Clinical trial NCT01775930
Conditions: Kidney Cancer
Keywords: Kidney Cancer Refractory Renal Cell Carcinoma RCC Clear cell kidney cancer with metastatic disease Carfilzomib
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-10-01; Completion date: 2019-01-18
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is learn if carfilzomib can help control kidney cancer. The safety of this drug will also be studied.

Carfilzomib is designed to block cancer cells from repairing themselves. If the cancer cells cannot repair themselves, this may cause them to die.

Detailed description:
Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive carfilzomib 2 days a week for the first 3 weeks of each 4-week study cycle (Days 1, 2, 8, 9, 15, and 16 of each cycle). Each dose is given by vein over about 30 minutes.

Before you receive the study drug, you will be given dexamethasone to help decrease the risk of side effects during the first cycle. You may ask the study staff for information about how the drugs are given and their risks.

During Cycle 1, you will receive extra fluid (saline) by vein before each dose of study drug. This is part of standard clinical care. This will also be done during Cycle 2, if the study doctor thinks it is needed.

You will remain in the clinic for an extra hour after receiving each dose during Cycle 1 and after the first dose of Cycle 2, to receive additional fluids by vein.

If you have any side effects from the drug, tell the study doctor right away. The study doctor may then lower the dose or keep the dose level the same.

Each study cycle is 4 weeks.

Study Visits:

Weeks 1, 2, and 3 of each cycle:

* Your vital signs and weight will be measured.
* Blood (about 3 teaspoons) will be drawn for routine tests

Every 4 weeks (+/-4 days):

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs and weight.
* You will be asked about any drugs or treatments you may be receiving and any side effects that you have had.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your blood sugar level and your pancreatic function, if the study doctor thinks it is needed. You will be asked to fast (not eat, and drink only water) for at least 8 hours before this blood draw.

Every 8 weeks (+/-7 days):

* You will have an x-ray of chest, CT scan of the chest and abdomen, and MRI scan of the brain to check the status of the disease. If the doctor thinks it is needed, you will also have a bone scan.
* If you can become pregnant, you will have a blood (about 2 teaspoons) pregnancy test.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, intolerable side effects occur, or you are not able to follow study directions.

End-of-Treatment Visit:

About 30 days after your last dose of the study drug:

* You will have a physical exam, including measurement of your vital signs and weight.
* You will be asked about any drugs or treatments you may be receiving and any side effects that you have had.
* Blood (about 3 teaspoons) will be drawn for routine and blood sugar tests.
* You will have an x-ray, CT scan, and MRI scan to check the status of the disease.

Long-Term Follow-up:

After you stop taking the study drug, the study staff will check your health status every 6 months for the rest of your life. The study staff will collect this information by either checking your medical record, emailing you, or calling you on the telephone. Each call should only last about 5 minutes.

This is an investigational study. Carfilzomib is FDA approved and commercially available in treatment of multiple myeloma. The use of carfilzomib in kidney cancer is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Patients receive Carfilzomib at dose of 20 mg/m2 over 30 minutes by vein infusion on Days 1 and 2 and a dose of 56 mg/m2 over 30 minutes by vein infusion on Days 8, 9, 15, and 16 of each 4 week cycle.
Interventions: intervention 1: Carfilzomib
Intervention descriptions: intervention 1: 20 mg/m2 over 30 minutes by vein infusion on Days 1 and 2 and a dose of 56 mg/m2 over 30 minutes by vein infusion on Days 8, 9, 15, and 16 of each 4 week cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2012-0694 
May 9, 2014
Page 1
 
 
 
Study Title: Phase II Study of Carfilzomib in Patients with Refractory Renal Cell 
Carcinoma 
Institution Name: University of Texas MD Anderson Cancer Center 
Principal Investigator Information: 
Name: Eric Jonasch, M.D.  
Address: 1155 Pressler Street, Unit 1374 
Phone No:  (713) 792-2830 
Fax No: (713) 745-1625 
Email Address: ejonasch@mdanderson.org 
 
Co-Investigators: Nizar Tannir, M.D. 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
C
degrees Centigrade 
F
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
ASaT 
All Subjects as Treated 
AST 
aspartate aminotransferase 
bid 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CRO 
clinical research organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full Analysis Set 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 


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h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2
millimeter(s) squared 
mm3 
millimeter cubed 
MR 
minimal response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-
 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QDx5 
daily dosing for five days 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 


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SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results
SPEP
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
Tumor lysis syndrome 
TTP 
time to tumor progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
WBC 
white blood count 


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1
INTRODUCTION   
1.1 
DISEASE SPECIFIC BACKGROUND 
Cancers of the kidney and renal pelvis are diagnosed in nearly 60,000 individuals in the USA 
every year, and approximately 13,000 will die annually.1  Renal cell carcinoma (RCC) 
comprises the majority of these diagnoses, and clear cell renal cell carcinoma (ccRCC) is the 
most common histological subtype.  
Renal cell carcinoma has seen the approval of a significant number of agents in the past 
seven years, with a strong emphasis on VEGF and VEGF receptor targeting agents,2-5 as well 
as mammalian target of rapamycin (mTOR) blocking agents.6,7  Although these agents have 
clearly provided prolonged progression free survival (PFS) relative to placebo or to cytokine 
therapy, and have as a group increased OS of patients with advanced RCC, they possess 
several shortcomings.  The first is that these agents are rarely curative.  Additionally, VEGF 
ligand and receptor inhibitors do not target the tumor cell, and mTOR inhibitors appear to 
exert cytostatic, and not cytotoxic effects.   There is clearly room in the RCC therapeutic 
space to explore new mechanisms of action for treatment of this disease.  
1.2 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a 
wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin 
conjugation system.  Ubiquitinated proteins are cleaved within the proteasome by one or 
more of three separate threonine protease activities: a chymotrypsin-like activity, a trypsin-
like activity, and a caspase-like activity.  8 
1.3 
CARFILZOMIB BACKGROUND 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsin-like active site of the 20S proteasome.  Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib 
(Velcade®).8  In addition, when measured against a broad panel of proteases including 
metallo, aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-
proteasomal proteases when compared to bortezomib.9-11 
1.3.1 
CARFILZOMIB TOXICOLOGY STUDIES 
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by the drug 
maker, Onyx, carfilzomib was administered to rats and monkeys as two complete two-week 
cycles of QDx5 for five days with nine days rest12.  Administration to rats at 12 mg/m2, the 
severely toxic dose in 10% of animals (STD10), caused > 90% proteasome inhibition in red 
blood cells one hour after dosing.  Overall, stronger inhibition of the proteasome and longer 
duration of inhibition was tolerated with carfilzomib compared with bortezomib.  Daily 


Protocol 2012-0694 
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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 tumors12.  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.  DLTs 
included effects on the gastrointestinal, renal, pulmonary, and cardiovascular systems and 
appeared to related to Cmax effects.  Of note, neutropenia was not observed; rather, transient 
neutrophilia was seen following acute dosing.  Renal, cardiovascular and gastrointestinal 
toxicities were similar to those observed with bortezomib.  Finally, cyclical 
thrombocytopenia, likely due to inhibition of platelet budding from megakaryocytes, was 
similar to that seen with bortezomib.  Proteasome inhibition in the blood in excess of 90% 
was achievable at well-tolerated doses, which contrasts with the ~70% proteasome inhibition 
achieveable with bortezomib at its maximum tolerated dose (MTD).  In summary, these 
animal toxicity studies support the tolerability of carfilzomib in clinical studies, even on 
intensive dosing schedules and at doses achieving proteasome inhibition in excess of what 
can be achieve with bortezomib at its MTD on a less intensive schedule. 
1.3.2 
CARFILZOMIB PRECLINICAL ANTITUMOR ACTIVITY 
Based upon the results of in vitro and in vivo studies, it is anticipated that the more intense 
and longer duration of proteasome inhibition that can be achieved with carfilzomib will result 
in enhanced anti-tumor activity relative to bortezomib.  Continuous (72 hr) exposure to 
carfilzomib is associated with potent cytotoxic and pro-apoptotic activity across a broad 
panel of tumor-derived cell lines in culture1,6.  Incubation of hematologic tumor cell lines 
with carfilzomib for as little as one hour leads to rapid inhibition of proteasome activity 
followed by accumulation of polyubiquitinated proteins and induction of apoptotic cell death.  
Carfilzomib has also been demonstrated to be cytotoxic in bortezomib-resistant tumor cell 
lines1,6. 
The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice 
implanted with a variety of tumor cell lines.  In a human colorectal adenocarcinoma model 
HT-29, administration of carfilzomib on a twice-weekly Day 1, Day 2 schedule resulted in 
significant reduction in tumor size and was superior to a twice-weekly Day 1, Day 4 schedule 
using the same dose of carfilzomib, and a once-weekly dosing schedule using twice the dose 
level.  Bortezomib at its MTD has no activity in this xenograft model using the standard Day 
1, Day 4 schedule.13 


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A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed.  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-
Macroglobulinemia, and Hod
 
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 
o be the clinical 
sequelae of rapid tumor lysis syndrome (TLS) and/or cytokine release.  This effect was 
notable for fever, chills, and/or rigors occurring during the evening following the first day of 
infusion.  On the second day, three of five subjects with multiple myeloma experienced an 
increase in creatinine to Grade 2 (including the subject with the DLT).  This elevation was 
rapidly reversible and all three subjects were rechallenged with carfilzomib without 
recurrence of the events.  Interestingly, all three subjects had a rapid decline in serum and/or 
urine M-protein levels; two subjects achieved a PR and the third subject achieved a minimal 
response (MR).  There were no consistent changes in potassium, calcium, phosphorous, or 
uric acid levels although some increases in LDH and other markers of tumor lysis were 
noted.  Because of the possible TLS and reversible creatinine elevations, hydration and very-
low dose dexamethasone prophylaxis were instituted in subsequent studies and have 
essentially elimi
-
 
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.14 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 


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immunomodulatory agents.  Stable disease also occurred in four NHL and five MM subjects, 
-weekly 
doses, is not possible with bortezomib.  These results led to the initiation of two Phase 2 
studies.  A dose escalation study was also performed, PX-171-007, which is described in 
more detail in section 1.4.    
 
Two Phase 2 clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 
(N=46) in relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM.15  In both 
studies, patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day 
schedule.  In these studies there were four cases of suspected or documented TLS prior to 
institution of the prophylaxis guidelines.  Since these guidelines were implemented, no 
further cases of TLS have been reported including in >350 additional patients with relapsed 
or refractory MM treated in ongoing Phase II studies.  In both studies, the most common 
adverse events were fatigue, anemia, thrombocytopenia (primarily cyclical), gastrointestinal, 
and dyspnea.  Almost all were Grades 1 or 2.  There were reported cases of increased 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.15 
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).15 
2, has subsequently been 
incorporated into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize 
the clinical benefit of carfilzomib.  Patients receive 20 mg/m2 for the first cycle and 27 
mg/m2 thereafter.  The study completed enrollment of 266 patients by the end of 2009 and 
may form the basis for an accelerated approval NDA filing by the end of 2010.  To date, this 
dosing schedule has been well tolerated.14 An independent Safety Oversight Group (SOG) 
evaluated the safety data from the 40 of 250 patients to be enrolled on the 20/27 schedule and 
agreed that the trial should proceed without modification.  No cases of TLS were observed 
and rates of BUN and creatinine elevation dropped sharply, with Grade 3/4 renal impairment 
dropping to 2.2% in A1( from 15% in A0), most likely due to hydration and very low dose 
dexamethasone.  The other most common adverse events were similar to the A0 portion of 
the study.  Treatment-emergent peripheral neuropathy remains low on this portion of the 
study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date on PX-171-003-
A1.15  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 


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similar in the two cohorts, with Grade 3 neutropenia in ~5% without any Grade 4 neutropenia 
to date.15 
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).13,16  The median TTP was 7.6 and 5.3 months in these two groups, respectively.  Thus, 
carfilzomib can induce very high levels of response in patients who have not previously been 
treated with bortezomib and, even in bortezomib-treated patients, substantial anti-tumor 
activity is observed.  Of note, disease control (PR + MR + SD) was achieved in ~65% of 
patients with progressive MM entering the study.  Patients on these studies have been treated 
for >12 cycles with good tolerability and no cumulative 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.   
. 
 
PX-171-006 is an ongoing Phase 1b study in patients with relapsed, multiple myeloma in 
which carfilzomib is administered in combination with lenalidomide (Revlimid®) and 
-
 is given on Days 1, 8, 15, and 22 in 
all cases.  Carfilzomib is administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide is 
administered PO on Days 1 through 21.   
Enrollment has closed in this study, and no MTD was reached.  The maximum per protocol 
doses of carfilzomib (27mg/m2) with lenalidomide 25mg and low dose dexamethasone are 
being used. After 8 patients tolerated these doses well, an additional 44 patients were 
enrolled in an expansion  cohort at this level, and this regimen is being taken into Phase III 
in study PX-171-009.17 
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-
[n=6]) were reversible. 4 patients had drug-related SAEs as follows: transient G3 sinus 
bradycardia, G3 upper respiratory tract infection, febrile neutropenia, and G3 diarrhea + G3 
urinary infection. ORR and CBR for the 29 evaluable patients are 59% and 72%, 
respectively. Response data is shown in the table below. Initial responses improved with 
continued therapy, (up to 18 cycles). Median duration of response has not been reached 


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(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: 
 
CRd: Cohorts 1 5 
(CFZ: 15 to 20 mg/m2; LEN: 10 to 25 mg)  
Response 
Relapsed (n=16) 
Refractory 
(n=13) 
Overall  
(n=29) 
   
 
5 (31) 
1 (8) 
6 (21) 
   
 
7 (44) 
4 (31) 
11 (38) 
   
 
9 (56) 
8 (62) 
17 (59) 
   
 
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 27mg/m2, suggesting that carfilzomib will combine well with 
other anti-cancer agents.   
1.4 
DOSE RATIONALE 
Preliminary data suggest that carfilzomib as a single agent can produce substantial response 
rates in myeloma subjects across a variety of dosing cohorts.  Responses were seen over a 
wide therapeutic window, from 15 to 27 mg/m2.  Maximum proteasome inhibition was seen 
at doses 11 mg/m2 and higher in whole blood samples taken 1 hour after the first dose.  The 
final analysis of the human pharmacokinetic (PK) data is ongoing but appears to be rapid and 
similar to the results from the animal studies.  Carfilzomib is rapidly cleared from plasma 
with an elimination 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 min infusion as compared to a rapid IV 
bolus.  Toxicities observed with IV bolus injection of carfilzomib above the MTD at a dose 
of 48 mg/m2 include evidence of prerenal azotemia (transient increases in BUN > creatinine) 
as well as lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death 
occurred in ~50% of animals at 48 mg/m2 when carfilzomib was given as a bolus. 
Administration of the same dose (48 mg/m2) as a 30 min continuous infusion was well 
tolerated, with no changes in BUN and creatinine and substantially reduced signs of lethargy, 
piloerection, or dyspnea.  Moreover, all animals in the infusion treatment groups survived.  
The only toxicity observed following infusion of carfilzomib for 30 min was gastrointestinal 


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bleeding.  The reduced toxicity seen with dosing by infusion may reflect the reduced Cmax of 
carfilzomib vs that with bolus dosing.  Inhibition of the pharmacological target of carfilzomib 
(the chymotrypsin-like activity of the proteasome) was equivalent in the bolus and infusion
treatment groups.   
In the clinic, the MTD of carfilzomib has not been reached in the multiple myeloma (MM) 
2 of carfilzomib (bolus 
administration over 2-
nts overall and can be tolerated for 
>12 cycles in late stage MM patients with substantial comorbidities.  
A phase 1 dose escalation study (PX-171-007) of single agent carfilzomib administered is 
ongoing and as of 10 July 2009, over 65 patients with solid tumors had started treatment in 
the initial Phase 2 portion of the study at 36 mg/m2 (bolus administration over 2-
review of the tolerability of 36 mg/m2 carfilzomib in these patients indicates that this regimen 
was very well tolerated with only one DLT (fatigue) and an overall adverse event profile 
similar to that seen with the 27mg/m2 carfilzomib experience with bolus dosing (see IB for 
details). Three patients completed > 12 cycles of therapy at 36 mg/m2 with no evidence of 
cumulative toxicity.  There were no significant DLTs observed; the majority of 
discontinuations on the study were due to progressive disease. Because of the long-term 
tolerability carfilzomib, the Phase 1b portion of this study was reopened, and a separate arm 
for multiple myeloma was added.  
In the PX-171-007 trial, patients were treated with carfilzomib given as a 30-minute infusion 
in order to potentially minimize Cmax-related infusion events. 
ECOG performance status 0 2 with relapsed and/or 
regimens were eligible for the study. In each 28-day cycle, carfilzomib was given as a 30-
min intravenous (IV) infusion on days (D) 1, 2, 8, 9, 15, and 16.  C1D1 and 2 doses were 20 
mg/m2, followed by cohort escalation to 36, 45, 56, or 70 mg/m2 (stepped-up dosing).   Prior 
to infusion of 
2, 8 mg for >45 mg/m2) was 
given as premedication to mitigate potential infusion-related reactions.  The MTD was 
 experienced treatment-related dose-
limiting toxicity (DLT) during the first cycle or, when appropriate, the maximum planned 
dose, with doses ranging from 36 mg/m2 to 70 mg/m2.  No DLTs were seen in the initial 
20/36 mg/m2, 20/45 mg/m2, or 20/56 mg/m2 dose cohorts.  Reversible DLTs were recorded 
in 2 patients in the 20/70mg/m2 cohort; both patients were successfully rechallenged and 
continued on treatment at reduced doses.  The MTD was determined as 56 mg/m2 and this 
cohort was expanded to a total of 24 patients.  At 20/56 mg/m2, 38% of patients have started 
at least 7 cycles of treatment and 79% did not require dose reductions due to an AE.  A total 
of 28 patients were evaluable for efficacy.  20 patients were evaluable in the 20/56 mg/m2 
cohort. Four patients from this cohort withdrew, 3 due to early-onset toxicity (including 
hypertension, neutropenia, and thrombocytopenia) that prevented escalation to 56 mg/m2. 
One patient withdrew consent.  ORR for the expanded 20/56 mg/m2 cohort was 60%.  
Median duration of response for the 20/56 mg/m2 cohort was 8 months and median TTP as 
well as PFS was 7 months.  
2 cohort were 
thrombocytopenia (38%), anemia (21%), and hypertension (13%).  The majority of the AEs 


Protocol 2012-0694 
May 9, 2014
Page 12
 
 
 
in this cohort were G1 2 in severity.  There was 1 report of peripheral neuropathy (G1) in the 
20/56 mg/m2 cohort.   
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.  These data indicate that carfilzomib does not exacerbate underlying renal 
-
gy of the BUN/creatinine elevations observed 
with IV bolus carfilzomib.18 
1.5  
STUDY RATIONALE  
A von Hippel Lindau (VHL) mutation or functional inactivation occurs in the large majority 
of cases of ccRCC, which results in the dysregulation of a number of key cellular functions, 
including control over proangiogenic signaling.  As a result, ccRCC secrete vascular 
endothelial growth factor (VEGF) as well as other proangiogenic factors, and histological 
evaluation of the tumor demonstrates a high degree of vascularity.  VHL also regulates the 
cilia centrosome cycle via the primary cilium, and has been shown to bind to p53.  Strategies 
to manage the consequences of VHL inactivation will ideally remediate all of these 
pathways.  This is a very difficult to do, as each of the VHL functions are quite separate and 
would require specific therapeutic interventions.   
Approximately one third of VHL disruption occurs via missense mutations, which generate 
full-length, but destabilized protein in the cell.  Evaluation of the functional status of some of 
the most common mutations provides evidence that residual functionality is preserved.  
These findings raise the possibility that by stabilizing point-mutated pVHL in the cell, either 
functionality can be restored, thereby providing a differentiation effect on the tumor cell, or 
will result in aggregation of mutated VHL resulting in tumor-cell specific toxicity.   
One potential approach to achieve this goal is to inhibit the proteasome.  Preliminary data 
show that MG132 and bortezomib are capable of upregulating point-mutated pVHL in 786-0 
RCC cell lines.  
A phase II study evaluating bortezomib was published in 2004.  In this treatment refractory 
patient group, four out of 37 patients showed prolonged progression free survival (PFS). A 
high throughput screen and candidate compound assessment revealed that agents with 
proteasome inhibition properties were able to stabilize point-mutated VHL. 19,20  Further 
analysis of bortezomib function in parental 786-0 RCC cell and in, W117A, VHL WT and 
R167Q VHL infected 786-0 cells showed that VHL levels were increased with bortezomib 
dosages that were not lethal to cells, and raised HIF2a levels either very little (in case of 
parental and W117A cells) or not at all [wt VHL and VHL R167Q (not shown)].  Xenograft 
experiments are currently being performed to further explore the mutational subtypes most 
likely to benefit from carfilzomib and bortezomib treatment.   


Protocol 2012-0694 
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A paper by Kondagunta et al 21 assessed the efficacy and toxicity of bortezomib in patients 
with metastatic RCC. Thirty-seven patients with metastatic RCC were treated with 
bortezomib. The first 25 patients enrolled onto the trial were treated with a dose of 1.5 
mg/m2. The dose was decreased to 1.3 mg/m2 for the subsequent 12 patients, because more 
than 50% of the patients treated at the higher dose required dose reductions. Bortezomib was 
given by intravenous administration on a twice-weekly schedule for 2 weeks followed by 1 
week without treatment until progression or unacceptable toxicity occurred. Twenty-three 
patients (62%) previously had undergone nephrectomy, and 19 patients (51%) had previously 
been treated with cytokine therapy.  Of the 37 assessable patients, the best response was a 
partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients 
(38%; 95% CI, 23% to 55%). The four patients with partial response experienced response 
durations of 8, 8+, 15+, and 20+ months. Grade 2 or 3 sensory neuropathy was present in 10 
patients (53%) overall. One patient in the 1.5 mg/m2 group had grade 3 sensory neuropathy; 
no grade 3 sensory neuropathy was seen in the 1.3 mg/m2 group.  Although a relatively low 
response rate was seen in this study, approximately ten percent demonstrated a striking and 
prolonged benefit from bortezomib therapy.  It is possible that this response is linked to the 
VHL genotype.  Unfortunately, no samples were retrievable from these patients for 
hypothesis testing (R. Motzer, personal communication).   
The molecular characteristics of this subgroup are not known.  These findings raise the 
hypothesis that treatment of advanced RCC patients with a well-tolerated proteasome 
inhibitor will specifically benefit patients whose tumors carry specific molecular 
characteristics. Our preliminary data suggest that point-mutated VHL in the tumor may be a 
marker of patient benefit.  
    


Protocol 2012-0694 
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To test this hypothesis, we will perform a phase II study on patients with metastatic ccRCC 
refractory to at least one conventional agent.  Because this is a hypothesis generating study, 
inclusion criteria will be open to all patients with clear cell histology.  We will collect tumor 
tissue on these patients and determine whether mutational type is associated with clinical 
benefit.   
2
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
1.  To assess progression free survival (PFS) of carfilzomib therapy in patients 
refractory or intolerant to at least one prior systemic therapy. 
2.2 
SECONDARY OBJECTIVES 
1. To assess overall response rate (ORR) 
2. To assess overall survival (OS) 
3. To assess safety of carfilzomib treatment in patients with metastatic RCC 
4. To assess PFS and ORR as a function of VHL mutation subtype 
3
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a single arm, single-center, non-randomized study of Carfilzomib in Patients with 
Refractory Renal Cell Carcinoma. Up to 40 patients will be enrolled over two years. Patients 
will receive carfilzomib at a dose of 20 mg/m2 over 30 minutes via IV infusion on Days 1 
and 2 and a dose of 56 mg/m2 over 30 minutes via IV infusion on Days 8, 9, 15, and 16 of 
each 4 week cycle. Week 4 of each cycle will be a rest week; the patient will not receive any 
treatment with the study drug.  Days 1, 8, 15 and the start of the rest week may occur within 
+/- 4 days;  Days 2, 9, 16 and the start of the next cycle will be adjusted accordingly, per 
physician approval.  Patients will be restaged every 8 weeks and will continue on therapy 
until meeting a reason for removal as discussed in section 5.5. 
4
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA   
1. Biopsy proven clear cell kidney cancer with metastatic disease. Progressive 
disease or intolerance to at least one but not more than three (3) prior systemic 
therapy(ies) 
2. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 


Protocol 2012-0694 
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non-nodal lesions and short axis for nodal lesions) as  20 mm with conventional 
techniques or as 
10 mm with spiral CT scan. 
3. Age 
18 years 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 2  
5. Adequate hepatic function, with serum ALT and AST 
.0 times the upper 
limit of normal and serum direct and total 
1.5 times the  upper limit 
of normal  
6. 
9/L; patients with an ECOG 
9/L 
7. 
 (80 g/L) within 14 days prior to beginning study 
treatment (subjects may be receiving red blood cell [RBC] transfusions in 
accordance with institutional guidelines); Patients with an ECOG performance 
 (transfusion 
assistance acceptable) 
8. 
 50 × 109/L; Patients with an ECOG performance status of 2 at 
study entry must have a p
 100 × 109/L  
9. C
30 mL/minute, either measured or calculated 
using a standard formula (eg, Cockcroft and Gault) 
10. Written informed consent in accordance with federal, local, and institutional 
guidelines.  
11. Females of childbearing potential (FCBP) must agree to ongoing pregnancy 
testing and to practice contraception during the study and for a period of 6 
weeks after you stop receiving the study drug 
12. Male subjects must agree to practice contraception during the study and for a 
period of 6 weeks after you stop receiving the study drug  
4.2 
EXCLUSION CRITERIA 
1. Brain metastases not controlled with surgery, whole brain radiotherapy, or with 
sterotactic radiosurgery 
2. Systemic therapy within two weeks of treatment initiation 
3. Pregnant or lactating females 
4. Major surgery within 21 days prior to beginning study treatment 
5. Acute active infection requiring treatment (systemic antibiotics, antivirals, or 
antifungals) within 14 days prior to beginning study treatment 
6. Known human immunodeficiency virus infection 
7. Active hepatitis B or C infection 


Protocol 2012-0694 
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8. Unstable angina or myocardial infarction within 4 months prior to beginning 
study treatment , NYHA Class III or IV heart failure, uncontrolled angina, 
history of severe coronary artery disease, severe uncontrolled ventricular 
arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute 
ischemia or Grade 3 conduction system abnormalities unless subject has a 
pacemaker 
9. Uncontrolled hypertension (defined by BP consistently > 150/100) or 
uncontrolled diabetes (defined by HbA1c > 8.5) within 14 days prior to 
beginning study treatment  
10. Nonhematologic malignancy within the past 2 years with the exception of 
a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid 
cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of 
Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer 
considered cured by surgical resection or unlikely to impact survival during the 
duration of the study, such as localized transitional cell carcinoma of the bladder 
or benign tumors of the adrenal or pancreas 
11. Significant neuropathy (Grades 3 4, or Grade 2 with pain) within 14 days prior 
to beginning study treatment  
12. Known history of allergy to Captisol® (a cyclodextrin derivative used to 
solubilize carfilzomib) 
13. Contraindication to any of the required concomitant drugs or supportive 
treatments, including hypersensitivity to all anticoagulation and antiplatelet 
options, antiviral drugs, or intolerance to hydration due to preexisting 
pulmonary or cardiac impairment 
14. Subjects with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis within 14 days prior to beginning study treatment 
15. Any other clinically significant medical disease or condition that, in the 
ability to give informed consent  
 
5
SUBJECT ENROLLMENT 
5.1 
SCREENING  
Within four weeks prior to starting study treatment:  
 Radiological studies shall include a chest X-ray, and CT scans of the chest and 
abdomen for the baseline tumor measurement, an MRI of the brain, and a bone scan. 
Appropriate additional studies should be obtained to fully define the extent and 
severity of existing or suspected malignant disease.  


Protocol 2012-0694 
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 A MRI of the spine should be obtained, if there is suspicion of evolving cord or nerve 
root compression. Spinal cord or nerve root compression syndromes should be 
managed before trial entry.  
 A skeletal survey and a CT scan of the pelvis will be ordered as clinically indicated at 
the discretion of the treating physician.  
Within two weeks prior to starting study treatment:  
 All patients must undergo a complete history and physical examination, including 
vital signs, ECOG performance status, recent weight loss, height, and current weight.  
 Concurrent non-malignant disease and medical therapy must be documented. On-
study forms must be filled out completely.  
 All prior anti-cancer treatment must be recorded in proper detail. Any residual 
toxicity from prior therapies should be recorded by using the grading schema in NCI 
Common Toxicity Criteria v4.0.  
 
s MSKCC prognostic criteria will be recorded. (Appendix 1).  
 Laboratory studies shall include CBC w/differential, platelet count, chemistry panel 
(total protein, albumin, alkaline phosphatase, AST and/or ALT, calcium, LDH, total 
bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, potassium, chloride, 
carbon dioxide, magnesium, glucose), amylase, lipase, and urinalysis (pH, specific 
gravity, ketones, RBC, WBC, bilirubin, and protein). T4, TSH will be obtained, 
fasting glucose will be obtained. Serum pregnancy test in female patients of 
childbearing potential will also be included and must be negative within 24 hours of 
beginning study treatment on this study.  Minimally elevated levels will be repeated 
to determine pregnancy vs. tumor marker. 
Optional studies with patient consent:  
 Nephrectomy or metastasectomy blocks or 20 unstained slides, 4 micron thickness on 
positively charged slides, will be acquired to test for VHL mutation status in tumor, 
as well as copy number analysis.  Banked/archived samples at MD Anderson or from 
an outside institution are acceptable.  A random blood sample will be drawn prior to 
first dose for a) plasma and serum analysis of cytokines and angiogenesis factors b) 
circulating monocytic cells.  
5.2 
EVALUATION DURING TREATMENT 


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On-study evaluations will consist of the following study activities every four weeks +/- four 
days:
 History and physical exam by physician, or mid-level provider at each scheduled visit 
 Vital signs (including weight) and ECOG performance status 
 Record concomitant medications.  
 Monitor for adverse events.  
 Serum chemistry including total protein, albumin, alkaline phosphatase, AST and/or 
ALT, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, 
potassium, chloride, carbon dioxide, magnesium, and fasting glucose at each 
scheduled visit.  Note: Patient must fast for 8 hours prior to glucose testing. 
 Hematology, including CBC with differential and platelet counts 
 Amylase and lipase will be repeated at each scheduled visit as clinically indicated 
 
Optional studies with patient consent every four weeks +/- four day:  
 Blood will be drawn for a) plasma and serum analysis of cytokines and angiogenesis 
factors and b) circulating monocytic cells.  
Note: Cycle 1 Day 1 blood testing will not be done if screening labs were done in the 
previous 7 days.  
On study evaluations will also consist of the following study activities every week during 
week 1, 2 and 3 of each cycle:  
 Vital signs (including weight)  
 Serum chemistry including alkaline phosphatase, AST and/or ALT, calcium, LDH, 
total bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, potassium, chloride, 
carbon dioxide, and glucose 
 Hematology including CBC with differential and platelet counts 
In addition to the above, the following will be performed every eight weeks+/- 7 days:  
 Repeat radiologic studies (CT, MRI, Chest x-ray and bone scan as indicated) to 
evaluate disease progression or response (in accordance with restaging of disease). 


Protocol 2012-0694 
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Studies to confirm a complete response or document progressive disease will be 
performed as needed.  
Serum pregnancy test in female patients of childbearing potential
5.3 
END OF TREATMENT  
The following study activities will be completed within 30 days of treatment discontinuation 
for any reason:  
 Physical exam 
 Vital Signs including weight  
 Radiologic assessment and assessment of response 
 Serum chemistry including total protein, albumin, alkaline phosphatase, AST and/or 
ALT, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, 
potassium, chloride, carbon dioxide, magnesium, and glucose  
 Hematology to include: CBC with differential and platelet count 
 Record for concomitant medications 
 Monitor for adverse events and followed until resolution 
Optional studies with patient consent:  
 Blood will be drawn for a) plasma and serum analysis of cytokines and angiogenesis 
factors b) circulating monocytic cells  
5.4 
SURVIVAL UPDATES 
Survival updates will take place at 6 month (+/- 1 month) intervals from the off treatment 
date. This will consist of a phone call, e-mail or medical record review.   
5.5 
DURATION OF THERAPY 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 Disease progression 


Protocol 2012-0694 
May 9, 2014
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 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study, or 
 
for further treatment in the judgment of the investigator. 
6
TREATMENT PROCEDURES 
6.1 
DRUG PREPARATION AND ADMINISTRATION.   
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. 
The lyophilized product is reconstituted with Water for Injection to a final carfilzomib 
concentration of 2.0 mg/mL prior to administration.  The dose will be calculated using the 
. Subjects with a BSA > 2.2 m2 will receive a dose based 
upon a 2.2 m2 BSA.  Dose adjustments do not need to be made for weight gains/losses of 
 20%.   
DOSE LEVELS:  
Dose level 
Carfilzomib Dose 
0
20 mg/m2 IV over 30 minutes on days 1 and 2 and 
56 mg/m2 IV over 30 minutes on days 8, 9, 15 and 
16 of each cycle 
-1 
20 mg/m2 IV over 30 minutes on days 1 and 2 and 
45 mg/m2 IV over 30 minutes on days 8, 9, 15 and 
16 of each cycle 
-2 
20 mg/m2 IV over 30 minutes on days 1 and 2 and 
36 mg/m2 IV over 30 minutes on days 8, 9, 15 and 
16 of each cycle 
IV hydration will be given immediately prior to carfilzomib during Cycle 1.  This will 
consist of 250 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 (eg, 
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.     


Protocol 2012-0694 
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Page 21
 
 
 
Carfilzomib will be given as an IV infusion over approximately 30 minutes.  More rapid 
infusion must not be performed.  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.  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. 
6.2 
DEFINITION OF DOSE-LIMITING TOXICITY  
Subjects will be evaluated for toxicity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 4.0.   
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf  
The following events will be considered dose limiting toxicities for purposes of applying 
early stopping rules described in Section 8. 
Non-hematologic: 
 
 pain 
 
ing nausea, vomiting, diarrhea) 
 
 
 
 
 Any non-hematologic toxicity requiring a dose reduction within Cycle 1  
 Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from 
Cycle 1 or drug related toxicity newly encountered on Day 1 of Cycle 2.  
Hematologic: 
 Grade 4 neutropenia  (ANC < 0.5 x 109
 
 Febrile neutropenia (ANC <  1.0 x 109
 
 Grade 4 thrombocytopenia (platelets < 25.0 x 109
 
 Grade 3-4 thrombocytopenia associated with bleeding 
 Any hematologic toxicity requiring a dose reduction within Cycle 1 
 Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from 
Cycle 1 or drug related toxicity newly encountered on Day 1 of Cycle 2.  
6.3 
DOSE REDUCTIONS/ADJUSTMENTS  
The dose of carfilzomib should be held and/or reduced according to the following guidelines: 


Protocol 2012-0694 
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Study drug will be withheld from subjects with: 
 Grade 4 lymphopenia persisting for > 14 days, if lymphopenia was not pre-existing 
 Grade 4 thrombocytopenia with active bleeding 
Grade 4 anemia and thrombocytopenia (without active bleeding) do not require the 
carfilzomib dose to be withheld.  However, subjects should receive supportive measures in 
accordance with institutional guidelines. For patients with Grade 4 thrombocytopenia 
without evidence of bleeding, study drug dosing may occur at the discretion of the 
investigator. 
The following table outlines the dose reduction guidelines for carfilzomib for 
thrombocyctopenia and neutropenia: 
 
 
Thrombocytopenia 
 
Recommended Action
When Platelets:
Carfilzomib
Fall to < 25,000/mm3 
Interrupt carfilzomib, follow CBC 
weekly 
25,000/mm3 
Resume at full dose
Subsequently drop to < 25,000/mm3 
Interrupt carfilzomib, follow CBC 
weekly 
25,000/mm3 
Resume at 1 dose decrement
 
Neutropenia 
 
Recommended Action
When ANC
Carfilzomib
Falls to < 0.5 × 109/L
Interrupt carfilzomib
add filgrastim if Gr 3 with fever or 
Gr 4, follow CBC weekly 
Returns to > 1.0 × 109/L 
(if neutropenia was the only toxicity 
noted) 
Resume at full dose
Returns to > 1.0 × 109/L 
(if other toxicity noted) 
Resume at 1 dose decrement
Subsequently drops to < 0.5 × 109/L
Interrupt carfilzomib
Returns to > 1.0 × 109/L
Resume at full dose


Protocol 2012-0694 
May 9, 2014
Page 23
 
 
 
.
St
baseline.  
After resolution 
or return to baseline, if the adverse event was not 
treatment-related, subsequent treatment with carfilzomib may resume at full dose.  If the 
event was treatment-related, subsequent treatment with carfilzomib will resume at one level 
dose reduction.  If toxicity continues or recurs, a 2nd carfilzomib dose reduction 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. 
If the subject tolerates the reduced dose for two cycles, subject may be dose escalated to the 
dose prior to reduction 
If there is no resolution of toxicity after 2 weeks of withholding treatment (up to 3 weeks for 
infection treatment), the subject will be withdrawn from the study. 
Dose adjustment guidelines for non-hematologic toxicities are summarized as follows: 
Symptom
Recommended Action
 
Carfilzomib
Allergic reaction/hypersensitivity
 
Grade 2  3
full dose. 
Grade 4
Discontinue
Tumor lysis syndrome  
-fold increase 
in LDH 
Hold carfilzomib until all 
abnormalities in serum chemistries 
have resolved.  Reinstitute at full 
doses. 
Infection Grade 3 or 4
Hold carfilzomib until systemic 
treatment for infection complete.  If 
no neutropenia, restart at full dose.  
If neutropenic, follow neutropenic 
instructions. 
Herpes zoster or simplex of any grade
Hold carfilzomib until lesions are 
dry. Reinstitute at full dose 


Protocol 2012-0694 
May 9, 2014
Page 24
 
 
 
Gr 2 treatment emergent neuropathy 
with pain or Grade 3 neuropathy 
Continue to dose.  If neuropathy 
persists for more than two weeks 
Gr 2 without pain. Then restart at 1 
dose decrement 
Grade 4 neuropathy
Discontinue
Renal Dysfunction
 
Hold until CrCl > 30 mL/minute; 
restart at 1 dose decrement 
Congestive heart failure
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 no resolution after 2 
weeks, the subject will be withdrawn 
from the study.
Other non-hematologic toxicity assessed 
as carfilzomib-related > Grade 3 
Hold dose until toxicity resolves to 
 Grade 1 or baseline.  Restart at 1 
dose decrement. 
Increased Creatinine or Decreased CrCl 
A phase I study of Carfilzomib in patients with relapsed and refractory multiple myeloma 
and varying degrees of renal insufficiaency has been initiated and preliminary results were 
reported at the 2009 American Society of Hematology meeting.  At the time of this 
preliminary analysis, 22 patients had been treated on the trial.  Ten patients had creatinine 
clearance  > 80 mL/min; 9 had creatine clearance 50-79 mL/min; 9 patients had creatinine 
clearance 30-49 mL/min; 9 patients had creatine clearance < 30 mL/min and 2 patients were 
on chronic dialysis.  Adverse events in these patient groups were similar regardless of degree 
of renal dysfunction and included anemia, fatigue, and diarrhea as the most common adverse 
events observed.   


Protocol 2012-0694 
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Page 25
 
 
 
Dose Adjustment Guideline for Renal Dysfunction 
Renal Dysfunction 
Recommended Action 
Normal to mild  
(CrCl >50 mL/min) 
Full dose 
Moderate  
(CrCl 31 50 mL/min) 
Full dose 
Severe 
 30 mL/min) 
Hold carfilzomib until CrCl > 30 mL/min; restart  
at one level dose reduction 
Infections 
Subjects with active or suspected infections should have treatment withheld until infection 
has resolved and anti-infective treatment has been completed.  After the infection has 
resolved and anti-infective treatment has been completed, treatment may continue at the 
original dose.  If there is no resolution of toxicity after 3 weeks, the subject will be 
withdrawn from the study. 
Congestive Heart Failure (CHF) 
Any subject with symptoms of CHF or any other suspected acute cardiac event, whether or 
not drug related, must have the dose held until resolution.  After the event has resolved or 
returned to baseline, treatment may continue at a reduced dose, with the approval of the 
Onyx Medical Monitor, or the subject may be withdrawn from the study.  If there is no 
resolution of CHF after 2 weeks, the subject will be withdrawn from the study. 
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Carfilzomib does not need 
to be held in the following cases: 
 Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days with adequate 
treatment of anti-emetics or anti-diarrheals)  
 Grade 3 fatigue (unless persisting for >14 days) 
 Alopecia 
 
Grade 3 hyperglycemia attributed to dexamethasone 
Missed doses will not be replaced during a cycle.  If a subject misses more than 2 doses 
within 1 cycle without notifying the research nurse, for reasons other than toxicity, the 
subject will be discontinued.  


Protocol 2012-0694 
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Page 26
 
 
 
4
Dose modifications and delays different from those stated in the protocol, for management of 
toxicities, will be permitted at the discretion of the Investigator. 
6.4 
SAFETY CONSIDERATIONS 
Based upon the experience in the Phase 1 and 2 clinical studies with carfilzomib, the 
following observations are noted:  
 
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.    
 
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 4 mg PO/IV will be administered prior to all carfilzomib doses 
during the 1st cycle and prior to all carfilzomib doses during the first (56mg/m2) 
cycle. If treatment-related fever, rigors, chills, and/or dyspnea are observed post any 
dose of carfilzomib after dexamethasone has been discontinued, dexamethasone (4 
mg PO/IV) should be re-started and administered prior to subsequent doses.  
 Acyclovir or similar should be given to all subjects, per physician preference, unless 
contraindicated. 
 CrCl changes are mostly transient, reversible, and non-cumulative. All subjects 
should be well hydrated.  Clinically significant electrolyte abnormalities should be 
corrected prior to dosing with carfilzomib. Renal function must be monitored closely 
during treatment with carfilzomib.  Serum chemistry values, including creatinine, 
must be obtained and reviewed weekly. Carfilzomib must be held for subjects with a 
CrCl  30 mL/min at any time during study participation as outlined in Section 6.3.2 
 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.  
3, carfilzomib dosing must be held.  If 
platelet counts do not recover, the dose of carfilzomib may be reduced or held 
according to the Dose Reductions / Adjustments rules outlined in Section 6.3.1. 
 Subjects should have anemia corrected in accordance with the Institutional 
guidelines. 


Protocol 2012-0694 
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 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.   
TLS, which may be associated with multiorgan failure, has been observed in treatment 
Cycles 1 and 2 in some patients with MM who have been treated with carfilzomib.  This is 
unlikely to be an issue for patients with RCC.   
6.4.1.1  
Hydration and Fluid Monitoring 
1. 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 
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 into 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. 
6.4.1.2  
Laboratory Monitoring 
Subjects with laboratory abnormalities consistent with lysis of tumor cells (e.g., serum 
-
 should not 
receive the scheduled dose.  Subjects with such abnormalities should be re-evaluated again 
within the next 24 hours (or sooner, if clinically indicated) and then periodically as clinically 
indicated.    
6.4.1.3  
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.  


Protocol 2012-0694 
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6.4.1.4  
Management of Tumor Lysis Syndrome 
If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring should be instituted.  
Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer 
therapeutic and supportive care, including dialysis, as clinically indicated. 
All cases of TLS must be reported to Onyx as a Serious Adverse Event (SAE) through the 
normal process within 24 hours of the clinical site becoming aware of the event. 
6.5 
CONCOMITANT MEDICATIONS 
Concomitant medication is defined as any prescription or over-the-counter preparation 
including vitamins and supplements.  Concomitant medications should be recorded from 14 
.  Any change in 
concomitant medications must be recorded. 
Female subjects of child-bearing potential must agree to use dual methods of contraception 
for the duration of the study.  Male subjects must agree to use a barrier method of 
contraception for the duration of the study if sexually active with a female of child-bearing 
potential. 
Dexamethasone 4 mg PO/IV will be administered prior to all carfilzomib doses during the 
first cycle.  If treatment-related fever, rigors, chills, and/or dyspnea are observed post any 
dose of carfilzomib after dexamethasone has been discontinued, dexamethasone (4 mg 
PO/IV) should be re-started and administered prior to subsequent doses.  
Subjects should receive acyclovir or similar (famiciclovir, valacyclovir) anti-varicella (anti-
herpes) agent prophylaxis. 
All subjects must receive prophylaxis with hydration (see Section 6.1). 
Allopurinol (in subjects at risk for TLS due to high tumor burden) is optional and will be 
 mg 
PO BID (Cycle 1 Day -2, Day -1), continuing for 2 days after Cycle 1 Day 1 (total of 4 days), 
then reduce dose to 300 mg PO QD, continuing through Day 17 of Cycle 1.  Allopurinol dose 
should be adjusted according to the package insert.  Subjects who do not tolerate allopurinol 
should be discussed with the Lead Principal Investigator. 
Subjects may receive RBC or platelet transfusions if clinically indicated in accordance with 
institutional guidelines.  Subjects who require repeated platelet transfusion support should be 
discussed with the Lead Principal Investigator 
Approved bisphosphonates and erythropoietic agents are allowed.  Subjects may receive 
antiemetics and antidiarrheals as necessary, but these should not be administered unless 


Protocol 2012-0694 
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indicated.  Colony-stimulating factors may be used if neutropenia occurs but should not be 
given prophylactically.  
Subjects may receive RBC or platelet transfusions, if clinically indicated, per institutional 
guidelines.  Subjects who require repeated platelet transfusion support should be discussed.  
Subjects may receive supportive care with erythropoietin or darbepoetin, in accordance with 
institutional guidelines. 
Vitamins and supplements should be recorded on the concomitant medication page.  All 
transfusions and/or blood product related procedures must be recorded on the appropriate 
form. 
Concurrent therapy with an approved or investigative anticancer therapeutic is not allowed.  
Other investigative agents (e.g., antibiotics or antiemetics) should not be used during the 
study. 
7
SAFETY AND ADVERSE EVENT REPORTING 
 
7.1 
REPORTING REQUIREMENTS 
 
7.1.1 
ADVERSE DRUG REACTION REPORTING 
Toxicity will be scored using CTC Version 4.0 for toxicity and adverse event reporting.  A 
copy of the CTC Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the CTC 
Version 4.0.  
 
Adverse events for this protocol will be documented and entered into the Department of 
Genitourinary Medical Oncology Oracle database (GURU) and used as the case report form 
according the Recommended Adverse event Recording Guidelines for Phase II protocol.   
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
  
  
  
 
  
  
Unrelated 
Phase I 
Phase I 
Phase I         
Phase II 
 
Phase I         
Phase II  
Phase III 
Phase I          
Phase II  
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I         
Phase II 
 
Phase I         
Phase II  
Phase III 
Phase I         
Phase II  
Phase III 
Possible 
Phase I          
Phase II 
Phase I         
Phase II  
Phase III 
Phase I          
Phase II  
Phase III 
 
Phase I          
Phase II  
Phase III 
Phase I          
Phase II  
Phase III 
Probable 
Phase I         
Phase II 
Phase I         
Phase II  
Phase I          
Phase II  
 
Phase I          
Phase II  
Phase I          
Phase II  


Protocol 2012-0694 
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Phase III 
Phase III 
Phase III 
Phase III 
Definitive
Phase I         
Phase II 
Phase I         
Phase II  
Phase III 
Phase I          
Phase II  
Phase III 
Phase I         
Phase II  
Phase III 
Phase I  
Phase II  
Phase III 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
 
either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience  any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
 Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 


Protocol 2012-0694 
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  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event).
 All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy.  
 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
 
7.1.4 
INVESTIGATOR COMMUNICATION WITH SUPPORTING 
COMPANIES: 
Expedited Reporting by Investigator to Onyx 
The Investigator must inform Onyx in writing by Fax at the contact information listed below 
of all Expedited Safety Reports submitted to the relevant Regulatory Agencies.  These 
notifications should be performed in parallel to the Regulatory Agency submissions [e.g., 
within 7 calendar days for any Fatal or Life-threatening SUSARs and within 15 calendar 
days for all other SUSARs}, but in no case any later than 1 business day from the submission 


Protocol 2012-0694 
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date. This will be documented on an MD Anderson Serious Adverse Event Form.  This form 
must be completed and supplied to Onyx 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 Serious Adverse Event Form, and submitted to Onyx in the same timelines as 
outlined above.  The institutional protocol number should be included on all reports to Onyx.   
to Onyx on a biannual basis in the form of a line listing in 
English.  The line listing must include the following information; patient initials, date of 
birth, sex, SAE onset date, SAE stop date, event name (term), outcome, date of first dose of 
study drug(s), date of last dose of study drug(s) prior to the event, action taken with study 
Pharmacovigilance Contact Information: 
OnyxFax:  
(800) 783-7954 
SAE hotline:  (650)-266-2501) 
e-mail:  
adverse.events@onyx-pharm.com 
7.2 
PREGNANCY 
If a subject or spouse or partner of a subject becomes pregnant while enrolled in this clinical 
trial or up to three months following administration of carfilzomib, Onyx Drug Safety must 
be notified within 24 hours of the Investigator, designee, or site personnel learning of the 
pregnancy (See Onyx Drug Safety and Pharmacovigilance Contact information above).  If 
the subject is pregnant, carfilzomib must be withheld.   
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. 
8
STATISTICAL ANALYSIS 
Statistical Considerations: 
Goal: This institutional, single-arm, phase II trial will investigate the progression-free 
survival (PFS) of a new therapy, carfilzomib, as post-first-line therapy for patients with 
recurrent or refractory clear cell renal cell carcinoma (CCRCC). Additionally, estimations of 
the treatment effect between patients with and without the VHL mutation will be calculated 
to build evidence for future trials. 


Protocol 2012-0694 
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Endpoints:   The primary endpoint is PFS which is defined as the time from enrollment to 
progression or death, whichever comes first.  Progression will be defined according to 
RECIST version 1.1.  Any patients who are alive and free of disease at the time of analysis 
will be censored at the date of the most recent tumor assessment.  Safety will be an important 
secondary endpoint.  Adverse events will be recorded by CTCAE version 4.0 with 
information regarding relationship to the study drug.  Whether or not a patient had to be 
discontinued from therapy due to predefined severe toxicity will also be recorded. Additional 
endpoints will include the response rate and overall survival.  Response is defined as a CR or 
PR by RECIST.  Overall survival will be defined as the time from enrollment to death, 
regardless of cause.  Patients who are alive at the time of analysis will be censored on the 
date they were last in contact with study personnel. 
Sample Size: Up to 40 patients will be enrolled on this trial.  The number is small due an 
expectation of slow accrual.  This is due to both the rarity of this disease as well as the fact 
that this treatment is delivered intravenously while other new treatments are oral.  With the 
slow accrual, the choice of 40 patients is based on the feasibility of completing the trial 
within 2 years while retaining acceptable operating characteristics.   
Using the monitoring method established by Thall et al,22 PFS is assumed to follow an 
exponential distribution.  Calculations were performed using TTEDesigner. Denote the 
historical median PFS as mH and the median PFS for this study as mE. Under a Bayesian 
model, we will further assume that mH has an inverse gamma (IG) prior with parameters 
(shape, scale) = (3.25, 5.625), with median PFS=2.5 months and variance = 5. We also 
assume that mE follows IG prior with parameters (shape, scale) = (2.0625, 2.65625) with the 
same median PFS of 2.5 months, but with a much larger variance (100) to reflect the greater 
uncertainty about the PFS in patients treated with carfilzomib.  The PFS data will be 
monitored continuously and the study will be terminated early if Pr(mH  + d < mE| data) <  
0.014, where d= 2.5 months. Specifically, the trial will be stopped early if, given the current 
data, there is less than 1.4% chance that the median PFS in patients treated with carfilzomib 
will improve by more than 2.5 months over the historical control. While this is a large 
improvement in PFS, with a doubling of the median, 2 previous trials in this patient 
population have resulted in similar improvements.   First, in a randomized phase III trial 
examining everolimus vs placebo, everolimus had a median PFS of 4.9 months vs 1.9 months 
in the placebo group. 7 In an earlier phase III trial examining sorafenib vs placebo, the PFS 
was 5.5 vs 2.8 months, respectively.3  The operating characteristics of this decision rule are 
summarized in the table below.  
Operating characteristics for futility monitoring based on PFS. 
True median PFS (month)
Pr(stop early) 
Average Number of 
Patients Treated 
1 
>0.99 
4.3 
2 
0.99 
9.9 
2.5 
0.84 
18.0 
3 
0.55 
25.6 


Protocol 2012-0694 
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4 
0.16  
35.1    
5 
0.06 
37.9 
6 
 0.03 
38.9    
7 
0.02 
39.4  
Implementation: Monitoring of PFS will be performed through the Clinical Trial Conduct 
website (https://biostatistics.mdanderson.org/ClinicalTrialConduct), which is housed on a 
secure server at MDACC and maintained by the MDACC Department of Biostatistics. 
Access to the website will be gained through usernames and passwords provided by the 
MDACC Department of Biostatistics to personnel responsible for enrolling patients and 
reviewing and analyzing patient data. Training on the use of the Clinical Trial Conduct 
website to enroll and monitor patients on the study will be provided by the study 
biostatistician for study personnel. 
Safety monitoring: Toxicity will be monitored in all patients. Based on the method of Thall 
(1995)23 continual monitoring after the 5th patient is planned. Calculations were performed in 
Multc Lean.  Denote the probability of extreme toxicity by 
E, where extreme toxicity is 
defined as any toxicity that requires discontinuation of carfilzomib.  This does not include 
voluntary patient withdrawals due to unpleasant symptoms, but patients meeting the 
definition of dose-limiting toxicity as defined in section 6.2 and then have required dose 
reductions/adjustments as defined in Section 6.3.  Additionally, patients who later resume 
therapy will not be counted as being discontinued.  We assume 
E ~ beta (0.40, 1.6).  Our 
stopping rule is given by the following probability statement: Pr(
E > 0.20 | data)  >0.95. 
That is, we will stop the trial if, at any time during the study, we determine that there is more 
than a 95% chance that the extreme toxicity rate is more than 20%. Additionally, we denote 
the probability of extreme toxicity in standard therapies by 
S. We assume S ~beta (200, 
800).  The stopping boundaries for this toxicity rule are to terminate the trial if the number of 
required treatment discontinuations compared to the number or patients on trial exceeds the 
limits in this table. 
Stopping Criteria for Excessive Treatment Discontinuations 
If there are this many 
discontinuations 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Stop if this many 
patients (or fewer) have 
been entered on the trial 
7 
11 
14 
18 
21 
25 
29 
33 
37 
40 
 
The Operating Characteristics for Toxicity Monitoring 
 
True toxicity rate 
Probability of  
Stopping Early 
 
Median (25th %ile, 75th %ile) 


Protocol 2012-0694 
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0.10 
0.006 
40 (40, 40) 
0.20 
0.13 
40 (40, 40) 
0.25 
0.32 
40 (27, 40) 
0.30 
0.57 
32 (13, 40) 
0.40 
0.91 
13 (7, 24) 
0.50 
0.99 
7 (6, 13) 
Analysis Plan:  For discrete or categorical data, descriptive statistics will include tabulations 
of frequencies.  For continuous data, summary statistics including n, mean, standard 
deviation, median, minimum and maximum will be computed.  The estimate of the posterior 
median time to progression and its 95% credible interval will be estimated.   
The Kaplan-Meier method24 will be utilized to display progression-free and overall survival 
for the whole group and by the VHL mutation versus normal subgroups. Exact 95% binomial 
confidence intervals for the response rates will be computed overall and for VHL mutation 
subgroups. Patient adverse events will be tabulated by symptom grade and relationship to 
study drug.   
9
INVESTIGATIONAL PRODUCT 
9.1 
CARFILZOMIB DESCRIPTION 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-
((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-
((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The 
molecular formula is C40H57N5O7 and the molecular weight is 719.91.  It specifically 
functions as an inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads 
to the accumulation of protein substrates within the cell and induction of apoptosis.   
9.2 
FORMULATION 
Carfilzomib for Injection will be provided as a lyophilized powder which, when 
reconstituted, contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium 
citrate buffer (pH 3.5) containing 10% (w/v) sulfobutylether- -cyclodextrin (SBE- -CD, 
Captisol®).   
9.3 
STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2 8ºC under the conditions outlined 
in the separate Pharmacy Manual, in a securely locked area to which access is limited to 
appropriate study personnel. 


Protocol 2012-0694 
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9.4 
ACCOUNTABILITY 
Onyx, Inc. and the Investigator will maintain records of each shipment of investigational 
product.  The records will document shipment dates, method of shipment, batch numbers, 
and quantity of vials contained in the shipment.  Upon receipt of the investigational product, 
the designated recipient at the study site will inspect the shipment, verify the number and 
condition of the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection by representatives of 
Onyx and by regulatory authorities.  
Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must 
be readily available for inspection by representatives of Onyx and by regulatory authorities.  
Only sites that cannot destroy unused drug on-site will be required to return their unused 
supply of investigational product. 
10 
REGULATORY OBLIGATIONS 
10.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) 
and International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice 
(GCP), the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
Institutional Review Board (IRB) or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB or Ethics Committee.  
Before the investigational drug is shipped to the Investigator, the Investigator or designee 
will provide Onyx with a copy of the IRB or Ethics Committee approval letter stating that the 
study protocol and any subsequent amendments and informed consent form have been 
reviewed and approved. 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics 
Committee 
annual report to the IRB or Ethics Committee and copies of the IRB or Ethics Committee 
continuance of approval must be provided to Onyx as follows: 
Onyx Inc. 
Regulatory Department 
2100 Powell St. 
Emeryville, CA 94608 


Protocol 2012-0694 
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Onyx will provide study sites with any expedited safety reports generated from any ongoing 
studies with carfilzomib
other safety 
information which changes the risk/benefit profile of carfilzomib during the conduct of the 
study, to allow him/her to fulfill his/her obligation for timely reporting to the IRB/ECs and 
other Investigators participating in the study. 
Upon completion of the trial, the Investigator must provide the IRB or Ethics Committee and 
Onyx 
 
10.2 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by Onyx, 
its designee, the FDA and/or other applicable regulatory authority.  The access may consist 
of trial-related monitoring, audits, IRB or Ethics Committee reviews, and FDA inspections. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 
11 
REFERENCES 
 
1. Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 
2010 
2. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic 
renal-cell carcinoma. N Engl J Med 356:115-24, 2007 
3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell 
carcinoma. N Engl J Med 356:125-34, 2007 
4. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic 
renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061-8, 
2010 
5. Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. 
Lancet 370:2103-11, 2007 
6. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for 
advanced renal-cell carcinoma. N Engl J Med 356:2271-81, 2007 
7. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 
372:449-56, 2008 


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8. Bortezomib summary basis of approval 
(www.fda.gov/cder/foi/nda/2003/21602_Velcade.htm).  
9. Arastu-Kapur S, Shenk KD, Parlati F, et al: Non-proteasomal targets of proteasome 
inhibitors bortezomib and carfilzomib, Am Soc Hematology, 2008, pp 2765 
10. Demo SD, Kirk CJ, Aujay MA, et al: Antitumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res 67:6383-91, 2007 
11. Bross PF, Kane R, Farrell AT, et al: Approval summary for bortezomib for injection in 
the treatment of multiple myeloma. Clin Cancer Res 10:3954-64, 2004 
12. Kirk CJ, Jiang J, Muchamuel T, et al: The selective proteasome inhibitor carfilzomib is 
well tolerated in experimental animals with dose intensive administration, Am Soc 
Hematology, 2008, pp 2765 
13. Wang L, Siegel D, Kaufman JL, et al: Updated results of bortezomib-naive patients in 
PX-171-004, an ongoing open-label, phase II study of single agent carfilzomib (CFZ) in 
patients with relapsed or refractory myeloma (MM). , Am Soc Hematology Annual 
Meeting, 2009, pp 302 
14. Alsina M, Trudel S, Vallone MK, et al: Phase I single agent antitumor activity of twice-
weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in 
hematologic malignancies., Am Soc Hematology, 2007, pp 411 
15. Jagannath S, VIj R, Stewart K, et al: The multiple myeloma research consortium 
(MMRC). Final results of PX-171-003-AO, part 1 of an open-label, single arm, phase II 
study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma 
(MM). , Am Soc Clinical Oncol Annual Meeting, 2009, pp 8504 
16. Siegel D, Wang L, Orlowski RZ, et al: PX-171-004, an ongoing open label, phase II 
study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma 
(MM): updated results form the bortezomib-treated cohort. , Am Soc Hematology Annual 
Meeting 2009, pp 303 
17. Niesviszky R, Wang L, Orlowski RZ, et al: Base Ib multicenter dose escalation study of 
carfilzomib plus lenalinomide and low dose dexamethaosne (CRd) in relapsed and 
refractory multiple myeloma (MM), Am Soc Hematology Annual Meeting, 2009, pp 304 
18. Badros AZ, VIj R, Martin TA, et al: Phase I study of carfilzomib in patients with relapsed 
and refractory multiple myeloma and varying degress of renal insufficiency. , Am Soc 
Hematology Annual Meeting, 2009, pp 3877 
19. Ding, Z., Feng, Z., Fikes, N. A., Gao, M., Si, W., Sobieski, M. M., Stephan, C. C., Mills, 
G. B., and Jonasch, E. (2011). High throughput screening to identify molecules that alter 
VHL stability  
20. Ding, Z., German, P., Bai, S., Feng, Z., Gao, M., Si, W., Sobieski, M. M., Stephan, C. C., 
Mills, G. B., and Jonasch, E. (2012). Agents That Stabilize Mutated von Hippel-Lindau 
(VHL) Protein: Results of a High-Throughput Screen to Identify Compounds That 
Modulate VHL Proteostasis. J Biomol Screen 17, 572-580. 


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21. Kondagunta, G. V., Drucker, B., Schwartz, L., Bacik, J., Marion, S., Russo, P., 
Mazumdar, M., and Motzer, R. J. (2004). Phase II trial of bortezomib for patients with 
advanced renal cell carcinoma. J Clin Oncol 22, 3720-3725.
22. Thall PF, Wooten LH, Tannir NM: Monitoring event times in early phase clinical trials: 
some practical issues. Clin Trials 2:467-78, 2005 
23. Thall PF, Simon RM, Estey EH: Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med 14:357-79, 1995 
24. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat 
Assoc 53:457-481, 1958 
 
 
 


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Appendix 1  MSKCC Prognostic Factors 
 
Risk factors associated with shorter survival 
Karnofsky performance status < 80% or ECOG  2 
 
High serum lactate dehydrogenase (> 1.5 X upper limit of normal) 
 
Low hemoglobin (< lower limit of normal) 
 
High corrected serum calcium (> 10 mg/dl; corrected calcium = total calcium  0.707 
[albumin 3.4]) 
 
Absence of nephrectomy 
 
 
Stratification 
Favorable risk:            0 risk factors 
 
Intermediate risk: 
1 or 2 risk factors 
 
Poor risk: 
 
3 risk factors