 (see section 14.2)
14.1.2 Fresh Tissue (Phase I part only)

Autologous neoplastic B-cells derived from fresh tissue samples (lymph node biopsy 
specimen or organ specimen) will be exposed ex vivo to carfilzomib versus bortezomib 
+/- rituxan (including appropriate controls). Response to therapy will be measured. 
Additionally, genetic profiling (microarray), to determine activated B-cell (ABC) 
versus germinal B-cell (GBC) phenotype and protein profiling (protein arrays), in 
particular, changes in Bcl-2 family protein profile and/or inactivation of NF-κB 
signaling after ex vivo exposure of NHL cells to carfilzomib (compared to bortezomib), 
will be performed to examine potentially prognostic factors for response to C-R-ICE.
14.2 PK/PD Model Development
A pharmacologically-driven PK/PD model will be developed to elucidate the temporal 
relationship between carfilzomib concentrations and the time course of proteasome inhibition, 
along with temporal relationships with thrombocytopenia and neutropenia. This model will allow 
assessment of the dose and schedule at which carfilzomib facilitates maximal proteasome 
inhibition and thus lead to an increase response rate, while modulating the degree of severe 
toxicities. In addition, the effect of concomitant administration of rituximab, ifosfamide, 
carboplatin, and etoposide will be incorporated into the model to assess their potential effects on 
efficacy and/or toxicity.
First, a variety of compartmental population PK structural models will be evaluated to 
characterize the plasma concentration versus time profile following administration of carfilzomib 
using a nonlinear mixed effects modeling approach NONMEM®. The physiologic 
pharmacokinetic models explored will be described by the estimation of mean structural model 
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parameters (e.g. plasma volumes of distribution and clearances), the magnitude of inter-animal 
variability (IIV) in these parameters and the magnitude of residual variability (RV). For each 
model, the fit will be assessed by examination of several diagnostics. For comparisons of 
hierarchical models, the change in the minimum value of the objective function (MVOF), a 
statistic that is proportional to minus twice the log likelihood of the data, will be examined.
Using a sequential approach, a population PK/PD structural model will be developed for 
carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity 
endpoints in the proposed study using NONMEM. This PK/PD model will describe the potential 
relationship between carfilzomib exposure in relation to proteasome inhibition to the time course 
of thrombocytopenia and neutropenia as indicators of pharmacodynamic response. The 
relationship between carfilzomib concentrations and these pharmacodynamic endpoints will be 
initially explored graphically and various structural models will be applied to the data and 
evaluated. Similar to the PK model development, criteria such as the precision of parameter 
estimates, magnitude of residual variability, and goodness-of-fit will be utilized for PK/PD 
model selection. The PK/PD model could be expanded to include attributes that are indicators of 
pharmacodynamic response from the concomitant medications of rituximab, ifosfamide, 
cisplatin, and etoposide which will modulate the overall response rate. 
Assay for Proteasome Inhibition.  This measures (but does not distinguish from) the activity of 
beta5 (constitutive proteasome) and LMP7 (immunoproteasome).  Analysis of biomarkers that 
predict for response following treatment with proteasome inhibitors will also be performed on 
PBMC and whole blood plasma samples ((1) 10 ml green top tube with each blood draw) taken 
at time points below in Cycle 1 only:  Day 1 of Cycle 1, pre-dose and 1 hr post end of infusion; 
Day 2 of Cycle 1, pre-dose and 1 hr post end of infusion and Day 3, Cycle 1, prior to rituximab 
administration..
Samples will be sent to Roswell Park Department of Medicine Lymphoma/Myeloma Laboratory 
for processing. Tube station #621 in Roswell Park Cancer Cell Center.
For additional information regarding the handling of samples please contact Cory Mavis at 
716-868-5333 or 716-845-3464.
Furthermore, the final PK/PD model will be used to conduct a clinical trial simulation to predict 
pharmacokinetic outcomes of various dosing regimens (94, 95) to guide dosing and scheduling 
of C-R-ICE in relation to safety and efficacy endpoints. The simulation results will allow 
prediction of the exposure-response relationships for different doses and schedules of 
carfilzomib to achieve the desired responses.
15 ETHICAL AND REGULATORY STANDARDS
15.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each subject (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
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procedure. It is the responsibility of the investigator to ensure that the subject is made aware of 
the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the subject log and subject records; although 
personal information may be reviewed by authorized persons, that information will be treated as 
strictly confidential and will not be made publicly available. The investigator is also responsible 
for obtaining subject authorization to access medical records and other applicable study specific 
information according to Health Insurance Portability and Accountability Act regulations (where 
applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the subject is treated, in accordance with the Declaration of 
Helsinki, Good Clinical Practice, and according to the guidelines in this protocol, including 
attached appendices.
15.2 Informed Consent
The Investigator is responsible for obtaining written consent from each subject or the subject's 
legally authorized representative in accordance with ICH-GCP guidelines using the approved 
informed consent form, before any study specific procedures (including screening procedures) 
are performed. The informed consent form acknowledges all information that must be given to 
the subject according to ICH-GCP, including the purpose and nature of the study, the expected 
efficacy and possible side effects of the treatment(s), and specifying that refusal to participate 
will not influence further options for therapy. Any additional information that is applicable to the 
study must also be included. Additional national or institutionally mandated requirements for 
informed consent must also be adhered to. The subject should also be made aware that by 
signing the consent form, processing of sensitive clinical trial data and transfer to other countries 
for further processing is allowed.
The Investigator shall provide a copy of the signed consent form to the subject and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the subject file. At any stage, the subject may withdraw from the study and such a 
decision will not affect any further treatment options.
16 STUDY RESPONSIBILITIES
16.1 Data Collection
Data entry into the database is to be completed in a timely fashion (approximately within 
28 days) after the subject’s clinic visit. If an AE is considered serious it is captured on both the 
Adverse Event page and the Serious Adverse Event Form, which is handled in an expedited 
fashion.
Data management activities will be performed using EXPeRT. EXPeRT is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
EXPeRT Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
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production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs. EXPeRT is compliant with all relevant technical aspects of 
relevant GCP guidelines.

The system can generate accurate copies of stored data and audit trail information in 
human readable form.

System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.

The system is designed to periodically force users to change their passwords and 
verifies that user ID and password combinations remain unique.

The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
16.2 Maintenance of Study Documents
Essential documents should be retained per Roswell Park policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park. It is the 
responsibility of Roswell Park to inform the Investigator/institution as to when these documents 
no longer need to be retained. If, for any reason, the Investigator desires to no longer maintain 
the study records, they may be transferred to another institution, another investigator, or to 
Roswell Park upon written agreement between the Investigator and Roswell Park.
17 ADMINISTRATIVE RULES
17.1 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation.
17.2 Termination of the Study
It is agreed that, for reasonable cause, either the Investigators or the Sponsor, Roswell Park may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, Roswell Park may terminate the study at any time 
upon immediate notice if it believes termination is necessary for the safety of subjects enrolled in 
the study.
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17.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
18 APPENDICES
Appendix A. Ann Arbor Staging System
A staging system is a way for members of the cancer care team to summarize the extent of a 
cancer’s spread. The staging system most often used to describe the extent of non-Hodgkin 
lymphoma in adults is called the Ann Arbor staging system. 
The stages are described by Roman numerals I through IV (1-4). Lymphomas that affect an 
organ outside of the lymph system (an extranodal organ) have E added to their stage (for 
example, stage IIE), while those affecting the spleen have an S added.
Stage I
Either of the following means the disease is Stage I:

The lymphoma is in only 1 lymph node area or lymphoid organ such as the thymus (I).

The cancer is found only in 1 area of a single organ outside of the lymph system (IE).
Stage II
Either of the following means the disease is Stage II:

The lymphoma is in 2 or more groups of lymph nodes on the same side of (above or 
below) the diaphragm (the thin band of muscle that separates the chest and abdomen). 
For example, this might include nodes in the underarm and neck area but not the 
combination of underarm and groin nodes (II).

The lymphoma extends from a single group of lymph node(s) into a nearby organ (IIE). 
It may also affect other groups of lymph nodes on the same side of the diaphragm.
Stage III
Either of the following means the disease is Stage III:

The lymphoma is found in lymph node areas on both sides of (above and below) the 
diaphragm.

The cancer may also have spread into an area or organ next to the lymph nodes (IIIE), 
into the spleen (IIIS), or both (IIISE).
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Stage IV
Either of the following means the disease is Stage IV:

The lymphoma has spread outside of the lymph system into an organ that is not right 
next to an involved node.

The lymphoma has spread to the bone marrow, liver, brain or spinal cord, or the pleura 
(thin lining of the lungs).
Other modifiers may also be used to describe the lymphoma stage:
Bulky Disease
This term is used to describe tumors in the chest that are at least one-third as wide as the chest, or 
tumors in other areas that are at least 10 centimeters (about 4 inches) across. It is usually 
designated by adding the letter X to the stage. Bulky disease may require more intensive 
treatment.
A vs. B
Each stage may also be assigned an A or B. The letter B is added (stage IIIB, for example) if a 
person has any of the B symptoms listed below:

Loss of more than 10% of body weight over the previous 6 months (without dieting)

Unexplained fever of at least 101.5°F

Drenching night sweats
These symptoms usually mean the disease is more advanced. If a person has any of these, then 
more intensive treatment is usually recommended. If no B symptoms are present, the letter A is 
added to the stage.
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Appendix B. Karnofsky Performance Status Scores
Definition
Score
Normal; no complaints; no evidence of disease
100
Able to carry on normal activity; minor signs or symptoms of disease
90
Normal activity with effort; some sign or symptoms of disease
80
Cares for self; unable to carry on normal activity or do active work
70
Requires occasional assistance, but is able to care for most personal needs
60
Requires considerable assistance and frequent medical care
50
Disabled; requires special care and assistance
40
Severely disabled; hospitalization is indicated, although death not imminent
30
Very sick; hospitalization necessary; active support treatment is necessary
20
Moribund; fatal processes progressing rapidly
10
Dead
0
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Appendix C. Cockcroft-Gault Calculation for Creatinine Clearance
 =
[(140  Age) ∗ Body Mass (in kg)] 
[72 ∗ Serum Creatinine (in mg/dL)] 
If the patient is female, multiply the above by 0.85. If the patient is obese (> 30% over ideal body 
weight), use ideal body weight in calculation of estimated CrCL.
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Appendix D. Amgen ISS FAX Transmittal Form - Carfilzomib   Investigator Sponsored Study
Amgen ISS
FAX Transmittal Form
Carfilzomib
20159860 / IST-CAR-591 / Phase I/Ib Study of Carfilzomib plus Rituximab plus Ifosfamide plus Carboplatin plus 
Etoposide (C-R-ICE) in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)
To:   Amgen Global Safety
Toll-free #:1-888-814-8653
Email (Only for sponsors with a secure
 email connection with Amgen): 
svc-ags-in-us@amgen.com
              
AMGEN ISS PROTOCOL 
#: 20159860 / IST-CAR-591
Sponsor: Roswell Park 
Sponsor Contact Name: _________________________
Fax No: ____________________________________
Phone No:___________________________________
Date: _______________________________________
Use this form as a cover page for an individual report, for batched individual reports, and for line listings. 
***NOTE: Please use data reconciliation fax cover sheet to submit data reconciliation line listings.
Fax transmission contents (Check all that apply): 
To be sent immediately after each single case submission to RA, EC, IRB or DMC:
     
 Expeditable Serious Adverse Events/Serious Adverse Drug Reactions
          # of Reports Submitted: _____
To be sent in regular intervals per contractual agreement (eg, as batched individual 
reports or line listings):
     
 Serious Adverse Drug Reactions                        # of Reports Submitted: _____
          Period from __________ to __________
  
 
     
 Serious Adverse Events                                     # of Reports Submitted: _____
(does NOT apply for marketed Amgen products)
          Period from ________    to   ________
          
Other Reports (to be sent as per contractual agreement eg, pregnancy/lactation reports)
     
 Specify type of report: _________________      # of Reports Submitted: _____
           Period from ________    to   ________
    
Total # of pages in this transmission, including cover page: _____
DDMMM/YYYY
DD/MMM/YYYY
DD/MMM/YYYY
DD/MMM/YYYY
      DD/MMM/YYYY
     DD/MMM/YYYY
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Appendix E Instructions for Network Sites
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday   Friday; 8: 00 AM to 4: 30 PM EST
716-845-3870
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT
Informed consent must be obtained by the site Investigator/designee from any participants 
wishing to participate, prior to any study specific procedures.
An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.
All consent changes must be reviewed by RPCI Network Office prior to submission to the 
site IRB.
The informed consent must be IRB approved.
Always check that the most up to date version of the IRB approved consent is being used.
Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the 
study binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 1 Protocol Registration Instructions
Contact the RPCI Network Monitor to verify that a slot is available in the open cohort 
when a participant has been identified. Do not have the participant sign consent prior to 
verifying an open slot.
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•
After the participant signs consent, the Subject Screening and Enrollment Log must 
be faxed or emailed to the RPCI Network Monitor within 1 business day. The RPCI 
Network Monitor will confirm receipt of the Subject Screening and Enrollment Log and 
email the participant ID number.
•
When the participant has met eligibility, a signed eligibility checklist and other 
requested documentation will be faxed or emailed to the RPCI Network Monitor.
•
Within 1 business day of receipt of the eligibility check list, the RPCI Network 
Monitor will fax or email the cohort assignment and dose level.
•
An email must be sent by the site to confirm receipt of the cohort assignment and to 
provide the planned treatment start date.
4.
STUDY DEVIATIONS
If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the study.
ALL study deviations will be recorded on the Study Deviation Log.
Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION
Study documents must be filled out completely and correctly. Ditto marks are not allowed.
If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
Do NOT use white-out, magic marker, scratch-outs.
Do NOT erase entries.
Use only black ink for documentation on the accountability form and any other study 
forms.
It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.
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Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).
A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
Study drug supply will only be used in accordance with the IRB approved study.
Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.
Drug accountability forms must be stored with study related documents.
Each medication provided for this study and each dosage form and strength must have its 
own DARF.
Dispensing the wrong study supply is considered a medication error.
NEVER replace investigational agents with commercial product.
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines. The site will notify the RPCI Network Monitor within 1 business 
day of being made aware of the SAE. A preliminary written report must follow within 1 
business day of the first notification using the following forms:
RPCI SAE Source form
MedWatch 3500A 
See section 11 for additional reporting information
A complete follow-up report must be sent to the RPCI Network Monitor when new 
information becomes available.
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8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 11.5.
For all adverse events occurring that are unanticipated and related or possibly related to 
the research drug, biologic or intervention, the participating physician or delegated 
research staff from each site will notify their local IRB in accordance with their local 
institutional guidelines. The site must also notify the RPCI Network Monitor within 1 
business day of being made aware of the Unanticipated Problem by completing the RPCI 
Unanticipated Problem Report Form and faxing or emailing it to the RPCI Network 
Monitor.
 
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APPENDIX F
Roswell Park Cancer Institute Form
Specimen Shipment Form
Study Number:  I 240813
Patient ID: 2408VU_ _
Date Collected: 
Specimen Type: 
Specimen Site:
Fax a copy to:
Cory Mavis
716-845-7188
Note: Specimen must be shipped between Mondays to Thursdays 
Please schedule surgical procedures accordingly to adhere to shipment days.
Ship via overnight mail (check AM delivery)
FedEx the Original form with the specimen to:
Roswell Park Cancer Institute
Department of Medicine Lymphoma/Myeloma Laboratory
CCC Bldg. 3rd Floor, Rm 304
Attn: Study Number – I  201611
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845--3464
Fax: 716-845-7188
Contact:  cory.mavis@RoswellPark.org 
PLEASE INDICATE THE APPROPRIATE SAMPLE BEING SHIPPED
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