A Response-Adapted Clinical Trial of Weekly Carfilzomib With or Without Rituximab for Waldenström's Macroglobulinemia and Marginal Zone Lymphoma
Phase: PHASE2
Conditions: Marginal Zone Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Waldenstrom Macroglobulinemia, Refractory Marginal Zone Lymphoma, Refractory Waldenstrom Macroglobulinemia, Waldenstrom Macroglobulinemia
Sponsor: University of Washington

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IRO RECD AUG 28 2018 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCH INSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
A Response-Adapted Clinical Trial of Weekly Carfilzomib with or without Rituximab for 
Waldenstrom's Macroglobulinemia and Marginal Zone Lymphoma 
Principal Investigator: Stephen D. Smith, MD 
Associate Professor, University of Washington 
Associate Member, Fred Hutchinson Cancer Research Center 
Seattle Cancer Care Alliance 
Statistical Consultant 
Vicky Wu, PhD  
Version: 4.0, Date 08/01/2018 
This trial is supported by a grant from the NCCN. 
FHCRC IRB Approval 
OCT 02 2018 
Document Released Date 
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SCHEMA 
Registration: WM and MZL, N=24. (At least 5 Rituximab-refractory) 
1 
Carfilzomib (CFZ) for two, 28 day-cycles as follows: 
CFZ 20 mg/m2 as a 30-min IV infusion on Day 1 of cycle 1 
If tolerated, CFZ 56 mg/m2 as a 30-min IV infusion on Days 8 and 15 of cycle 1 
If tolerated, CFZ 70 mg/m2 as a 30-min IV infusion on Days 1, 8, and 15 of cycle 2 
I 
Assess paraprotein and/or nodal response; BM Bx (research) 
I 
If minimal response (MR: 25% or greater m-protein reduction) for WM, or PR for MZL: continue CFZ x 4 more cycles at 
70 mg/m2 dose level (days 1, 8, and 15) as tolerated. 
If not: Continue CFZ x 4 more cycles at 70 mg/m2 dose level if tolerated, and add rituximab 375 mg/m2 weekly x 4 
doses (cycle 3) then monthly (cycles 4-6) 
Note: Study to be stopped for futility if < 3 of the first 9 subjects achieve initial response with CFZ alone 
I 
Note: Study accrual to be suspended if cardiotoxi ly limits are exceeded, or rituximab cannot be delivered per 
protocol (see section 12) 
Stop therapy after 6 total CFZ cycles: Surveillance for up to 1 year (measured from time of study drug start) 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES 	
 	
4 
2.0 
BACKGROUND 	
 4 
3.0 
DRUG INFORMATION 	
 5 
4.0 
STAGING CRITERIA 	
 6 
5.0 
ELIGIBILITY CRITERIA 	
 	
6 
6.0 
REGISTRATION 	
 7 
7.0 
TREATMENT PLAN 	
 7 
8.0 
REQUIREMENTS TO BEGIN A NEW CYCLE AND DOSAGE MODIFICATIONS 	
 9 
9.0 
CONCOMITANT THERAPY 	
 	
 12 
10.0 
STUDY PROCEDURES 	
 13 
11.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 	
 14 
12.0 
STATISTICAL CONSIDERATIONS 	
 14 
13.0 
CORRELATIVE STUDIES 	
 	
 15 
14.0 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS/ADVERSE REACTIONS 	
 16 
15.0 
DATA AND SAFETY MONITORING PLAN 	
 	
20 
16.0 
RECORDS 	
 20 
17.0 
REGULATORY RESPONSIBILITIES OF SPONSOR-INVESTIGATOR 	
 20 
18.0 
TERMINATION OF THE STUDY 	
 21 
19.0 
REFERENCES 	
 22 
20.0 
APPENDIX 	
 24 
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1.0 	
OBJECTIVE 
1.1 	
Primary Objective: Determine the overall response rate of single-agent weekly CFZ, 
measured after 2 cycles of therapy, in WM and MZL. 
1.2 	
Secondary Objectives: 
1.2.1 	
Assess safety and tolerability of single agent, weekly CFZ in patients with WM 
and MZL, and determine the tolerability of weekly CFZ+rituximab for applicable 
patients. . 
1.2.2 Estimate the time to best response, response duration, and survival with weekly 
CFZ for WM and MZL 
1.2.3 Evaluate the overall response rate associated with weekly CFZ in a subset of 
patients with rituximabrefractory WM or MZL 
2.0 BACKGROUND 
2.1 	
Waldenstram's macroglobulinemia (WM) and marginal zone lymphoma (MZL) are 
incurable subtypes of non-Hodgkin lymphoma (NHL) with a protracted natural history.1. 2  
Therapy for WM and MZL, extrapolated from more common NHL subtypes, has been 
historically characterized by increasing toxicity of alkylating agents alone or in 
combination, and successively shortening remissions. WM and MZL patients present 
with unique features including high rates of marrow compromise in WM, paraprotein-
related complications in WM, and autoimmune phenomena or infections in MZL. This 
context points to a significant unmet need for specific therapies for patients with WM and 
MZL. 
Recent therapeutic advances including the successful application of rituximab, 
proteasome inhibitors (PI), and more recently cell signaling/kinase inhibitors.3. 4  While 
these agents have improved the outlook for patients, the optimal combination, sequence, 
and dosing strategy of novel therapies remains undefined. Following demonstration of its 
activity in relapsed and refractory non-Hodgkin lymphoma in 2005, bortezomib was found 
efficacious in Waldenstram's and carries a consensus recommendation for use in 
relapsed or refractory disease.5-7 Bortezomib produces response rates of 80% or higher, 
when co-administered with rituximab, in WM in relapsed/refractory and newly diagnosed 
patients.8,9 In extranodal marginal zone lymphoma (MALT lymphoma), single-agent 
bortezomib showed a response rate of 48%, and 6/11 patients when combined with 
rituximab in a smaller study, supporting further trials of proteasome inhibition in this 
histology.10,11 Thus, proteasome inhibition is a potentially effective strategy in both WM 
and MZL, justifying the study of this therapeutic class in both diseases. 
Nonetheless, the prototype proteasome inhibitor bortezomib is associated with well-
known neurotoxicity. The novel expoxyketone proteasome inhibitor carfilzomib (CFZ), 
with increased potency and selectivity compared to bortezomib, has shown favorable 
results with an attenuated risk of neuropathy in patients with WM and multiple 
myeloma.12-14  CFZ is currently approved for treatment of relapsed/refractory multiple 
myeloma in patients who have received 1 or more lines of therapy as a single agent, and 
in combination with dexamethasone or lenalidomide plus dexamethasone, in patients 
who have received 1 to 3 prior lines of therapy. 
The approved dose of CFZ for relapsed/refractory multiple myeloma is as follows, and 
employs a priming dose and if tolerated, then escalating to 27 mg/m2 (over 10 minutes) 
when given in combination with lenalidomide and dexamethasone, or escalating CFZ to 
56 mg/m2 (given over 30 minutes) when given in combination with dexamethasone: 
CFZ in combination with lenalidomide and dexamethasone 
cycle 1: 20 mg/m2 over 10 minutes on days 1 and 2; if tolerated, increase dose to 27 
mg/m2 over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle 
cycles 2-12:27 mg/m2 over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day 
treatment cycle 
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cycles 13-18:27 mg/m2 over 10 minutes on days 1,2, 15, and 16 of a 28-day 
treatment cycle 
CFZ in combination with dexamethasone 
cycle 1: 20 mg/m2 over 30 minutes on days 1 and 2; if tolerated, increase dose to 56 
mg/m2 over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle 
cycle 2 and onwards: 56 mg/m2 over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 
28-day treatment cycle 
Results of CFZ for first-line treatment of WM in combination with rituximab and 
dexamethasone have recently been published in abstract form. The combination 
produced a response in 81% of patients, and 22/31 remain on study at 8 cycles of 
therapy; no neuropathy of grade 2 or higher was seen.12  However, the single-agent 
efficacy of CFZ in WM or other NHL is undefined, nor have response-adapted studies--
reserving combination therapy with rituximab for non-responders-- been reported. 
The dosing of carfilzomib has recently undergone evolution, with implications for patient 
convenience and the practical administration of therapy. CFZ was historically 
administered twice weekly, but recent data from multiple myeloma (MM) identified 
acceptable safety and promising efficacy once weekly administration at the so-called 
20/70 dose (CFZ 20 mg/m2 over 30 minutes on Cycle 1 Day 1,then 70 mg/m2 on D8 and 
D15 of cycle 1 and all days of future cycles; cycles are repeated every 28 days).15  In that 
study, only 12% of patient discontinued therapy due to adverse events. Despite 
limitations of cross-trial comparisons, adverse event rates were similar or lower than prior 
twice-weekly studies. This data, in addition to providing the basis for a large upcoming 
study using weekly carfilzomib in myeloma (NCT#02412878), support the proposed 
weekly dosing in this trial. 
CFZ has been associated with cardiac toxicity in clinical trials, possibly related to co-
administration of routine IV fluids, cardiac myocyte protein accumulation and oxidative 
damage, or combined reasons16. The rate of any-grade cardiac failure approaches 6-8% 
with CFZ, higher than after bortezomib although one study found no change in 
prospectively monitored ventricular function between these agents.14. 12• 15  Serial 
monitoring of the cardiac marker brain natriuretic peptide (BNP) has been evaluated as 
an early biomarker of cardiac risk, particularly in MM patients. Available data show 
variable sensitivity of BNP in predicting cardiac failure, and suggest further prospective 
study of this marker is warranted. 16, 19  This trial requires baseline evaluation of ejection 
fraction and will exclude patients with inadequate cardiac function, will suspend accrual 
for excess cardiotoxicity as in section 12, and will hold therapy for uncontrolled systolic 
hypertension and include blood pressure monitoring at home for selected patients. 
Overall, this will address the substantial unmet need of defining a disease-specific 
therapy for WM and MZL patients, clarify the efficacy and safety of single-agent 
carfilzomib, and employ a response-adapted strategy adding rituximab added for initial 
non-responders as described in section 2.2. 
2.2 	
Response adapted therapy for WM and MZL: Rationale for the Addition of Rituximab for 
Initial Carfilzomib Non-responders 
This approach offers promise to define the single-agent activity of CFZ, and reduce 
unneeded exposure to combination CFZ+ R therapy in a proportion of WM and MZL 
patients. In addition, this provides an opportunity to perform correlative studies which 
may help optimize sequencing of therapy in future studies. The addition of rituximab is 
supported by its known significant single agent activity in WM and MZL, with over 50% of 
patients responding; it is also well tolerated, and does not appear to cause additive 
toxicity in combination with bortezomib.20-22  
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In this trial, rituximab will be administered for subjects who fail to achieve a minimal 
response in WM or at least a PR in MZL, after 2 cycles of CFZ single-agent therapy. A 
stopping rule is included to minimize unnecessary exposure to single-agent CFZ (see 
section 12.0, Statistical Methods). We will assess the efficacy and safety of this 
approach, while simultaneously evaluating secondary endpoints (such as modulation of 
the risk of tumor flare in WM) and correlative hypotheses (carfilzomib may upregulate 
CD20 expression to prime for rituximab response). Thus study is best regarded as a 
phase II study, with stopping for futility, powered to evaluate the response rate of single-
agent weekly CFZ in WM and MZL. 
3.0 	
DRUG INFORMATION: Carfilzomib (CFZ) and Rituximab 
3.1 	
CFZ is a synthetic small molecule peptide bearing the chemical name (25)-N-((S)-1-((S)- 
4-methyl-1-((R)-2-methyloxiran-2-y1)-1-oxopentan-2-ylcarbamoy1)-2-phenylethyl)-2-((S)-2-
(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. The molecular 
formula is C40H57N507 and the molecular weight is 719.91. It specifically functions as 
an inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis. 
3.1.1 	
FORMULATION: Carfilzomib for Injection will be provided as a lyophilized 
powder which, when reconstituted, contains 2 mg/mL isotonic solution of CFZ 
Free Base in 10 mM sodium citrate buffer (pH 3.5) containing 10% (w/v) 
sulfobutylether-6-cyclodextrin (SBE E CD, Captisol®). 
3.1.2 STORAGE Lyophilized Carfilzomib for Injection must be stored at 2-8°C in a 
securely locked area to which access is limited to appropriate study personnel. 
Additional drug information, in particular the Identified Risks of Carfilzomib, is 
contained in Appendix 20.1. Further information can be found in the product 
labelling. 
3.2 	
Rituximab is a monoclonal antibody directed against the CD20 antigen on B- 
lymphocytes, approved for treatment of CD20-positive Non-Hodgkin Lymphomas (NHL). 
Rituximab will be obtained from a commercial source. 
4.0 	
STAGING CRITERIA 
Staging and response assessment will follow the guidelines of the Vlth International Workshop for 
WM (Appendix 20.2 and 20.4), the Lugano criteria for nodal lymphoma23 and for spleen-only 
disease will follow guidelines of Matutes and colleagues.24  
5.0 	
ELIGIBILITY CRITERIA 
Patients with Waldenstrem Macroglobulinemia or Marginal Zone lymphoma who meet 
inclusion/exclusion criteria below are eligible. 
At least 5 patients with rituximab-refractory disease will be enrolled (best response of stable 
disease or progression while on treatment with, or progression within 6 months of, rituximab-
containing therapy). Accrual will be modified to ensure 5 rituximab-refractory patients are 
enrolled, without enrolling more than 24 total patients. 
5.1 	
Inclusion Criteria 
Waldenstram's macroglobulinemia (WM) or marginal zone lymphoma (MZL) based on 
institutional pathology review; see Appendix 20.3 for WM criteria. Patients may have 
either previously untreated or relapsed/refractory disease. 
Measurable disease: for WM presence of monoclonal IgM immunoglobulin concentration 
on serum electrophoresis, with lymphoplasmacytic marrow infiltrate; for MZL: measurable 
nodal disease measuring at least 1.5 cm in longest dimension, or splenomegaly. 
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Indication for initiation of therapy, as defined in protocol section 5.3 
Age greater than or equal to 18 years old 
Adequate hematopoiesis, including ANC >1,000/pL and platelet count >75,000/pL unless 
disease-related (due to marrow infiltration or splenomegaly). 
Serum creatinine <2.5 mg/dL or creatinine clearance >30 cc/min. 
Bilirubin <2 x ULN and AST and ALT <3 x ULN. 
All patients must be informed of the investigational nature of this study and have given 
written consent in accordance with institutional and federal guidelines. 
Expected survival of >90 days. 
Females of childbearing potential (FCBP) must agree to pregnancy testing and to 
practice contraception. 
Male subjects must agree to practice contraception. 
5.2 	
Exclusion Criteria 
Known HIV, Hepatitis C, or Hepatitis B positivity (subjects with hepatitis B surface antigen 
[SAg] or core antibody positivity, who are receiving and responding to antiviral therapy 
directed at hepatitis B or are negative for HBV DNA, are allowed) 
Candidate for potentially curative antibiotic therapy for gastric MALT. (Gastric MALT 
lymphoma patients with stage I/II H. pylori positive lymphoma must fail therapy with H.-
pylori directed therapy before being considered for this study.) 
ECOG performance status 3 or higher. 
Known active CNS involvement. 
Pregnant or lactating females 
Inadequate cardiac function, as measured by left ventricular ejection fraction (LVEF)that 
is less than or equal to 40%, or the presence of New York Heart Association (NYHA) 
classification of greater than stage II congestive heart failure. 
Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to 
screening 
Uncontrolled inter-current illness including, but not limited to, unstable angina, recent 
myocardial infarction within 6 months of screening and uncontrolled cardiac arrhythmias, 
psychiatric illness, or psychosocial difficulty that would limit compliance with study 
requirements. 
Non-hematologic malignancy within the past 3 years with the exception of a) adequately 
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma 
in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable 
prostate-specific antigen levels; or d) cancer considered cured by surgical resection or 
unlikely to impact survival during the duration of the study 
5.3 	
An indication for therapy initiation is required of all patients included on this trial. These 
listed below separately, for WM and MZL: 
5.3.1 	
WM: Symptoms related to WM including: fever, night sweats, weight loss, 
fatigue; evidence of hyperviscosity; symptomatic lymphadenopathy or 
lymphadenopathy measuring 5 cm or larger; symptomatic hepatomegaly and/or 
splenomegaly; other symptomatic organ or tissue infiltration; peripheral 
neuropathy due to WaldenstrOm's macroglobulinemia; or laboratory indications 
including symptomatic cryoglobulinemia, cold agglutinin anemia, immune 
hemolytic anemia or thrombocytopenia, nephropathy related to WaldenstrOm's, 
amyloidosis related to WaldenstrOm's, hemoglobin less than or equal to 10g/dL, 
platelet count less than or equal to 100,000/uL 
5.3.2 MZL: Symptoms related to splenomegaly or lymphadenopathy; evidence of rapid 
disease progression; high tumor bulk (presence of 3 lymph node groups 
measuring 3 cm or more, or one node or conglomerate measuring 7 cm or more), 
cytopenias due to bone marrow infiltration or hypersplenism (hemoglobin less 
than or equal to 10 g/dL, platelet count less than or equal to 100,000/uL); 
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autoimmune hemolytic anemia or thrombocytopenia. Advanced stage disease, 
disease-related effusions, end organ compromise (iron deficiency anemia, organ 
infiltration), are also permissible criteria for initiation of therapy on this study. 
6.0 	
REGISTRATION 
Subjects will be registered by institutional research staff prior to the start of protocol therapy. A 
complete, signed study consent and HIPAA consent are required for registration. 
7.0 	
TREATMENT PLAN 
7.1 	
Each cycle of CFZ therapy is given every 28 days. Up to 6 cycles of CFZ therapy will be 
administered on protocol. Four weekly doses of weekly rituximab, then 3 additional doses 
of monthly rituximab, will be administered to select patients who do not respond to CFZ 
following the first 2 cycles. (Total 7 doses of rituximab). 
We anticipate accrual of 24 patients over 18 - 24 months. Accrual will be limited to the 
first 9 patients initially then paused -- if needed-- to ensure the stopping rule (section 12.2 
and 12.3) has not been reached before additional patients are accrued. 
Plasmapheresis may be undertaken at any point in the study when clinically indicated. If 
protocol therapy is discontinued for disease progression requiring other treatment, 
patients may go on to receive other therapy at the discretion of their physician, but will be 
removed from this study. 
7.1.1 	
Dose and Administration 
Subjects with a BSA greater than 2.2 m2 should receive a dose based upon a 
BSA of 2.2 m2. 
Carfilzomib will be administered 20 mg/m2 over 30 minutes on Cycle 1 Day 1. If 
tolerated, the dose will be increased to 56 mg/m2 on D8 and D15 of cycle 1. 
Escalation to 70 mg/m2 starting with cycle 2 and beyond is allowed for all 
patients who have met criteria for ongoing therapy without delay due to toxicity, 
or need for dose modification as described in section 8.0.Cycles are repeated 
every 28 days. Do not administer as an IV bolus. 
A maximum of 6 total cycles may be given. 
7.1.1.1. 	
If 20 mg/m2 is not tolerated, it may be repeated with additional 
supportive care at clinical discretion for up to 4 weekly doses (Cl D1, 
Cl D8, Cl D15, and C2 D1) while reconsidering dose escalation. CFZ 
must then be escalated to 56 mg/m2 for at least 2 doses, prior to 
increasing to 70 mg/m2 as tolerated. 
Carfilzomib Therapy: Day 1, 8, and 15 of 28-day cycles 
Carfilzomib 
Cycle 1-6 (actual dates may vary +/- 3 days) 
Carfilzomib 20 mg/m2 over 30 minutes *with 
dexamethasone pre-medication 
Cycle 1 Day 1 
Carfilzomib 56 mg/m2 over 30 minutes *with 
dexamethasone pre-medication for cycle 1 
cycle 1 Day 8 and 15 
Carfilzomib 70 mg/m2 over 30 minutes 
All future days starting with Cycle 2 Day 1. 
Dose modification in response to toxicity is described under section 8.0 below. 
7.1.2 Required Premedication and Post-medication for Cycle 1, All Doses 
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For cycle 1: dexamethasone 8 mg orally or IV will be administered. Pre-medicate 
30 minutes to 4 hours prior to all doses in cycle 1, and as needed with future 
cycles to reduce the incidence and severity of infusion reaction. 
In addition, for cycle 1, 250 ml hydration using normal saline will be given pre-
dose on day 1, 8, and 15 unless contraindicated due to clinician judgment. This 
hydration is optional for future cycles. 
7.1.3 Supportive Care 
Consider antiviral prophylaxis for patients who have a history of herpes zoster 
infection, using Acyclovir 800 mg PO daily. Additional prophylaxis or monitoring 
for infections may be used for subjects deemed at high risk of bacterial, viral, or 
fungal infections. 
Premedication for rituximab will be administered according to standard, 
institutional guidelines. 
7.1.4 	
Blood pressure monitoring at least twice per week during cycle 1 will be 
conducted for patients with pre-existing systolic hypertension on medical 
therapy, or any who develop grade 3 hypertension or require the addition 
of antihypertensive therapy during cycle 1. 
7.2 	
Administration of Rituximab to CFZ Non-responders 
Subjects who fail to achieve at least a 25% M-protein reduction based on SPEP m-
protein quantification for WM, or partial response for MZL based on imaging, following 2 
cycles of CFZ therapy will receive rituximab concurrent with CFZ. 
7.2.1 	
Note: the bone marrow aspirate / biopsy after cycle 2 is exploratory and not to be 
used for response assessment or determination regarding rituximab. 
7.2.2 IV Rituximab, pre-medications, and hypersensitivity management will be 
administered according to standard institutional or pharmacy guidelines. 
RITUXIMAB weekly x 4 doses (cycle 3) then monthly (cycles 4-6) 
Treatment 
Cycle 3-6 for patients not responding to CFZ 
(actual dates may vary +/- 3 days; cycle timing 
refers to CFZ) 
C3 
D1,8,15,22 
C4D1 C5D1 C6D1 
Rituximab 375 mg/m2 
X, X, X, X 
X 
X 
X 
7.2.3 Following rituximab administration for WM, weekly laboratory evaluation of IgM 
levels (to evaluate for Ig M flare for clinical and study data purposes) is required. 
(See section 10, study calendar). As clinically indicated, viscosity measurement 
and other evaluation or management of hyper-viscosity syndrome, including 
plasmapheresis, should be undertaken. Weekly evaluation will continue until no 
longer clinically indicated. 
7.3 	
Criteria for removal from protocol treatment: (Note: Subjects discontinued from CFZ will 
not receive rituximab on study.) 
7.3.1 	
Symptomatic progression of disease after completion of at least 4 total cycles of 
CFZ therapy (with or without rituximab). IgM flare following rituximab (even if 
requiring plasmapheresis), or biochemical progression alone do not require 
removal from protocol treatment. 
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7.3.2 Inability to tolerate more than 20 mg/m2 of CFZ during the first 4 doses of 
therapy, despite maximal supportive care. 
7.3.3 Development of excess hematologic toxicity not responding to supportive care or 
persisting despite dose reductions—as outlined in Section 8.0 
7.3.4 Development of any other unacceptable toxicities unless prophylactic measures 
can be taken for subsequent cycles. 
7.3.5 Missed doses will not be replaced during a cycle. If a subject misses more than 
2 doses of any cycle for reasons other than toxicity, the subject will be 
discontinued. 
7.3.6 Delay of a treatment cycle for more than 4 weeks due to adverse events 
7.3.7 Completion of protocol treatment (maximum of 6 cycles, or 18 doses of CFZ). 
7.3.8 The patient may withdraw from the treatment at any time for any reason. 
7.3.9 Subjects may be removed from treatment in the event of study termination for 
any reason, as described under section 18.0. 
7.4 	
Early Termination for Futility 
As in section 12.2, the study will be stopped if two or fewer of the first 9 patients respond 
after cycle two. Previously enrolled subjects will continue on study as per the treatment 
plan (Section 7). 
8.0 	
REQUIREMENTS TO BEGIN A NEW CYCLE AND DOSE ADJUSTMENT GUIDELINES 
Parameters for retreatment and treatment modifications are as follows. Patients may be reduced 
to dose level -1 or 2, without impact on future enrolled patients (who will initiate the Starting 
Dose.) 
Dose levels are as follows: 
Starting Dose: CFZ 20 mg m2 (C1D1) then 56 mg/m2 (cycle 1 day 8 and 15), then 70 mg/m2 
(all future weekly doses) 
Dose level -1: CFZ 56 mg/m2 
Dose level -2: CFZ 27 mg/m2 
8.1 	
Requirements to Begin a New Cycle 
Subsequent cycles of CFZ therapy will not begin until the ANC is 500/111_ and the platelet 
count is 50,000/111_ unless related to disease infiltration. For patients with cytopenias 
related to marrow infiltration, return to the subject's baseline ANC and platelet count is 
adequate to resume a subsequent cycle. 
Treatments will also be delayed for reasons described in Section 8.2, or for clinically 
significant Grade 2 or 3 adverse events and unrelated Grade 4 adverse events at the 
discretion of the treating physician, or Principal Investigator. 
Therapy may be delayed a maximum of 4 weeks until these values are achieved for Day 
1 of each cycle. Hematopoietic growth factors and blood product support are allowed. 
There are no study parameters required for initiation of rituximab. Rituximab and CFZ 
should be started simultaneously during Cycle 3 for subjects who qualify (section 7.2), 
and are deemed fit for rituximab therapy by the investigator. 
Subjects who undergo dose reduction to dose level -2 may not undergo further dose 
changes. 
8.2 	
Specific management of toxicities are as follows: 
8.2.1 Neutropenia 
For the first instance of ANC 51000/uL with complications, or ANC 500/uL 
unless related to disease infiltration, GCSF support will be initiated. 
For the second such instance despite GCSF support, CFZ will be reduced to 
dose level -1. 
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Symptom 	
Recommended Action 
Carfilzomib 
Allergic reaction/hypersensitivity 
Grade 2 — 3 	
Hold until 5 Grade 1, reinstitute at full 
dose. 
Grade 4 	
Discontinue 
Grade 3 or higher systolic HTN 	
Hold until grade 2 or less, initiate medical 
management if clinically indicated, dose 
only when resolves or improves to Grade 2 
or less. 
Tumor lysis syndrome 
3 of following: 50% increase in 
creatinine, uric acid, or phosphate; 30% 
increase in potassium; 20% decrease in 
calcium; or 2-fold increase in LDH 
Hold CFZ until all abnormalities in serum 
chemistries have resolved. Reinstitute at 
full doses. 
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For the third instance or failure to achieve ANC 500/uL in 4 weeks, despite 
GCSF support, the subject will be reduced to dose level -2. If severe 
neutropenia persists, patients will be removed from study. 
For subjects with disease infiltration, GCSF support may be used at the 
discretion of the investigator. For ANC s500/uL without complications and 
attributable to disease infiltration, return to a subject's baseline is required 
and adequate, to start a new cycle. 
8.2.2 Thrombocytopenia 
For the first instance of platelets 525,000/uL, or at the discretion of the 
investigator for patients deemed at risk of bleeding complications, CFZ will 
be reduced to dose level -1. 
For the second instance of platelets s25,000/uL or failure to achieve platelet 
count of 25,000/uL or greater after 4 weeks, CFZ will be reduced to dose 
level -2. If further decreases are required, the patient will be removed from 
study therapy. 
8.2.3 Anemia 
There is no pre-specified dose reduction requirement for anemia, but growth 
factors or transfusion (where appropriate) may be used and CFZ may be dose 
reduced as clinically indicated. 
8.2.4 Dose Reductions for Non-Hematologic Toxicities 
Study drug should be held for Grade 3 events until resolved to 5 Grade 1 
or return to baseline, unless otherwise noted in the table below. 
All cases of grade 3 or greater systolic HTN (SBP >160) will require 
action per protocol including holding study drug and management 
/dosing only once BP is controlled. 
After resolution of the event to s Grade 1 or return to baseline, if the 
adverse event was not treatment-related, subsequent treatment with CFZ 
may resume at full dose. If the event was treatment-related, subsequent 
treatment with CFZ will resume at dose level -1. If toxicity continues or 
recurs, a 2nd CFZ dose reduction to dose level -2 may be permitted the 
discretion of the investigator. No more than two dose reductions will be 
permitted in an individual subject on study. If toxicity continues or recurs 
after two dose reductions, the subject should be removed from study. 
Dose adjustment guidelines for non-hematologic toxicities are summarized 
in the following table: 
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Infection Grade 3 or 4 
Herpes zoster or simplex of any grade 
Gr 2 treatment emergent neuropathy with 
pain 
Grade 3 neuropathy 
Grade 4 neuropathy 
Renal Dysfunction 
CrCI 5 15 mL/min 
Hold CFZ until systemic treatment for 
infection complete. If no neutropenia, 
restart at full dose. If neutropenic, follow 
neutropenic instructions. 
Hold CFZ until lesions are dry. Reinstitute 
at full dose 
Continue to dose. If neuropathy persists 
for more than two weeks hold CFZ until 
resolved to 5 Gr 2 without pain. Then 
restart at 1 dose decrement 
Withhold CFZ until resolved or returned to 
baseline. Subsequent treatment with 
carfilzomib should resume at a lower dose 
level. 
Discontinue 
Hold until CrCI > 30 mL/minute; restart at 1 
dose decrement 
Congestive heart failure 
Other non-hematologic toxicity assessed as 
CFZ-related > Grade 3 
Any subject with symptoms of congestive 
heart failure, whether or not drug related, 
must have the dose held until resolution or 
return to baseline, after which treatment 
may continue at a reduced dose, or the 
subject may be withdrawn from the study. 
If this results in a delay of treatment for 
more than 4 weeks, the subject will be 
withdrawn from the study. 
Hold dose until toxicity resolves to 
5 Grade 1 or baseline. Restart at 
1 dose decrement. 
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8.2.5 Missed Doses 
Missed doses will not be replaced during a cycle. If a subject misses 
more than 2 doses of any cycle for reasons other than toxicity, the 
subject will be discontinued. 
8.2.6 Changes in Body Surface Area (BSA) 
Dose adjustments do not need to be made for weight gains/losses of 
5 20%. Subjects with a BSA greater than 2.2 m2 should receive a dose 
based upon a BSA of 2.2 m2. 
8.2.7 	
Dosing Modifications 
Dose modifications and delays different from those stated in the protocol, 
for management of toxicities, will be permitted at the discretion of the 
Investigator. 
8.2.8 Safety Considerations 
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CC 9702 
Based upon the experience in the Phase 1 and 2 clinical studies with 
CFZ, 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, which may be the clinical 
sequelae of rapid tumor lysis and/or cytokine release. 
Should a "first dose" effect occur at any point during Cycle 1 or 2, 
treatment with high dose glucocorticoids (e.g. methylprednisolone 50-
100 mg) is recommended. In addition, intravenous fluids, vasopressors, 
oxygen, bronchodilators, and acetaminophen should be available for 
immediate use and instituted, as medically indicated. 
Dexamethasone 8 mg PO/IV will be administered prior to all CFZ doses 
during the 1st cycle. 
If treatment-related fever, rigors, chills, and/or dyspnea are observed 
post any dose of CFZ after dexamethasone has been discontinued, 
dexamethasone should be re-started and administered prior to 
subsequent doses. 
CrCI 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 CFZ. Renal 
function must be monitored closely during treatment with CFZ. Serum 
chemistry values, including creatinine, must be obtained and reviewed 
prior to each dose of CFZ during Cycles 1 and 2. Carfilzomib must be 
held for subjects with a CrCI < 15 mL/min at any time during study 
participation. 
Subjects with active or suspected infection of any kind that required 
systemic treatment should not be dosed with CFZ until the infection has 
resolved and if being treated with anti-infective, the course of antibiotics 
has been completed. 
Carfilzomib treatment can cause nausea, vomiting, diarrhea, or 
constipation sometimes requiring the use of anti-emetics or anti-
diarrheals. Fluid and electrolyte replacement should be administered to 
prevent dehydration. 
9.0 	
CONCOMITANT THERAPY 
Medications used during the course of the study should be documented. 
9.1 	
Prohibited Concomitant Therapy 
The administration of concurrent medications intended to treat WM or MZL are not 
allowed during protocol therapy, except plasmapheresis when clinically indicated. 
Concurrent radiation therapy is prohibited. 
Topical and inhaled corticosteroids to treat other medical conditions are allowed. 
Intermittent oral or IV corticosteroid administration is allowed as premedication prior to 
rituximab therapy or carfilzomib in cycle 1 or future cycles if clinically indicated; for 
management of nausea or vomiting; or for treatment of infusion reactions. 
9.2 Patients should be strongly discouraged from taking any "alternative" or "naturopathic" 
medications since these agents may interact with CFZ. Any use of these medications should 
be at the judgment of the treating physician and should be documented in the patient's 
medical record 
10.0 STUDY PROCEDURES AND CALENDAR 
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Pre-entry assessments other than laboratory tests may be done within 6 weeks of enrollment, 
and need not be repeated within that timeframe. Pre-entry laboratory studies must be done 
within 14 days of cycle 1. 
Required Studies 
Pre-Entryl 
(within 6 
wks of 
enrollment 
unless 
indicated) 
Day 1 of 
Each 
Cycle, +/- 
3 days 
Days 8 
and 15 
of each 
Cycle, 
+1-3 
days 
Cycle 
ycle 2 Day 
15 and 
Cycle
1
3 day 
Weekly for 
Cycles 3-6 
for all WM 
Rituximab 
_treated 
subjects 
End of 
Treatment 
(EOT)  
Follow 
-Up 
Physical 
Medical history 
X 
xli 
Physical exam 
X 
x11 
X7  
X8  
Vital signs 
including blood 
pressure (BP, 
HR, Temp, 
Respiratory rate) 
X 
X 
X 
Performance 
status 
X 
Response 
assessment 
X 
X 
X7  
Adverse event 
assessment 
X 
x11 
X7 
Patient home 
blood pressure 
monitoring 
Cycle 112 
Lab 
CBC with 
differential 
X 
xl, 
X 
X7  
X6  
Comprehensive 
metabolic panel 
X 
xi, 
X 
Serum LDH 
X 
xli 
X7 
Serum 
phosphorus 
X 
xi, 
for WM: SPEP 
with m-protein 
quantification, 
identification' 
X 
X 11  
X 
X8  
for WM: IgM 
(quantitative) 
X 
x il 
X 
X6  
X7  
X6  
for WM: Serum 
viscosity 
X 
B2 Microglobulin 
X 
X7  
Bone marrow 
studies 
X2  
X (for WM)5  
X2' 7  
Pregnancy test 
X3  
Hepatitis B 
testing 
X9  
X7  
Peripheral blood 
for flow cytometry 
X 
X5  
X7  
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BNP 
X 
xii_ 
cycles 
2,4,6 
only 
Radiology 
CT chest, 
abdomen and 
pelvis 
X4  
X 
X7  
X8  
MUGA or 
echocardiograml° 
xi() 
1 	
Pre-entry studies may be performed within 6 weeks of cycle 1 day 1 other than lab studies, which must be done within 14 days of 
Cycle 1 Day 1 of treatment. Baseline SPEP should be obtained for all patients, but repeat measurements are only required for WM 
patients. 
2 Baseline bone marrow aspirate and biopsy should be performed within 12 weeks of enrollment. Post therapy marrow will be 
performed only to confirm complete response, or as clinically indicated. Bone Marrow Studies include aspirate and unilateral biopsy 
with immunohistochemistry, as well as flow cytometry of the aspirate at baseline and after 2 cycles (baseline and post-cycle 2 cycle 
marrow aspirates are required for correlative analysis for WM patients). 
3 Pregnancy test in women of childbearing potential. 
4 CT imaging should be performed within 8 weeks of enrollment. CT neck should also be performed, if cervical adenopathy is 
present on physical exam. CT scans are repeated at interim analysis or during study protocol treatment for patients with 
nodal/extramedullary disease at baseline. CT scan should be performed in subjects with nodaVextramedullary disease post-therapy 
to assess response. 
5 For WM patients only, post-cycle 2 bone marrow and flow cytometry studies are required for correlative studies but will not be 
used for response assessment, which relies on SPEP (for WM) and CT imaging (for MZL). Post-cycle 2 studies may be performed 
any time after C2D15 dose of CFZ, up until Cycle 3 Day 1. 
6 For subjects receiving rituximab with WM, weekly quantitative IgM level (+/- 3 days) is to be measured. Further studies (serum 
viscosity, CBC, chemistries; additional clinical evaluations) may be performed if hyper-viscosity is suspected. Plasmapheresis may 
be performed as clinically indicated. 
7 Post therapy studies should be done 3 - 5 weeks post cycle 6 or after the patient's last cycle, whichever comes first. 
8 Follow-up should be done as per the clinical standard of care. A typical schedule includes every 3 months (total follow-up time 
from start of drug is 1 year). CT imaging as a standard of care surveillance measure should be performed no more frequently than 
every 6 months, unless a shorter interval is clinically indicated. 
9 Hepatitis B core Ab, Hepatitis B surface Ag; further testing as clinically indicated including HBV DNA 
Measurement of cardiac ejection fraction within 12 weeks of enrollment, by MUGA, echo, or other invasive/noninvasive testing, 
is allowed. 
For cycle 1 day 1 only, if history, physical exam, and labs are performed within 14 days of Cycle 1 day 1, they do not need to be 
repeated. BNP testing results, when associated with dyspnea or signs of cardiac disease, may be used to initiate further testing per 
investigator judgment. 
Home blood pressure monitoring at least twice per week will be conducted during cycle 1 for patients with pre-existing 
hypertension on medical therapy, or any who develop grade 3 hypertension or require the addition of antihypertensive therapy 
during cycle 1. Patients should record blood pressure on a provided diary during cycle 1. Dosing of CFZ must be held for grade 3 
or higher systolic hypertension as per section 8.2.4 
11.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
(See Appendix 20.3, and References 25,26, and 38) 
Diagnosis and response criteria are to be based on International Workshop36, Lugano response 
criteria23, and criteria of Matute et a124 for patients with splenomegaly alone. 
For WM, SPEP with m-protein quantification should be the primary means for assessing 
response to therapy, in addition to imaging, repeat immunofixation (to confirm CR), and marrow 
aspirate and biopsy when indicated. (Note that quantitative IgM by nephelometry is to be used 
for determining rituximab flare, as results may be available more rapidly.) 
12.0 STATISTICAL CONSIDERATIONS 
12.1 	
Accrual: We anticipate accrual of 24 patients over 18 -24 months. Accrual will be limited 
to the first 9 patients initially then paused -- if needed-- to ensure the stopping rule (section 12.2 
and 12.3) has not been reached before additional patients are accrued. 
12.2 	
Sample Size: This is a Simon 2 stage (minimax) design with stopping for futility. The 
primary endpoint is overall response rate, measured after 2 cycles of therapy. This 
model requires 24 total patients to be assessable after 2 cycles. 
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The null hypothesis, that the true response rate of single agent CFZ is 25%, will be tested 
against a one-sided alternative. In the first stage, 9 subjects will be enrolled. If two or 
fewer patients responds, the study will be stopped for futility. If 3 or more respond, a total 
of 15 more subjects will be enrolled. The null hypothesis will be rejected if 10 or more 
responses are observed in 24 assessable subjects. This design yields a type I error rate 
of .05, and a power of 80%, when the true response rate after 6 cycles of CFZ is 50%. 
Descriptive statistics will be used for baseline characteristics, and responses to 
treatment. Changes in mean fluorescence intensity pre- and post-CFZ of both CD20 and 
CD19 will be assessed compared using paired T testing. 
Estimate time to best response, time to progression, and survival outcomes for subjects 
using Kaplan-Meier analysis. 
12.3 	
Stopping Rule, and Rules for Suspending Accrual 
12.3.1 Futility: The study will be stopped if two or fewer of the first 9 patients respond 
after cycle two, as in section 12.2 above. 
12.3.2 Cardiac Toxicity: A composite endpoint of cardiotoxicity will lead to suspension of 
accrual, at the thresholds noted below: myocardial infarction, new onset atrial 
fibrillation, cerebrovascular accident, grade 4 hypertension, grade 3 left 
ventricular dysfunction, or grade 2 or higher heart failure. Events are counted per 
patient (i.e. a patient with more than one cardiac event counts only once toward 
this limit.) 
If there is sufficient evidence to suggest that the occurrence of any of the 
components of this composite "toxicity" (occurrence of at least one will constitute 
a "toxicity") exceeds a frequency of 10% of accrued patients, study accrual will 
be suspended pending review by the institutional data safety monitoring 
committee. Further accrual may be undertaken only with approval of that 
committee. Sufficient evidence will be taken to be any observed ratio associated 
with a lower 80% one-sided confidence limit that exceeds 0.10. 
Operationally, any of the following proportions of accrued patients 
experiencing cardiac toxicity (as defined above) would yield such a ratio: 2 
of the first 8 or fewer patients, 3 of the first 15 or fewer patients, 4 of the 
first 23 or fewer patients. 
If the true probability of toxicity is .05, the probability of stopping after 15 or 23 
patients is approximately .08 and .08, respectively. If the true probability of 
toxicity is .25, the probability of stopping after 15 or 23 patients is approximately 
.81 and .90, respectively (probabilities of stopping estimated from 5,000 
simulations). 
12.3.3 Inability to deliver rituximab therapy as per protocol: 
If per-prototol rituximab (as per protocol section 7.2) cannot be administered to 
at least 6 of the first eligible 12 patients for any reason, accrual will be suspended 
for review by the institutional data safety monitoring committee, before further 
accrual may proceed. 
13.0 CORRELATIVE STUDIES 
13.1 	
Assessment of CD19 and CD20 expression changes following CFZ therapy (all  
patients):  
Bortezomib modulates CD20 expression, and affects CDC, in a time- and concentration-
dependent manner.25. 26 Increased CD20 expression is observed in bortezomib-resistant 
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CC 9702 
cells, which in turn display increased sensitivity to rituximab-mediated complement-
dependent cytotoxicity. Furthermore, rituximab resistance appears to depend partly on 
CD20 down-expression.27-3° 
Therefore, we hypothesize that 1) rituximab-resistant patients will have lower CD20 
expression at baseline, and 2) that CFZ may increase CD20 expression after 2 cycles. 
We will explore, albeit with small sample size of WM patients, whether response to 
subsequent rituximab in initial CFZ nonresponders is associated with CD20 expression. 
We postulate that overall, it may be possible to increase CD20 expression to prime tumor 
cells for optimal rituximab effect, with implications for sequencing these therapies. 
Methods: Peripheral blood samples from each patient before therapy and again after 2 
cycles of CFZ (see Study Calendar, Section 10.0), will be submitted to UW for 
quantitative evaluation of CD19 and CD20 surface expression (measuring mean 
fluorescence intensity). 
13.2 	
Correlating Marrow Response Using Flow Cytometry with Paraprotein Response (WM  
patients only): Response assessment in WM undergoes continual evolution, but still 
relies on magnitude of the IgM paraprotein reduction. However, discordant responses 
are commonly observed between paraprotein levels, node size, and marrow involvement 
and appear to vary based on therapy given. IgM levels have been reported to decrease 
rapidly with proteasome inhibitors, transiently flare following rituximab, and lag behind 
marrow responses after fludarabine; best paraprotein response may be delayed, 
occurring months following therapy.22,31,32 Flow cytometry is particularly suited for 
quantifying the lymphoid cells in the marrow of WM patients.33. 34 The degree of B cell 
lymphoid involvement at end of treatment is prognostic—WM patients with less than 5% 
clonal B cells as in marrow samples by flow cytometry have superior outcomes.35  
Methods: Marrow samples from WM patients will be evaluated before treatment, after 
cycle 2, and at the end of study for patients with CR for flow cytometric evaluation of both 
lymphoid and plasma cell components, and reported descriptively alongside paraprotein 
responses. 
13.3. Specimen Requirements: Submission for flow cytometry 
A 5-10 mL specimen of peripheral blood or BM aspirate in a lavender- (EDTA) or 
green- (sodium heparin) tube is acceptable for each draw. 
Storage/Transport Temperature: Specimens can be transported with a cold pack 
or wet ice, but do not fix or freeze specimens. 
If no significant amount of bone marrow aspirate is obtained, a fresh bone 
marrow biopsy in RPMI (cell culture medium) may be submitted for flow 
cytometry. 
Formalin-fixed bone marrow biopsies or clots should be submitted for 
morphological evaluation and immunohistochemical studies, but they cannot be 
used for flow cytometry immunophenotyping. 
Unacceptable Conditions: Frozen specimens, specimens greater than 48 hours 
old, specimens fixed in formalin for flow cytometry 
13.4 	
Specimen Shipping Address 
Attn: Katy Dougherty, Hematopathology Lead 
Seattle Cancer Care Alliance 
Hematopathology Laboratory G7800 
825 Eastlake Ave E. 
Seattle, WA 98109 
14.0 REPORTING REQUIREMENTS FOR ADVERSE EVENTS/ADVERSE REACTIONS 
14.1 	
Adverse Events Definitions 
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Severity 	
Description 
GRADE 1 — Mild 
GRADE 2 — Moderate 
GRADE 3— Severe 
GRADE 4 — Life-threatening 
GRADE 5 — Fatal 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of 
daily living (preparing meals, shopping, using the 
phone, managing money, etc.). 
Medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
activities of daily living (bathing, dressing, feeding 
self, toileting, taking medications, not bedridden). 
Life —threatening consequences; urgent intervention 
indicated. 
Death 
CC 9702 
An AE is any untoward medical occurrence in a study subject administered an 
investigational product and that does not necessarily have a causal relationship with this 
treatment. 
An AE therefore can be any unfavorable and unintended sign (including laboratory 
finding), symptom or disease temporally associated with participation in an investigational 
study, whether or not considered drug-related. In addition to new events, any increase in 
the severity or frequency of a pre-existing condition that occurs after the subject signs a 
consent form for participation is considered an AE. This includes any side effect, injury, 
toxicity, or sensitivity reaction. 
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current I B or prescribing information for a marketed compound. Also, 
reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs. For example, an event more specific or 
more severe than described in the IB would be considered "unexpected". 
Whenever possible, the most current version of the Common Terminology Criteria for 
Adverse Events (CTCAE) should be used to describe the event and for assessing the 
severity of AEs (see Appendix D). Any events representing a change in the CTCAE 
Grade need to be reported on the AE case report form. 
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject's medical history. 
Causality 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows: 
Yes, the event is suspected to be related if: 
there is a clinically plausible time sequence between onset of the AE and administration of 
study treatment; and/or 
there is a biologically plausible mechanism for the study treatment to cause or contribute to 
the AE; and/or 
the event responds to withdrawal of the study medication (de-challenge) and/or recurs with 
re-challenge (when clinically feasible); and/or 
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CC 9702 
the AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, or 
procedures 
No, the event is NOT suspected to be related if 
the AE is more likely to be explained by the subject's clinical state, underlying disease, 
concomitant medication, study or non-study procedure; and/or 
the time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
the event is unlikely to be related to the investigational product(s) 
14.2 	
Adverse Events Reporting Procedures 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing 
condition or laboratory finding) with an onset date after the first dose of study drug must 
be promptly documented on the appropriate summary. Details of the event must include 
severity, relationship to study drug, duration, action taken, and outcome. Serious 
adverse events (SAEs) will be recorded on the appropriate form. 
All AEs that are considered related to study drug must be followed to resolution or 
stabilization if improvement is not expected. 
AEs should be reported from the time the subject receives their first dose of study drug, 
through 30 days post-last dose of study drug or initiation of a new anti-cancer therapy, 
whichever occurs first. In addition, the Investigator should report any AE that may occur 
after this time period that is believed to have a reasonable possibility of being associated 
with study drug. If a subject discontinues study prior to receiving any study drug, AEs 
must be reported through the end-of-study visit. AEs which completely resolve and then 
recur should be recorded as a new AE. For subjects who complete the end of study visit 
less than 30 days following their last dose of study drug, a follow up of ongoing AEs 
should be attempted by telephone, and documented in the subject's source. AEs 
continuing at 30 days post-last dose should have a comment in the source by the 
Investigator that the event has stabilized or is not expected to improve. 
The Principal Investigator is responsible for evaluating ajl AEs, obtaining supporting 
documents, and determining thsat documentation of the event is adequate. Adverse 
events will be assigned a severity grade using the most current version of the NCI-
CTCAE. 
Grade 3 or higher AE's will be recorded, including laboratory abnormalities. Grade 1 and 
2 abnormalities should only be recorded if they require treatment or are otherwise 
considered clinically significant by the Investigator. 
The Principal Investigator may delegate reporting and AE assessment duties to Sub-
investigators and must ensure that these Sub-investigators are qualified to perform these 
duties under the supervision of the Principal Investigator. 
14.3 	
Serious Adverse Events Definitions 
An SAE is one that meets the following criteria: 
Death 
Life threatening experience defined as any adverse experience that places the 
subject, in the view of the Investigator, at immediate risk of death at the time of 
occurrence; i.e., it does not include a reaction that, had it occurred in a more severe 
form, might have caused death. 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
(except scheduled hospitalizations for non-acute, unrelated cause such as an 
elective surgery) 
Results in persistent or significant disability/incapacity 
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Is a congenital anomaly/birth defect in the offspring of an exposed subject 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE, when, based upon appropriate medical 
judgment, it jeopardizes the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
Any death occurring within 30 days of the subject receiving study drug, regardless of the 
subject having discontinued from the study must be reported as an SAE. 
14.4 	
Serious Adverse Event Reporting and Documentation Requirements 
All SAEs occurring from the time that the subject signs consent for study participation 
through 30 days after the last administered dose of study drug will be reported. All SAEs 
regardless of relationship to study drug must be followed to resolution or to stabilization if 
improvement or resolution is not expected. 
If a subject is permanently withdrawn from the study because of a SAE, this information 
must be included in the initial or follow-up SAE report as well as the appropriate form for 
Study Discontinuation. 
The Investigator is also responsible for notifying the Institutional Review Board (IRB) in 
accordance with local regulations, of all SAEs. 
Additionally, the Investigator is responsible for reporting adverse events to Amgen and 
NCCN as described below: 
14.5 	
Expedited Reporting 
The Investigator must inform Amgen and NCCN via email at the contact information listed 
below of all Expedited Safety Reports submitted to the relevant Regulatory Agencies 
within 24 hours. This must be documented on a FDA 3500A MEDWATCH or CIOMS I 
form and must be completed and supplied to Amgen in English. 
The initial report must be as complete as possible, at a minimum including the serious 
adverse event term (s), patient identifier, date of awareness of the event, an assessment 
of the causal relationship between the event and the investigational product(s), and name 
of the reporter (investigator). Information not available at the time of the initial report 
(e.g., an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up MEDWATCH or CIOMS I form and submitted to 
Amgen and NCCN in the same timelines as outlined above. The Amgen protocol number 
(IST-CAR-XXX) and the institutional protocol number should be included on all reports to 
Amgen and NCCN. 
All other SAE's will be sent to Amgen and NCCN on a quarterly basis in the form of a line 
listing in English. The line listing must include the following information; patient initials, 
date of birth, sex, SAE onset date, SAE stop date, event name (term), outcome, date of 
first dose of study drug(s), date of last dose of study drug(s) prior to the event, action 
taken with study drug(s) the Investigator's assessment of causality (relationship to CFZ), 
and the Investigator's assessment of expectedness to CFZ. The sponsor reserves the 
right to review the CRFs or source documents in response to any inquires by regulatory 
agencies that the sponsor may receive. 
Amgen Pharmacovigilance Contact Information 
Amgen Global Safety 
Phone: 	
800-77-AMGEN 
Fax: 	
1-888-814-8653 (using SAE fax cover sheet to be provided in Open Study Packet) 
Email: 	
svc-ags-in-usamgen.com 
  
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CC 9702 
NCCN Contact Information: 
Fax: 	
(215) 358-7699 
Email: 	
ORPReportsnccn.orq 
14.6 Pregnancy 
If a subject or spouse or partner of a subject becomes pregnant while enrolled in this 
clinical trial, Amgen Drug Safety and NCCN must be notified within 24 hours of the 
Investigator, designee, or site personnel learning of the pregnancy (See Amgen Drug 
Safety and Pharmacovigilance and NCCN Contact information above). If the subject is 
pregnant, CFZ must be withheld. 
Subjects, spouses, or partners will be followed through the outcome of the pregnancy. 
The Investigator will be required to report the results to Amgen Drug Safety and NCCN. 
If the outcome of the pregnancy meets a criterion for immediate classification as an 
SAE—spontaneous abortion (any congenital anomaly detected in an aborted fetus is to 
be documented), stillbirth, neonatal death, or congenital anomaly—the Investigator 
should repeat the procedures for expedited reporting of SAEs as outlined above. 
15.0 DATA AND SAFETY MONITORING PLAN 
Ongoing trial oversight is carried out by the Principal Investigator. The Principal Investigator will 
review acquired data and adverse events on a regular basis. The data recorded within the 
research charts and protocol database is compared with the actual data that is available from the 
medical record and/or clinical histories. Data detailed in the research case report forms includes 
the nature and severity of all toxicities, which are also reported as described above. 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the 
provisions of this plan, Fred Hutchinson Cancer Research Center (FHCRC) Clinical Research 
Support coordinates data and compliance monitoring conducted by consultants, contract 
research organizations, or FHCRC employees unaffiliated with the conduct of the study. 
Independent monitoring visits occur at specified intervals determined by the assessed risk level of 
the study and the findings of previous visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients. The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to 
continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
16.0 RECORDS 
Research staff under the supervision of the investigators will maintain case report forms and 
secured databases on the relevant clinical and laboratory data. Records maintained in 
investigators' offices will be secured with access limited to study personnel. Authorization for 
access to medical records will be obtained from all patients in accordance with provisions of the 
Health Insurance Portability and Accountability Act (HIPAA). 
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CC 9702 
17.0 REGULATORY RESPONSIBILITIES 
The Principal Investigator will ensure that the study is conducted in accordance with all applicable 
institutional, state, and federal regulatory requirements, including, but not limited to: compliance 
with requirements for IRB and other regulatory approvals, monitoring responsibilities, reporting 
obligations, and compliance with standards for written informed consent from all patients entering 
the study. In addition, the Principal Investigator will ensure oversight of the study via data and 
safety monitoring as described above. 
18.0 TERMINATION OF THE STUDY 
Patients may be removed from this study at any time per their discretion. Individual patients may 
be removed from this protocol if they develop any untoward side effects from the study treatment 
or for other reasons as described under section 7.7. 
The study will be closed to accrual upon treatment of the total planned number of study subjects. 
The study will be completed following treatment of all study subjects and completion of follow-up 
and data analysis as described in the protocol. If the study drug becomes unavailable for any 
reason, the study will be suspended until drug availability resumes or terminated as appropriate. 
In addition, there are stopping rules in place for lack of efficacy as detailed in the statistical 
section. The Principal Investigator may terminate the study at any time. The IRB and FDA also 
have the authority to suspend or terminate the study should it be deemed necessary. 
The Principal Investigator shall provide Amgen with a final study report no later than one (1) 
calendar year after study completion. The report shall include all AEs generated by the Study, 
irrespective of whether the AEs are serious or non-serious, and a causality assessment for each 
AE, regardless of whether the AE is related to the investigational drug. 
19.0 REFERENCES 
Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakes M. Waldenstrom's 
macroglobulinemia: clinical features, complications, and management. J Clin Oncol. 2000;18(1):214-226. 
Thieblemont C. Clinical presentation and management of marginal zone lymphomas. Hematology Am 
Soc Hematol Educ Program. 2005:307-313. 
Ghobrial IM, Leleu X, Azab AK, et al. Novel therapeutic agents in Waldenstrom's macroglobulinemia. 
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Kastritis E, Terpos E, Dimopoulos MA. Emerging drugs for Waldenstrom's macroglobulinemia. Expert 
Opin Emerg Drugs. 2011;16(1):45-57. 
O'Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome 
inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin 
Oncol. 2005;23(4):676-684. 
Dimopoulos MA, Chen C, Kastritis E, Gavriatopoulou M, Treon SP. Bortezomib as a treatment option in 
patients with Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2010;10(2):110-117. 
Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment recommendations from the Fourth 
International Workshop on Waldenstrom's Macroglobulinemia. J Clin Oncol. 2009;27(1):120-126. 
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Treon SP, loakimidis L, Soumerai JD, et al. Primary therapy of Waldenstrom macroglobulinemia with 
bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 
2009;27(23):3830-3835. 
Ghobrial IM, Hong F, Padmanabhan S, et al. Phase II trial of weekly bortezomib in combination with 
rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 
2010;28(8):1422-1428. 
Conconi A, Martinelli G, Lopez-Guillermo A, et al. Clinical activity of bortezomib in relapsed/refractory 
MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group 
(IELSG). Ann Oncol. 2011;22(3):689-695. 
de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study of weekly or twice-weekly 
bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell 
lymphoma. J Clin Oncol. 2009;27(30):5023-5030. 
Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment 
offers a neuropathy-sparing approach for treating Waldenstrom's macroglobulinemia. Blood. 
2014;124(4):503-510. 
Kortuem KM and Stewart AK. Carfilzomib. Blood. 2013;121(6):893-897. 
Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for 
relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152. 
Berenson JR, Cartmell A, Bessudo A, et al. CHAMPION-1: a phase 1/2 study of once-weekly 
carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127(26):3360-
3368. 
Grandin EW, Ky B, Cornell RF, Carver J, Lenihan DJ. Patterns of cardiac toxicity associated with 
irreversible proteasome inhibition in the treatment of multiple myeloma. J Card Fail. 2015;21(2):138-144. 
Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience 
from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761. 
Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib 
and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a 
randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. 
Atrash S, Tullos A, Panozzo S, et al. Cardiac complications in relapsed and refractory multiple 
myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5:e272. 
Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab 
for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). 
Leuk Lymphoma. 2004;45(10):2047-2055. 
Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of Waldenstrom's macroglobulinemia with 
rituximab. J Clin Oncol. 2002;20(9):2327-2333. 
Treon SP, loakimidis L, Soumerai JD, et al. Primary therapy of Waldenstrom macroglobulinemia with 
bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 
2009;27(23):3830-3835. 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-3068. 
Matutes E, Oscier D, Montalban C, et al. Splenic marginal zone lymphoma proposals for a revision of 
diagnostic, staging and therapeutic criteria. Leukemia. 2008;22(3):487-495. 
Bil J, Winiarska M, Nowis D, et al. Bortezomib modulates surface CD20 in B-cell malignancies and 
affects rituximab-mediated complement-dependent cytotoxicity. Blood. 2010;115(18):3745-3755. 
Verbrugge SE, Al M, Assaraf YG, et al. Overcoming bortezomib resistance in human B cells by anti-
CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible 
proteasome inhibitors. Exp Hematol Oncol. 2013;2(1):2-3619-2-2. 
Czuczman MS, Olejniczak S, Gowda A, et al. Acquirement of rituximab resistance in lymphoma cell 
lines is associated with both global CD20 gene and protein down-regulation regulated at the 
pretranscriptional and posttranscriptional levels. Clin Cancer Res. 2008;14(5):1561-1570. 
Golay J, Lazzari M, Facchinetti V, et al. CD20 levels determine the in vitro susceptibility to rituximab 
and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 
2001;98(12):3383-3389. 
Takei K, Yamazaki T, Sawada U, Ishizuka H, Aizawa S. Analysis of changes in CD20, CD55, and 
CD59 expression on established rituximab-resistant B-lymphoma cell lines. Leuk Res. 2006;30(5):625-
631. 
Singh V, Gupta D, Arora R, Tripathi RP, Almasan A, Macklis RM. Surface levels of CD20 determine 
anti-CD20 antibodies mediated cell death in vitro. PLoS One. 2014;9(11):e111113. 
Chen Cl, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed 
Waldenstrom's macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical 
Trials Group. J ClinOncol. 2007;25(12):1570-1575. 
Varghese AM, Rawstron AC, Ashcroft AJ, Moreton P, Owen RG. Assessment of bone marrow 
response in Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma. 2009;9(1):53-55. 
Barakat FH, Medeiros LJ, Wei EX, Konoplev S, Lin P, Jorgensen JL. Residual monotypic plasma cells 
in patients with waldenstrom macroglobulinemia after therapy. Am J Clin Pathol. 2011;135(3):365-373. 
Morice WG, Chen D, Kurtin PJ, Hanson CA, McPhail ED. Novel immunophenotypic features of 
marrow lymphoplasmacytic lymphoma and correlation with Waldenstrom's macroglobulinemia. Mod 
Pathol. 2009;22(6):807-816. 
Garcia-Sanz R, Ocio E, Caballero A, et al. Post-treatment bone marrow residual disease > 5% by flow 
cytometry is highly predictive of short progression-free and overall survival in patients with Waldenstrom's 
macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011;11(1):168-171. 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenstrom macroglobulinaemia: 
update from the Vlth International Workshop. Br J Haematol. 2013;160(2):171-176. 
20.0 APPENDIX 
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20.1 	
Identified Risks of CFZ 
A Phase 1 clinical trial, PX-171-002, testing CFZ in subjects with relapsed/refractory 
hematologic malignancies, is completed7. During the dose escalation portion of the trial, 
36 subjects received CFZ on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Subjects with 
Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), WaldenstrOm's 
Macroglobulinemia, and Hodgkin's Lymphoma (HL) were enrolled on the study. 
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses 
ranged from 1.2 to 15 mg/m2) of three subjects each. At the 20 mg/m2 dose level, one of 
eight patients had a Grade 3 renal failure at Cycle 1, Day 2 which was considered 
possibly related to study drug and lasted for six days. The patient continued on study for 
the remainder of Cycle 1 before having disease progression. At the 27 mg/m2 dose 
level, one of six subjects experienced a DLT during Cycle 1, consisting of severe hypoxia 
with pulmonary infiltrates following Day 2 of dosing. In subjects where the 27 mg/m2  
dose was efficacious, a "first dose effect" was seen that included a constellation of 
findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome (TLS) 
and/or cytokine release. This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion. On the second day, three of five 
subjects with multiple myeloma experienced an increase in creatinine to Grade 2 
(including the subject with the DLT). This elevation was rapidly reversible and all three 
subjects were rechallenged with CFZ without recurrence of the events. Interestingly, all 
three subjects had a rapid decline in serum and/or urine M-protein levels; two subjects 
achieved a PR and the third subject achieved a minimal response (MR). There were no 
consistent changes in potassium, calcium, phosphorous, or uric acid levels although 
some increases in LDH and other markers of tumor lysis were noted. Because of the 
possible TLS and reversible creatinine elevations, hydration and very-low dose 
dexamethasone prophylaxis were instituted in subsequent studies and have essentially 
eliminated clinically significant TLS/creatinine elevations and the other "first-dose" effects. 
Hematologic toxicities were primarily mild or moderate. The thrombocytopenia reported 
with CFZ 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 CFZ, subjects with thrombocytopenia should be 
supported as clinically indicated rather than having treatment reduced due to 
thrombocytopenia. 
Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM7. Four MM patients 
achieved a partial response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 
mg/m2 dose, and two of five at the 27 mg/m2 dose. The responses have been rapid in 
onset, beginning in some subjects after 1-2 doses. The duration of response (DOR) 
ranged from 134 to 392 days. The minimal effective dose was 15 mg/m2 wherein >80% 
proteasome inhibition in peripheral blood and mononuclear cells was observed one hour 
after dosing. The median number of prior therapies for subjects on this trial was five, and 
responses were seen in subjects who had relapsed from (including some refractory to) 
bortezomib and/or immunomodulatory agents. Stable disease also occurred in four NHL 
and five MM subjects, with subjects on therapy for up to 409 days. Such prolonged 
therapy, at "full" twice-weekly doses, is not possible with bortezomib. 
20.2 Response Assessment for WM 36  
Complete response (CR) 
Absence of serum monoclonal IgM protein by immunofixation 
Normal serum IgM level 
Complete resolution of extramedullary disease, i.e., lymphadenopathy and 
splenomegaly if present at baseline 
Morphologically normal bone marrow aspirate and trephine biopsy 
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Very good partial response (VGPR) 
Monoclonal IgM protein is detectable 
90% reduction in serum IgM level from baseline* 
Complete resolution of extramedullary disease, i.e., lymphadenopathy/ 
splenomegaly if present at baseline 
No new signs or symptoms of active disease 
Partial response (PR) 
Monoclonal IgM protein is detectable 
50% but <90% reduction in serum IgM level from baseline* 
Reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if 
present at baseline 
No new signs or symptoms of active disease 
Minor response (MR) 
Monoclonal IgM protein is detectable 
25% but<50% reduction in serum IgM level from baseline* 
No new signs or symptoms of active disease 
Stable disease(SD) 
Monoclonal IgM protein is detectable 
<25% reduction and <25% increase in serum IgM level from baseline* 
No progression in extramedullary disease, i.e., lymphadenopathy/splenomegaly 
No new signs or symptoms of active disease 
Progressive disease (PD) 
25% increase in serum IgM level* from lowest nadir (requires confirmation) 
and/or 
progression in clinical features attributable the disease 
*This study will employ M protein measurement by densitometry (SPEP) for primary measurement of 
response. 
20.3 	
Diagnostic Criteria for WM (all are required) 
IgM monoclonal gammopathy of any concentration 
10% or greater bone marrow infiltration by small lymphocytes showing 
plasmacytoid/plasma cell differentiation, with a predominantly intratrabecular pattern of 
bone marrow infiltration 
surface Igm+, CD5 +/-, CD10 CD19+, CD20+, CD23-, CD25+, CD27+, FMC 7+, 
CD103-, CD138- immunophenotype*. Variations from this profile can occur. However, 
care should be taken to satisfactorily exclude other lymphoproliferative disorders. This is 
most relevant in CD5+ cases, for which CLL and mantle cell lymphoma require specific 
exclusion before her diagnosis of WM can be made. 
*The plasmacytic component will be CD138+, CD38+ and CD45- or dim. 
20.4 	
Response criteria for Splenic MZL and Enrolled Patients with Spleen-Only /Spleen and 
marrow Disease24: 
For patients with Splenectomy: response will be considered when there is at 
least 50% improvement on the blood counts, non-progressive lymphocytosis and 
no change or improvement in the degree of BM infiltration. 
For patients solely with splenomegaly, absent CT-measurable disease: 
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Partial response: 50% or greater improvement in the disease manifestations. 
This should include resolution or decrease in spleen size, improvement on 
cytopenias and resolution or decrease in lymphadenopathy if present. BM 
should show a decrease in the level of lymphoid infiltration and improvement 
of the hemopoietic reserve. 
Complete response: Resolution of organomegaly, normalization of the blood 
counts (Hb412 g d11; platelets4 100 1011 ; neutrophils 41.5 1011 and no 
evidence of circulating clonal B cells). No evidence or minor BM infiltration 
detected by immunohistochemistry. 
No response and progressive disease: Less than 10% improvement on the 
disease manifestations or deterioration of the above, respectively. 
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