Conditions: Metastatic Renal Cell Carcinoma RCC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a Phase I/II trial of the combination pegylated IFN-alpha 2b with ixazomib in metastatic renal cell carcinoma (mRCC). Researchers believe that by disabling the protein complex NF-kB, which controls the transfer of genetic information; using the study drug Ixazomib, they can promote necrotic cell death of RCC using interferon alpha - 2b. They hypothesize that the combination of ixazomib with IFN will lead to increased necrotic cell death in RCC tumors and consequent clinical benefit to patients.

Patients will receive ixazomib capsules and pegylated IFN alfa 2b injection in this research study. Treatments will be given weekly and 4 weeks of treatment make up one cycle.

Detailed description:

Arms:
arm 1: Ixazomib capsules and pegylated IFN alfa 2b injections weekly. Ixazomib will be taken for the last 3 weeks of 28 day cycle. Pegylated IFN alfa 2b injection will be administered weekly, each week of the 28 day cycle.

Interventions: intervention 1: Ixazomib intervention 2: Pegylated IFN-alpha 2b
Intervention descriptions: intervention 1: The prescribed administration of ixazomib doses in this study is 1.5-4.0 mg ixazomib weekly for 3 out of 4 weeks in each cycle (1 cycle=28 days). intervention 2: Weekly injection

Protocol document:
Prot_SAP_000.pdf: 
GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 1 
 
 
 
GU-071 Phase I/II Study of Ixazomib with Pegylated IFN-alpha 2b (pIFN) in Metastatic 
Renal Cell Carcinoma (mRCC) 
 
Principal Investigator: 
Daniel M. Geynisman, M.D. 
Medical Oncology, Temple Health 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-728-3889 
Fax 215-728-3639 
daniel.geynisman@fccc.edu 
 
Co-Investigators: 
 
Elizabeth Plimack, M.D., M.S. 
Medical Oncology 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-728-3889 
Fax 215-728-3639 
elizabeth.plimack@fccc.edu 
 
Statistician: 
Elizabeth Handorf, PhD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-728-4773 
elizabeth.handorf@fccc.edu  
 
Laboratory Collaborators: Siddharth Balachandran, Ph.D. 
Assistant Professor 
Immune Cell Development & Host Defense 
Program  
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-214-1527 
Fax 215-728-3574 
 
siddharth.balachandran@fccc.edu 
 
Edna Cukierman, Ph.D. 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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Associate Professor 
Cancer Biology 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-214-4218 
Fax 215-728-3616 
edna.cukierman@fccc.edu 
 
 
 
IND# 124536 
Protocol Ver. Amendment 3:  
 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .........................................................................................................3 
PROTOCOL SUMMARY ........................................................................................................5 
STUDY OVERVIEW DIAGRAM ...........................................................................................9 
SCHEDULE OF EVENTS .....................................................................................................10 
LIST OF TABLES ..................................................................................................................12 
LIST OF FIGURES ................................................................................................................12 
1. BACKGROUND AND STUDY RATIONALE ................................................................15 
Metastatic Renal Cell Carcinoma .......................................................................................15 
Scientific Rationale for Combination Ixazomib and IFN in RCC ......................................15 
Previous clinical experience with IFN in RCC ..................................................................17 
Previous clinical experience with proteasome inhibition (bortezomib) in RCC ................17 
Previous clinical experience combining IFN with bortezomib ..........................................17 
Ixazomib .............................................................................................................................18 
Preclinical Experience ....................................................................................................18 
Clinical Experience .........................................................................................................19 
Pharmacokinetics and Drug Metabolism ........................................................................20 
Overall Clinical Trial Experience Using the Oral Formulation of Ixazomib .................21 
Oral Single-Agent Studies ..............................................................................................26 
Oral Combination Studies ...............................................................................................27 
Most Common ≥ Grade 3 Treatment-Related Adverse Events in Overall Oral 
Population .......................................................................................................29 
Most Common ≥ Grade 3 Treatment-Related Adverse Events in Oral Single-Agent 
Studies.............................................................................................................31 
Most Common ≥ Grade 3 Treatment-Related Adverse Events in Oral Combination 
Studies.............................................................................................................34 
Clinical Safety Summary ................................................................................................41 
Potential Benefits ............................................................................................................43 
IFN-α-2b: Description, PK, PD, and safety data ................................................................44 
2. STUDY OBJECTIVES ......................................................................................................50 
Phase I Primary Objective ..................................................................................................50 
Phase II Primary Objective .................................................................................................50 
Phase II Secondary Objectives ...........................................................................................50 
Phase II Exploratory Objectives .........................................................................................50 
3. STUDY ENDPOINTS ........................................................................................................50 
Phase I Primary Endpoint ...................................................................................................50 
Phase II Primary Endpoint ..................................................................................................50 
Phase II Secondary Endpoints ............................................................................................50 
Exploratory Endpoints for Phase I and II ...........................................................................51 
4. STUDY DESIGN ...............................................................................................................51 
4.1 
Phase I: Dose Escalation .......................................................................................51 
4.1.1 
Definition of Dose Limiting Toxicity .............................................................53 
4.2 
Phase II: Dose Expansion .....................................................................................54 
4.3 
Number of Patients ...............................................................................................54 
4.4 
Duration of Study .................................................................................................54 


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4.5 
Definition of Unacceptable Toxicity ....................................................................55 
4.6 
Exploratory endpoints and Protocol for Exploratory Analysis .............................55 
5. 
STUDY POPULATION .............................................................................................58 
5.1 
Inclusion Criteria ..................................................................................................58 
5.2 
Exclusion Criteria .................................................................................................59 
5.3.1 
Patient Registration ...............................................................................................60 
6 
STUDY DRUG ...........................................................................................................61 
6.1 
Description of Investigational Agents ..................................................................61 
6.2 
Study Drug Administration...................................................................................62 
6.3 
Dose-Modification Guidelines ..............................................................................63 
6.4 
Management of Clinical Events ............................................................................64 
6.5 
Excluded Concomitant Medications and Procedures ...........................................71 
6.6 
Permitted Concomitant Medications and Procedures ...........................................72 
6.7 
Precautions and Restrictions .................................................................................73 
6.8 
Preparation, Reconstitution, and Dispensing ........................................................74 
6.9 
Packaging and Labeling ........................................................................................75 
6.10 
Storage, Handling, and Accountability .................................................................76 
6.11 
Study Compliance .................................................................................................77 
6.12 
Treatment Assignment ..........................................................................................77 
6.13 
Termination of Treatment and/or Study Participation ..........................................77 
6.14 
Long Term Follow Up ..........................................................................................77 
7 
ADVERSE EVENTS..................................................................................................78 
7.1 
Definitions ............................................................................................................78 
7.1.1 
Adverse Event Definition ...............................................................................78 
7.1.2 
Serious Adverse Event Definition ..................................................................78 
7.1.3 
Severity Rating ...............................................................................................79 
7.1.4 
Expectedness ...................................................................................................80 
7.2 
Procedures for Reporting Serious Adverse Events ...............................................80 
7.2.1 
Site reporting responsibilities: ........................................................................81 
7.2.2 
ERP Reporting Responsibilities: ....................................................................83 
7.3 
Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events ...................................................................................................................84 
8 
STATISTICAL AND QUANTITATIVE ANALYSES .............................................85 
8.1 
Statistical Methods ................................................................................................85 
8.1.1 
Definition of Phase II and exploratory endpoints and Analytic Plan .............85 
8.1.2 
Sample Size Determination ............................................................................86 
8.1.3 
Randomization and Stratification ...................................................................87 
8.1.4 
Populations for Analysis .................................................................................87 
8.1.5 
Demographic and Baseline Characteristics ....................................................87 
8.1.6 
Safety Analysis ...............................................................................................87 
9 
MEASUREMENT OF EFFECT ................................................................................88 
10 
ADMINISTRATIVE REQUIREMENTS ..................................................................92 
10.1 
Product Complaints ..............................................................................................92 
10.2 
Compliance with Protocol and Protocol Revisions ..............................................93 
10.3 
Data Collection .....................................................................................................93 
10.4 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ..............93 


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10.5 
Records Retention .................................................................................................93 
11 
REFERENCES ...........................................................................................................94 
12 
APPENDICES ............................................................................................................98 
12.1 
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ....98 
12.2 
Cockcroft-Gault Equation .....................................................................................98 
12.3 
Statistical Considerations and Operating Characteristics for Phase II .................99 
 
PROTOCOL SUMMARY  
Title of Study:  Phase I/II Study of Ixazomib with Pegylated IFN-alpha 2b (pIFN) in 
Metastatic Renal Cell Carcinoma (mRCC) 
Investigators:  Daniel M. Geynisman, M.D. (PI), Elizabeth Plimack, M.D., M.S., Yu-
Ning Wong, M.D., MSCE, Marijo Bilusic, M.D., PhD. 
Study Center(s):  Fox Chase Cancer Center, Temple University Health System 
Concept and Rationale:  The Balachandran laboratory at Fox Chase Cancer Center has 
discovered that interferon (IFN) induces necrotic death in cells lacking either NF-kB pro-
survival signaling or the adaptor protein FADD.  Although FADD is currently not 
druggable, NF-kB can be disabled by the proteasome inhibitor bortezomib, and the 
Balachandran lab has shown that IFN induces the selective necrotic demise of renal 
cancer cells when NF-kB pro-survival signaling is neutralized by bortezomib.  
Mechanistically, NF-kB induces the expression of antioxidant enzymes that quench 
reactive oxygen species (ROS) and prevent accrual of these toxic respiratory byproducts. 
When NF-kB is disabled, IFN induces ROS accumulation to toxic levels, leading to 
mitochondrial dysfunction, respiratory failure, and eventual necrotic death. As cancer 
cells are more reliant on mitochondrial bioenergetics than normal, quiescent cells, it is 
expected that IFN-induced necrosis in the setting of NF-kB inhibition will be selective 
for tumor. 
Simultaneous to the above work, 
Millennium has developed the first 
orally available proteasome 
inhibitor, ixazomib.  Given the 
similarities in in vitro potency and 
specificity for proteasome active 
sites between bortezomib and 
ixazomib, we propose to test the 
preclinical findings from the 
bortezomib/IFN combination in 
RCC to a phase I/II trial of ixazomib 
in combination with pegylated IFN-
alpha 2b in mRCC patients.   
 
We hypothesize that the combination of ixazomib with pegylated IFN-α will lead to 
increased necrotic cell death in RCC tumors and consequent clinical benefit to 
patients. 
Phase I Primary Objective:  To determine the safety, tolerability and RP2D of the 
combination of pegylated interferon with ixazomib. 
Phase II Primary Objective:  To determine progression free survival (PFS) 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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Phase II Secondary Objectives:  
 
To determine the composite rate of unacceptable toxicity at 8 weeks 
 
To determine the overall response rate (ORR) using RECIST v1.1 
Phase II Exploratory Objectives:  
1. To examine changes in STAT1 phosphorylation and MHC1 up regulation in 
PBMCs as a pharmacodynamics indicator of IFN activity 
2. To use archived FFPE tumor tissue to correlate activated tissue stroma (i.e., 
desmoplasia) with serum IL-6 levels and patient outcomes 
3. To use archived FFPE from past biopsies for IHC analysis of nuclear NF-κB p65 
and phospho-STAT1 in order to test whether those patients with the most 
apparent constitutive pathway activation related to either of these two markers are 
generally more or less responsive to the combination therapy.  
Phase I Primary Endpoint:  
1. Presence or absence of dose-limiting toxicity during one cycle of pegylated 
interferon alpha with ixazomib 
Phase II Primary Endpoint:  
1. Progression free survival at 8 and 16 weeks using RECIST v 1.1. 
Phase II Secondary Endpoints: 
1. Unacceptable toxicity rate at 8 weeks (any grade 5 toxicity, grade 4 
neuropsychiatric toxicity or grade 4 clinically significant non-hematologic 
toxicity thought to be definitely, probably or possibly related to study drug) 
2. Overall response rate at 8 and 16 weeks using RECIST v1.1.  
Exploratory Endpoints for Phase I and II:  
1. To examine changes in STAT1 phosphorylation and MHC1 up regulation in 
PBMCs as an indicator of IFN activity 
2. To use archived FFPE tumor tissue to correlate activated tissue stroma (i.e., 
desmoplasia) with IL-6 and patient outcomes 
3. To use archived FFPE from past biopsies for IHC analysis of nuclear NF-κB p65 
and STAT1. 
Study Design: The study will be conducted at a single center: Fox Chase Cancer Center.  
It will be open label and non-randomized.  It will begin with a ‘3+3’ phase I component 
to asses initial safety, tolerability and RP2D, followed by a phase II using a two-stage 
design.  The design is meant to incorporate an early stopping rule for futility and toxicity, 
and to allow for an endpoint of PFS at 8 and 16 weeks rather than overall response.  We 
believe PFS is a more valid endpoint given the scientific rationale of tumor necrosis 
rather than apoptosis resulting in radiographic disease stabilization rather than shrinkage.   
Schema: 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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Number of Patients:  
1. Phase I: Minimum=12; Maximum=18; final 3 patient being part of Phase  II 
2. Phase II: Minimum=14; Maximum=31 
3. Total maximum=49 
Main Criteria for Inclusion/Exclusion:  
Inclusion:  Male or female patients 18 years or older; Patients must have a diagnosis of a 
metastatic renal cell carcinoma with a ≥50% clear cell component; Eastern Cooperative 
Oncology Group (ECOG) performance status 0, 1, or 2; Adequate hematologic, hepatic 
and renal function; Measurable disease by RECIST 1.1.; Receipt of at least two lines of 
prior therapy for metastatic RCC; Patients with stable brain metastasis are eligible 
provided they received definitive therapy (EBRT, gamma knife, surgery) no sooner than 
14 days prior to registration and are off all steroids. 
Exclusion: Previous use of interferon, ixazomib or bortezomib; Untreated central 
nervous system involvement;  Grade 3 peripheral neuropathy; Grade 2 peripheral 
neuropathy with pain on clinical examination during the screening period. 
Intervention and Mode of Delivery: Pegylated interferon alpha given subcutaneously 
weekly with weekly oral ixazomib. 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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Duration of Intervention and Evaluation:  
Phase I: Evaluation at day 28 for toxicity, tolerability and dose-limiting toxicity for 
escalation decision.  Treatment can continue indefinitely if beneficial (continual response 
or stable disease or symptomatic clinical benefit as defined by the investigator) to patient.  
Evaluation at 8 and 16 weeks for efficacy and these patients may continue indefinitely as 
well if showing signs of clinical benefit.  
Phase II: Evaluation at 8 and 16 weeks.  If treatment is beneficial (as per above 
definition) to the patient, it can continue indefinitely beyond 16 weeks. 
Statistical Methods: 
Phase I:  
The first part of the study will be a phase I dose escalation enrolling at a minimum 12 
candidates using a 3+3 stepwise design with doses for escalation and de-escalation and 
rules for each noted below.   
 
 
Dose level 
Ixazomib mg 
Pegylated IFN µg/kg/week 
-2 
2.3 
2 
-1 
3 
2 
1 (starting dose level) 
3 
3 
2 
3 
4.5 
3 (expected RP2D) 
4 
4.5 
 
Phase II: 
 
Definition of primary endpoint:  Progression free survival at 8 and 16 weeks using 
RECIST v 1.1, defined from date of treatment initiation to date of progression according 
to RECIST or death, or is censored at the date of the last imaging. If patient is not 
evaluated at 8 and/or 16 weeks then the patient is not considered as alive and 
progression-free. 
 
 
 
Definition of secondary outcomes/endpoints:   
1. Composite of unacceptable toxicity at 8 weeks (grade 4 non-hematologic 
toxicity thought to be definitely, probably or possibly related to study drug) 
2. Overall response using RECIST v1.1. 
 
 
Definition of exploratory objectives: 
1. Changes in STAT1 phosphorylation and MHC1 up regulation in PBMCs from 
pre-treatment to start of cycle 2, 3, 4, 8, 12, 14, 16 and end of study. 
2. Degree of desmoplasia in archived FFPE tumor samples and change in serum 
IL-6 
3. Degree of nuclear NF-κB p65 and STAT1 in archived FFPE tumor samples 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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STUDY OVERVIEW DIAGRAM  
Screening with Radiographic Staging 
▼ 
Study Entry 
▼ 
Phase I dose escalation (12-18 patients) 
▼ 
Phase II expansion (14- 31 patients) 
▼ 
Progression free survival follow-up 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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SCHEDULE OF EVENTS 
 
Screening 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
    future 
cycles 
 
≤  28 
days of 
study 
registration 
≤  7  days 
of study 
registration 
Wk 
1 
Wk 
21 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Subse-
quent 
Weeks 
Off 
Study 
Ixazomib2 
 
 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
x  
 
pIFN-α 2b3 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Physical exam 
 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Vital signs5 
 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Adverse event 
monitoring 
 
X 
 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Performance 
Status 
 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
CBC with 
differential 
 
X 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x4 
x 
Serum 
Chemistry6 
 
X 
 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x4 
x 
Serum 
amylase, 
lipase7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, lipid 
panel 
including 
triglycerides8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x8 
X 
B-HCG (if 
applicable) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT, PTT9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HgbA1C10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmic 
eye 
evaluation11 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic 
evaluation 
with tumor 
measurement 
x 
 
 
 
 
 
 
 
 
x12 
 
 
 
 
 
 
 
x12 
x12 
x12 
ECG  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
correlative 
analysis 
 
 
x13,14 
x 
x 
 
x14 
 
x 
 
x14 
 
 
 
x14 
 
 
 
x14 
x14 
Archival 
Tumor 
Procurement 
(optional)15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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1All patient visits week 2 and thereafter should occur on the same day each week +/- 2 days 
to allow for logistical issues. 
2Ixazomib: Weekly dose will depend on whether the patient is in phase I or phase II.  Doses 
will be escalated or de-escalated in phase I and dose de-escalation can occur in phase II 
based on toxicity.  Treatment is weeks 2-4 of each 4 week cycle (week 1 is off).   
3pIFN:  Once weekly dosing continuously.  Dose will be determined based on phase of study 
and detailed below.  
4At each visit which will occur every 4 weeks after the first 2 cycles. 
5Vital signs include temperature, pulse, respiratory rate, and blood pressure and will occur at 
each visit. 
6Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, lactate dehydrogensase, glucose, potassium, phosphorous, magnesium, total 
protein, SGOT, SGPT, sodium. 
7Amylase and lipase will be checked at baseline and re-assessed as clinically indicated. 
8Triglycerides and TSH have been known to be affected due to pIFN- α.  Will be checked 
every 3 cycles. 
9PT, PTT, INR may be checked more frequently as clinically indicated. 
10pIFN can exacerbate diabetes mellitus 
11If history of diabetic or hypertensive retinopathy 
12Radiologic evaluation and tumor measurements every 2 cycles while on study (every 8 
weeks) for the first 8 months (8 cycles) and then every 3 cycles (every 12 weeks) thereafter.  
Should be repeated at off study if not done in past 6 weeks. 
13Blood for correlative analysis should not be performed until patient is confirmed to be 
eligible and enrolled into the study. 
14Blood for exploratory analysis will be performed on Day 1, 8, 15 of  Cycle 1, Day 1, 15 of 
Cycle 2, Day 1 of Cycle 3 and 4 (after 3 weeks of ixazomib treatment) and thereafter on Day 
1 of  every 2 cycles (e.g. C6, C8 …) and at off study.  Blood can be collected on each day 
+/- 3 days. 
15Archival tumor or metastatic site biopsy tissue will be obtained for correlative analysis.  
This should not be performed until patient is confirmed to be eligible and enrolled into the 
study.  If none is available, the patient is still eligible to proceed with the trial, but every 
effort will be made to obtain the tissue. 
 
 
 
 
 
 
 
 
 
 


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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List of Tables 
Table 1-1:  Most Frequent Treatment-Emergent Adverse Events (in at Least 10% of 
Patients), Overall Safety Population 
Table 1-2:  Most Frequent Treatment-Emergent Treatment-Related Adverse Events (in at 
Least 10% of Patients) in the Overall Safety Population 
Table 1-3:  Treatment-Emergent Rash Events (Overall Safety Poplation) 
Table 1-4:  Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies 
Table 1-5: Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies 
Table 1-6:  Most Common Grade ≥ 3 Drug-Related TEAEs (Pooled Safety Population) 
Table 1-7:  Most Common Grade ≥ 3 Treatment-Related TEAEs: Oral Single- Agent Studies 
Table 1-8:  Most Common Grade ≥ 3 Treatment-Related Adverse Events: Oral Combination 
Studies 
Table 1-9:  Grade 3, Grade 3 or Greater, and Grade 4 Drug-Related Adverse Events in Oral 
Studies 
Table 4-1: Dose escalation for phase I 
Table 4-2:  Escalation Decision Rules 
Table 4-3: Dose Limiting Toxicity 
Table 6-1:  MLN908 and Pegylated IFN-α-2b Dose Adjustments during Phase II  
Table 6-2:  Ixazomib and Pegylated IFN-α-2b Dose Adjustments for Hematologic Toxicities 
Table 6-3:  Ixazomib and Pegylated IFN-α-2b Dose Adjustments (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
 
List of Figures 
Figure 1-1:  Novel IFN-γ-activated cell death and survival pathways for exploitation in renal 
cell carcinoma. 
Figure 1-2:  Most Frequently Reported Treatment-Emergent Adverse Events (all grades) by 
Pegylated IFNα-2b Dose Cohort Over 12 Weeks (core phase) 
Figure 1-3:  Most Frequently Reported Treatment-Emergent Adverse Events by Severity 
(n=29) Over 1 Year (extension phase) using Pegylated IFNα-2b 
Figure 1-4:  Toxicity. Grade 1-3, reported at least once during treatment with Pegylated 
IFNα-2b in mRCC 
Figure 1-5: Patient Toxicities with Pegylated IFNα-2b in mRCC (no grade 4 toxicities were 
observed) 
Figure 4-1:  Study Schema 
Figure 8-1: Flow diagram of statistical design for the study


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Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the plasma concentration versus time curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
Cmax 
single-dose maximum (peak) concentration   
CR 
complete response    
CT 
computed tomography 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FFPE 
GCP 
Formalin fixed, paraffin embedded 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GI 
Gastrointestinal 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous; intravenously 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 


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Abbreviation 
Term 
LFT 
liver function test(s) 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
OS 
PD 
Overall survival 
progressive disease (disease progression) 
progressive disease 
PF 
PFS 
PK 
Progression-free 
progression-free survival 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
QD 
quaque die; each day; once daily 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
RCC 
SAE 
Ready for Phase 2 Dose 
Renal Cell Carcinoma 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
t1/2 
terminal disposition half-life 
Tmax 
single-dose time to reach maximum (peak) concentration 
ULN 
upper limit of the normal range 
US 
United States 
UT 
WBC 
Unacceptable toxicity 
white blood cell 
WHO 
World Health Organization 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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1.    
BACKGROUND AND STUDY RATIONALE 
 
    
Metastatic Renal Cell Carcinoma 
Renal cell carcinoma (RCC) is a relatively rare cancer, comprising only 3.9% of all new 
cancer cases in the United States, with an estimated incidence of new cancers of the kidney 
and renal pelvis being 65,150 cases in 2013 and leading to 13,680 deaths.1  World-wide, 
RCC is diagnosed in approximately 170,000 individuals each year with over 72, 000 
deaths.2  Due to a lack of a proven screening intervention and an often clinically silent 
disease course, RCC often presents in an advanced or metastatic state and over half of RCC 
patients will at some point develop metastatic renal cell carcinoma (mRCC).3  Once 
metastatic, RCC is resistant to conventional chemotherapy and radiotherapy.4   
 
Over the last decade, advances in translational research have led to a rapid paradigm 
shift in the management of mRCC patients.  With the elucidation of the von Hippel-
Lindau/hypoxia-inducible factor (VHL-HIF) and mammalian target of rapamycin (mTOR) 
pathways in mRCC, seven new drugs have been approved since 2005 and many more are in 
clinical development.5  Currently FDA approved agents include vascular endothelial growth 
factor (VEGF) receptor tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and 
sorafenib; the mTOR inhibitors temsirolimus and everolimus, and the anti-VEGF 
monoclonal antibody bevacizumab.6    
 
Due to the above development, the median survival of patients with mRCC is now 
approaching 30 months (up from less than one year in 2000) and is poised to increase even 
further with the preliminary, but very promising results of novel immunotherapy 
approaches.7,8  Many patients are now living with metastatic disease for years as they 
undergo sequential drug treatments, sometimes surgeries (metastasectomies and/or 
cytoreductive or palliative nephrectomies) and targeted radiation treatments.9,10  
Unfortunately, although most patients with mRCC will have some benefit from the above 
mentioned therapy, virtually all will progress and will thus be in need of new interventions. 
 
 
 
 Scientific Rationale for Combination Ixazomib and IFN in RCC 
At Fox Chase Cancer Center, the Balachandran laboratory has focused on studying IFN-γ (a 
cousin of IFN-α) in RCC.  They hypothesized that given the ability of IFN-γ to provide 
lasting remission may stem from its pleiotropic nature: not only does IFN-γ activate a 
powerful immune response to the tumor, but it is also actively anti-angiogenic, and directly 
tumoricidal to susceptible RCC cells.  Concurrent deployment of this anti-neoplastic triad 
represents IFN’s unique advantage over small-molecule approaches, but these properties 
cannot be simultaneously exploited unless RCC-specific resistance mechanisms that limit 
IFN’s tumoricidal capacity are disabled and its toxic side effects are reduced or eliminated.   
 
The Balachandran lab showed that interferon (IFN) induces necrotic death in cells 
lacking either NF-kB pro-survival signaling11 or the adaptor protein FADD.12  When either 
pathway is disabled, IFN-γ activates a novel form of necrotic cell death (also called 
‘necroptosis’) dependent on the kinases PKR, RIP1 and RIP3 (Figure 2, red shading).  
Although FADD is currently not druggable, NF-kB can be disabled by the proteasome 
inhibitor bortezomib (Velcade), and the Balachandran lab has shown that IFN induces the 
selective necrotic demise of renal cancer cells when NF-kB pro-survival signaling is 


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neutralized by bortezomib.13  Mechanistically, NF-kB induces the expression of antioxidant 
enzymes that quench reactive oxygen species (ROS) and prevents accrual of these toxic 
respiratory byproducts. When NF-kB is disabled, IFN induces ROS accumulation to toxic 
levels, leading to mitochondrial dysfunction, respiratory failure, and eventual necrotic death 
(Figure 2). As cancer cells are more reliant on mitochondrial bioenergetics than normal, 
quiescent cells, it is expected that IFN-induced necrosis in the setting of NF-kB inhibition 
will be selective for tumor. 
Figure 1-1: Novel IFN-γ-activated cell death and survival pathways for exploitation in 
renal cell carcinoma. 
 
 
 
The Balachandran lab tested if Bzb could inhibit NF-κB in RCC cells and sensitize 
these cells to IFN-γ-induced necrosis. They found that Bzb inhibited both constitutive and 
inducible NF-κB activity in RCC cells (by 50-90%, depending on the cell line), comparable 
to that seen with a dedicated IKK inhibitor (IMD-0354).13 Importantly, Bzb reduced the 
expression of key NF-κB pro-survival target genes, including the critical target SOD2 
(which encodes the mitochondrial antioxidant enzyme MnSOD). They have previously 
shown that SOD2 is both necessary and sufficient for NF-κB-mediated protection against 
necrosis, suggesting that Bzb co-treament will sensitize RCC cells to IFN-γ-triggered 
necrosis.11 Indeed, they have found that Bzb sensitized multiple ATCC- and patient-derived 
RCC cell lines to IFN-γ-triggered necrotic death at clinically achievable doses for both 
agents. Similar results were obtained when the selective IKK inhibitor IMD-0354 was used, 
indicating that NF-κB inhibition contributes (at least in part) to Bzb’s ability to sensitize 
RCC cells to IFN-γ. Remarkably, the combination of IFN-γ + Bzb left normal kidney 
epithelial cells largely unharmed, for reasons we attribute to reduced dependence of 
constitutive NF-κB signaling (we hypothesize that RCC cells may be ‘addicted’ to tonic NF-
κB signals). In agreement with this hypothesis, patient-derived RCC specimens display 
nuclear staining of the NF-κB sub-unit RelA and a strikingly-elevated ‘NF-κB signature’ 
comprising several pro-survival targets (including SOD2), compared to paired normal 
kidney tissue.  Together, these findings strongly suggest that IFN-γ, in the setting of NF-κB 
blockade, will have clinical benefit in RCC.  
 


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  Previous clinical experience with IFN in RCC   
Immunotherapy with high-dose IL-2 or interferon-alpha was for many years considered the 
standard treatment for patients with mRCC.14  Therapy with these agents produced overall-
response rates of up to 30% and in up to 10% of the time the responses were durable.  With 
the advent of novel therapies noted above, IFN-α fell out of favor as a frontline therapeutic 
once small-molecule agents became available for RCC, for two major reasons: (1) poorly-
understood resistance pathways prevented IFN-α from directly killing RCC cells, and (2) its 
side-effect profile.  
 
Extensive work has been done examining IFN in those with metastatic RCC.15-17  
IFN-alpha is approved by the FDA to be used in combination with bevacizumab based on 
two phase III trials that demonstrated a progression-free survival (PFS), but not an overall 
survival (OS) benefit.18,19  In first line setting, an overall response rate (defined as complete 
response (CR) + PR) of ~7%-15% can be expected with single agent IFN with a 30%-50% 
SD rate.  Furthermore, combinations of IFN with other drugs such as sorafenib,20,21 
sunitinib,22 IL-2,23 fluorouracil,17 and monoclonal antibody therapy24 has been attempted 
with a manageable side-effect profiles and at times efficacy signals.  Furthermore, pegylated 
IFN has been studied in RCC with comparable results and toxicity profile to standard IFN, 
but allowing for once weekly administration.25-30  Given the rapid rise in VEGF and mTOR 
directed therapy for mRCC over the last 5-8 years, IFN is infrequently used as a first line 
therapy today.  Nevertheless, none of the recently approved agents for mRCC are curative 
and the most common response remains stabilization of disease.  Thus, further development 
of a novel IFN based combination based on sound scientific rationale makes sense as it may 
provide an additional option in the armamentarium for mRCC patients who have failed first 
line therapy. 
 
 
  Previous clinical experience with proteasome inhibition (bortezomib) in RCC   
Two clinical trials of bortezomib in patients with RCC have been reported.  After a 
establishing a dose level in a phase I trial31, Kondagunata et al treated 37 patients at a dose 
of 1.3-1.5 mg/m2 twice weekly, on a two week on, one week off schedule.32  Eighteen 
patients were treatment naïve and sixteen received IFN previously.  Bortezomib was given 
i.v. twice weekly.  Partial response (PR) rate was 11% with 3 patients experiencing long-
term PRs (8-20 + months); stable disease (SD) rate was 38%.  Common Grade 2 or higher 
adverse events (AEs) included constipation, fatigue, neuropathy and dyspnea.  A similar 
study by Davis et al treated 21 patients with only a single objective PR, thus leading to study 
termination.33  Though efficacy overall was modest in this study, bortezomab did show 
antitumor activity as a single agent for some RCC patients.  Given the similarity between 
bortezomib and Ixazomib, we would expect similar findings with Ixazomib. 
 
 
   Previous clinical experience combining IFN with bortezomib  
Based on preclinical work by Lesinski et al34, a phase I trial of fixed dosed IFN-alpha 2b (5 
MU/m2 s.c three times a week) with escalating doses of bortezomib once a week (1.0 
mg/m2, 1.3 mg/m2 and 1.6 mg/m2 dose levels) in metastatic melanoma patients was 
conducted, reported at the ASCO 2013 annual meeting and the manuscript is currently 


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submitted for review.35  A total of 16 patients were enrolled with most common Grade 3 
toxicity being fatigue, vomiting and diarrhea.  Grade 4 toxicity observed was fatigue and 
lymphopenia.  1 PR, 7 SD and 8 progressive disease (PD) were observed with a median PFS 
and OS of 2.5 and 10.3 months respectively.  Based on this phase I study, a weekly dose of 
1.3 mg/m2 of bortezomib was found to be safe in combination with IFN-alpha 2b.  
Correlative work showed a decrease in pro-angiongenic factors in the patient with a PR.  
This work supports the notion that combining IFN with a proteasome inhibitor is feasible 
and we propose to extend it to ixazomib. 
 
Study Rationale:  Based on strong preclinical data showing complementary and novel 
anti-tumor activity of IFN and bortezomib in RCC noted in the Balachandran 
laboratory, we propose a phase I/II trial of combination pegylated IFN-alpha 2b with 
ixazomib in metastatic RCC patients who have failed at least two prior lines of 
therapy.  We hypothesize that by disabling NF-kB via ixazomib, we can promote IFN 
induced necrotic cell death of RCC. We hypothesize that the combination of ixazomib 
with IFN will lead to increased necrotic cell death in RCC tumors and consequent clinical 
benefit to patients. 
 
 
 
Ixazomib  
Simultaneous to the above work, Millennium has developed the first orally available 
proteasome inhibitor, ixazomib.36  Ixazomib and its biologically active form, MLN2238, 
have a similar mechanism of action to bortezomib, with the most notable difference being a 
more rapid binding and dissociation from the proteasome.36  Antitumor activity has been 
noted in various preclinical xenograft models.37,38  Several phase I/II trials have examined 
both intravenous and oral formulations of ixazomib.39,40 Single-agent oral ixazomib MTD 
was established at 2.97 mg/m2 on a weekly dosing schedule (days 1, 8, and 15 every 28 
days) which was approximately equal to a fixed dose of 5.5 mg.  Adverse events were 
mostly hematologic or gastrointestinal and were in general manageable.  Importantly, 
peripheral neuropathy appears to be much less frequent with ixazomib compared to 
bortezomib (only 1 case of grade 3 peripheral neuropathy observed out of 60 patients).  In 
solid tumors, IV formulations of ixazomib have been explored, with most common AE 
including fatigue, thrombocytopenia, rash and nausea.  Thus, there is currently an ongoing 
randomized phase III trial in multiple myeloma using a weekly oral 4 mg dose of ixazomib 
in combination with lenalidomide and dexamethasone (clinicaltrials.gov NCT01564537).       
 
Given the similarities in in vitro potency and specificity for proteasome active sites 
between bortezomib and ixazomib, we propose to test the preclinical findings from the 
bortezomib/IFN combination in RCC to a phase I/II trial of ixazomib in combination with 
pegylated IFN-alpha 2b in mRCC patients.   
 
 
 
    
Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 


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Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and 
relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. 
Ongoing studies continue to investigate both single-agent ixazomib and ixazomib in 
combination with standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, 2 phase 3 trials in newly diagnosed MM 
(NDMM) (C16014) and RRMM (C16010) patient populations are currently evaluating 
ixazomib in combination with Revlimid and Dexamethasone (RevDex) versus 
placebo/RevDex. Both trials are combining ixazomib at a weekly dose of 4.0 mg on Days 1, 
8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a weekly dexamethasone 
dose of 40 mg. In addition, ongoing clinical pharmacology studies include evaluation of 
drug-drug interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of ixazomib alone 
(in Japanese patients) and in combination with lenalidomide and dexamethasone in Asian 
adult patients (including Japanese patients) with a diagnosis of NDMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 
13 studies. The emerging safety profile indicates that ixazomib is generally well tolerated. 
The adverse events (AEs) are consistent with the class-based effects of proteasome 
inhibition and are similar to what has been previously reported with VELCADE though the 
severity of some, for example peripheral neuropathy, is less. While some of these potential 
toxicities may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) 
studies (47%). Other common AEs reported in the pooled intravenous (IV) and PO safety 
populations include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a 
commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it. A high-
level term outline of rash events includes rashes, eruptions and exanthems NEC; pruritus 
NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose 
escalation phases of most trials reported in the IB have now completed enrollment, and 
gastrointestinal (GI) symptoms were the common dose-limiting toxicities (DLTs) when the 
use of prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts or 
phase 2 cohorts (as per each study), the incidence and severity of GI symptoms was 
mitigated by the use of the lower maximum tolerated dose (MTD)/recommended phase 2 
dose (RP2D) (as per each study) and standard clinical usage of anti-emetics and/or 
antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics has not 
been required as with other agents but (as outlined in Section 6.7) has been used according 
to standard practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n = 201) irrespective of causality to 
ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), 
vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%). The most 


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frequent (at least 20%) TEAEs reported with the PO formulation pooled from combination 
trials (irrespective of the combination) (n = 173), irrespective of causality to ixazomib, 
include diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation 
(33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), 
neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema (21%, each), fever 
(20%), cough (20%), hypokalemia (20%), neutropenia (20%), and upper respiratory tract 
infection (20%). Overall rash of all grades is reported in approximately 50% of patients and 
is more common when ixazomib is given in combination with lenalidomide where rash is an 
overlapping toxicity. 
 
Additional detailed information regarding the clinical experience of ixazomib may be found 
in the IB, including information on the IV formulation.   
The clinical experience and toxicities associated with oral Ixazomib are summarized below 
in section 1790898588. 
 
   
Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that ixazomib (measured as the 
biologically active boronic acid form of ixazomib [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral ixazomib is 
rapidly absorbed with a median time to first maximum plasma concentration (Tmax) of 
approximately 0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 
days.41  Results of a population PK analysis (N = 137) show that there is no relationship 
between body surface area (BSA) or body weight and clearance (CL).  Also, based on 
stochastic simulations for fixed dose, exposures are independent of the individual patient’s 
BSA.42  Based on these data, a recommendation was made for fixed dosing in clinical trials.  
An absolute bioavailability of 67% was determined for ixazomib using the population PK 
analysis.  Please refer to the current ixazomib IB and Safety Management Attachment 
(SMA) for information on the PK for IV doses of ixazomib. 
Hepatic metabolism appears to be the major route of elimination for ixazomib, with 
negligible urinary excretion of the parent drug (< 5% of dose).  In vitro studies of liver 
microsomes show that ixazomib is metabolized by multiple cytochrome P450 enzymes 
(CYPs) and non-CYP enzymes/proteins.  The rank order of relative biotransformation 
activity of the 5 major human CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) 
> 2C9 (12.1%) > 2C19 (< 1%).  Ixazomib is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, 
or 3A4, nor is it a time-dependent inhibitor of CYP3A4/5.  The potential for ixazomib 
treatment to produce DDIs via CYP inhibition is inferred to be low; however, there may be a 
potential for DDIs via CYP inhibition is inferred to be low.  However, there may be a 
potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor because of the 
potential for first-pass metabolism when ixazomib is administered via the PO route and 
because of the moderate contribution of CYP3A4- and CYP1A2-mediated metabolism of 
ixazomib in human liver microsomes.  Ixazomib may be a weak substrate of P-glycoprotein 
(P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 
(MRP2) efflux pump transporters.  Ixazomib is not an inhibitor of P-gp, BCRP, and MRP2.  
The potential for DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, 
inferred to be low.  Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 


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inhibitor, showed a 2-fold increase in area under the plasma concentration versus time curve 
(AUC) in the presence of ketoconazole. This resulted in the continued exclusion of strong 
CYP3A4 inhibitors in ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 
 
 
    
Overall Clinical Trial Experience Using the Oral Formulation of Ixazomib 
The emerging safety profile indicates that ixazomib is generally well tolerated with 
manageable and reversible AEs with both the IV and PO formulations. The types of AEs 
reported are similar for the 2 formulations, yet the frequency and severity differ. For 
instance, fatigue was the most common AE reported among the 146 patients treated in the 
IV studies and among the 384 patients treated in the PO studies, but the incidence was 
greater with the IV formulation (60% vs 47%, respectively). Other common AEs reported 
with both formulations include rash (28% vs 25% [all terms pooled]), nausea (40% vs 46%), 
thrombocytopenia (45% vs 32%), decreased appetite (38% vs 24%), vomiting (40% vs 
34%), and diarrhea (34% vs 46%). 
The most frequent AEs (those reported in at least 10% of the total safety population) 
occurring in the pooled safety population, regardless of ixazomib causality, are shown in 
Table 1-1.  The most common TEAEs reported as possibly related to study drug are shown 
in Table 1-2.  
Rash has been reported across studies; however, there is some variety in its 
characterization resulting in a difference in the use of preferred terms to report it. Therefore, 
Table 1-3 includes the list of specific rash preferred terms and rates of each for added 
clarity. The numbers represent reported events and not the number of unique patients or 
even the number of unique rashes in a given patient; and each patient is counted only once 
for each preferred term (eg, 2 reported events of rash macular and 1 reported event of 
pruritus in a single patient is reported as 1 rash macular and 1 pruritus). 
Two cases of Stevens-Johnson Syndrome and 3 cases of acute febrile neutrophilic 
dermatosis have been reported; these events were designated as ≥ Grade 3.  Across all 
studies, rash macula-papular was the most common treatment-emergent rash event reported 
(65 [12%]). 
Rashes, eruptions, exanthems NEC, and exfoliative conditions were fairly evenly distributed 
between recipients of IV and oral ixazomib. 
 
 
 
 
 
 
 
 
 
 
Table 1-1: Most Frequent Treatment-Emergent Adverse Events (in at Least 10% of 
Patients), Overall Safety Population 


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Table 1-2: Most Frequent Treatment-Emergent Treatment-Related Adverse Events (in 
at Least 10% of Patients) in the Overall Safety Population 
 
 
 
 


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Table 1-3: Treatment-Emergent Rash Events (Overall Safety Population) 
 


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  Oral Single-Agent Studies 
In the oral ixazomib single-agent studies, 197 (98%) of patients experienced at least 
1 TEAE (Table 1-4). The most common TEAEs in these studies included nausea (53%), 
fatigue (51%), diarrhea (44%), vomiting (38%), thrombocytopenia (34%), decreased 
appetite (32%), pyrexia (25%), constipation (23%), and anemia (21%). Overall, treatment 
emergent rash events (skin and subcutaneous tissue disorders) were reported for 45% of 
patients in the single-agent oral studies. 
 
Table 1-4: Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
 


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  Oral Combination Studies 
In the oral ixazomib combination studies, 163 (94%) of patients experienced at least 1 
TEAE (Table 1-5). The most common TEAEs in these studies included diarrhea (47%), 
fatigue (44%), nausea (38%), peripheral edema (35%), insomnia (29%), thrombocytopenia 
(28%), peripheral neuropathy (26%), neutropenia (25%), back pain (24%), and upper 
respiratory tract infection (20%). Overall, treatment-emergent rash events (skin and 
subcutaneous tissue disorders) were reported for 59% of patients in the oral combination 
studies. 


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Table 1-5: Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
 


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  Most Common ≥ Grade 3 Treatment-Related Adverse Events in Overall Oral 
Population 
Across all studies, 278 (52%) patients experienced at least one Grade 3 or greater TEAE that 
was considered at least possibly related to study treatment. These events are presented in 
(Table 1-6) according to route of administration and study type.  Details for IV studies and 
the oral single-agent and combination studies are provided in the sections that follow. 
Overall, 52% of patients across all studies experienced a Grade 3 or greater TEAE 
considered at least possibly related to treatment. Across all oral administration studies, 
transient, reversible thrombocytopenia (19%) was the most common Grade 3 or greater 
drug-related TEAE. The most common drug-related Grade 4 TEAE was also 
thrombocytopenia (9%).  In the oral single-agent studies, 48% of patients experienced at 
least one Grade 3 or greater TEAE considered possibly related to treatment. The most 
common Grade 3 or greater drug related TEAE was transient, reversible thrombocytopenia 
(19%). Grade 4 TEAEs considered at least possibly related to treatment were reported for 
9% of patients (Table 1-9); thrombocytopenia (11%) was the most common drug-related 
TEAE. 
In the oral combination studies, 55% of patients experienced at least 1 Grade 3 or 
greater 
TEAE considered possibly related to treatment. The most common Grade 3 TEAE 
considered possibly related to treatment was transient, reversible thrombocytopenia (14%). 


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The most common Grade 4 TEAE considered at least possibly related to treatment was 
thrombocytopenia (6%). 
Table 1-6:  Most Common Grade ≥ 3 Drug-Related TEAEs (Pooled Safety Population) 
 


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  Most Common ≥ Grade 3 Treatment-Related Adverse Events in Oral Single-
Agent Studies 
In the oral single-agent studies, Grade 3 or greater AEs related to study treatment were 
reported for 96 patients (48%) (Table 1-7). Thrombocytopenia was the most common TEAE 
regardless of study population or drug schedule being investigated. Rash maculopapular and 
diarrhea were equally common with thrombocytopenia in Study C16007 in patients with 
relapsed or refractory AL amyloidosis. 


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Table 1-7:  Most Common Grade ≥ 3 Treatment-Related TEAEs: Oral Single- Agent 
Studies 
 


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  Most Common ≥ Grade 3 Treatment-Related Adverse Events in Oral 
Combination Studies 
In the oral combination studies, at least 1 Grade 3 or greater AE deemed related to study 
treatment was reported for 95 patients (55%) (Table 1-8). Thrombocytopenia is less 
common when given in combination with lenalidomide and dexamethasone as compared to 
the frequency reported with single-agent ixazomib. Rash events are more common in 2 of 
the Len/Dex combination dose escalation studies (Studies C16005 and C16008), with 
anemia being most commonly reported in the phase 1 study in Asian patients (C16013). 
Ixazomib in combination with melphalan/ prednisone (Study C16006) demonstrates a higher 
frequency of hematologic toxicity, specifically thrombocytopenia and neutropenia, than 
reported in other combination studies. 
 
Table 1-8:  Most Common Grade ≥ 3 Treatment-Related Adverse Events: Oral 
Combination Studies 


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Table 1-9:  Grade 3, Grade 3 or Greater, and Grade 4 Drug-Related Adverse Events in 
Oral Studies 
 


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  Clinical Safety Summary 
 
Ixazomib has been evaluated as a single agent in phase 1 studies that have included 
patients with advanced solid tumors (Study C16001), lymphoma (Study C16002), RRMM 
(Studies C16003 and C16004), and AL amyloidosis (Study C16007).  Ongoing clinical 
pharmacology studies include Study C16009, a clinical trial evaluating drug-drug 
interactions with ketoconazole and rifampin, effect of food, and oral bioavailability. Study 
C16013 is investigating the safety and PK of ixazomib in combination with lenalidomide 
and dexamethasone in Asian adult patients with a diagnosis of RRMM. Study TB-
MC010034 (Japan) is a phase 1/1b PK and tolerability study of ixazomib in Japanese 
patients with RRMM. Ixazomib continues to be evaluated in combination with lenalidomide 
and low-dose dexamethasone in patients with newly diagnosed MM requiring systemic 
treatment (Study C16005, weekly in a 28-day cycle and Study C16008, twice weekly in a 
21-day cycle). 
Another combination being evaluated is ixazomib in combination with melphalan and 
prednisone in patients with newly diagnosed MM not eligible for stem cell transplant (Study 
C16006). 


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Late stage development is focused on development of the oral formulation. A phase 
3 trial is ongoing to evaluate oral ixazomib in combination with LenDex in RRMM (Study 
C16010) with a similar trial planned at the time of data cut for patients with NDMM. A 
phase 3 study in relapsed or refractory AL amyloidosis (Study C16011) is currently 
evaluating ixazomib in combination with dexamethasone versus physician’s choice of a 
Dex-based regimen. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients 
across 10 studies. (The overall safety population comprises 530 patients, but blinded 
aggregate data for SAEs and deaths is provided for an additional 123 patients enrolled in 
Study C16010. Therefore, for SAE and death data, the total number of patients is 653.) The 
emerging safety profile indicates that ixazomib is generally well tolerated with AEs 
generally consistent with the class-based effects of proteasome inhibition. While some of 
these potential toxicities may be severe, they can be managed by clinical monitoring and 
standard medical intervention. 
Fatigue was the most common AE reported among the 146 patients treated in the IV studies 
and 384 patients treated in the PO studies (60% and 47%, respectively). Other common AEs 
reported in the pooled IV and PO safety populations include nausea, thrombocytopenia, 
diarrhea, vomiting, and rash. Rash is a commonly reported TEAE; however, there is some 
variation in its characterization and causality resulting in different preferred terms to 
describe it.  
The dose escalation phase of most trials reported are now complete. GI 
symptoms were the most common DLTs when the use of prophylactic anti-emetics was not 
permitted per protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the 
incidence and severity of GI symptoms will be mitigated by the use of the lower MTD/ 
RP2D (as per each study) and standard clinical usage of anti-emetics and/or anti-diarrheal 
medications as deemed appropriate. 
 
As of 27 March 2013, at least 1 TEAE regardless of causality has been reported in 
515 of 530 patients (97%) across all ongoing/enrolling open label studies. The MTD has 
been determined in 8 clinical trials.  The most frequent (at least 20%) TEAEs reported with 
the IV formulation pooled from Studies C16001 and C16002 (n = 146), regardless of 
causality to Ixazomib, include fatigue (60%), thrombocytopenia (45%), nausea and vomiting 
(40% each), decreased appetite (38%), diarrhea (34%), pyrexia (31%), constipation (25%), 
and cough, anemia, peripheral edema, dyspnea, and headache (21% each).  
 
The most frequent (at least 20%) TEAEs reported with the PO formulation pooled 
from single-agent Studies C16003, C16004, C16007, and C16009 (n = 201) regardless of 
causality with Ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), 
thrombocytopenia (34%), vomiting (38%), decreased appetite (32%), fever (21%), and 
anemia (21%). In the single-agent group, the most frequent (at least 20%) TEAEs reported 
with the PO formulation pooled from combination trials (irrespective of the combination) in 
Studies C16005, C16006, C16008, and C16013 (n = 173), irrespective of causality to 
Ixazomib, include diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), 
constipation (33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting 
(26%), neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema (21% each), 
fever, cough, hypokalemia, neutropenia, and upper respiratory tract infection (20% each). 
 
The frequency of rash with single-agent Ixazomib is higher with the twice-weekly 
schedule than with the weekly schedule regardless of the formulation; however, the 
frequency with the weekly schedule approaches the twice-weekly rate when Ixazomib is 


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given in combination with an agent where rash is an overlapping toxicity, such as 
lenalidomide. One approach to managing the frequency of rash was the careful consideration 
of the RP2D for the combination trials where all toxicities over multiple cycles were taken 
into consideration. Additional approaches include the use of standard medical interventions 
such as the use of oral or topical antihistamines as medically appropriate or oral 
corticosteroids in more severe cases.  
Additionally, a rare risk is Stevens-Johnson Syndrome, a severe, life threatening, or deadly 
rash with skin peeling and mouth sores. 
 
As of 27 March 2013, at least 1 SAE has been reported for 241 patients (37%) across 
all ongoing Millennium-sponsored clinical studies with Ixazomib (including blinded data 
reported for patients enrolled in Study C16010). Regardless of causality, the most common 
SAEs include pneumonia (27 patients), pyrexia (21 patients), dehydration (20 patients), 
thrombocytopenia (17 patients), and vomiting (14 patients). 
 
As of 27 March 2013, a total of 83 patients experienced AEs that resulted in study 
drug discontinuation: 18 patients in Study C16001, 3 patients in Study C16002, 9 patients in 
Study C16003, 7 patients in Study C16004, 11 patients in Study C16005, 4 patients in Study 
C16006, 7 patients in Study C16007, 8 patients in Study C16008, 11 patients in Study 
C16009, 4 patients in Study C16010, and 1 patient in Study TB-MC010034. Fatigue and GI 
events were common reasons for discontinuation. 
 
As of 27 March 2013, 8 overdoses have been reported in Ixazomib clinical studies. 
One patient in Study C16001 received 2 doses of Ixazomib that were approximately 46% 
higher than was intended per the protocol. The patient experienced Grade 4 
thrombocytopenia (nadir 22,000/L) and some liver function elevations, b
ut no other issues 
including no elevation in creatinine. All laboratory abnormalities resolved 8 days after the 
overdose; the patient died due to disease progression 38 days after last dose of Ixazomib. In 
Study C16008, 1 patient was hospitalized for observation after taking Ixazomib on Days 1 
and 2 instead of Days 1 and 4; no AEs were reported. In Study C16005, there were 2 cases 
determined to be not serious. In Study C16001, 1 patient had a dose calculated incorrectly 
due to an error in height measurement; the patient received a 3% overdose, but did not 
experience any related SAEs. In Study C16008, a nonserious overdose was reported for a 
patient who mistakenly took the correct dose of Ixazomib on the wrong day (Day 2 vs Day 
4). In Study C16010, a patient mistakenly took 3 capsules of study drug instead of 1 capsule 
despite receiving proper instructions from study site personnel; the patient was withdrawn 
from the study for compliance reasons. Also in Study C16010, a patient took 40 mg of 
dexamethasone every day for 7 days instead of Day 1 only; the drug schedule was again 
provided to the patient following the overdose. 
As of 27 March 2013, a total of 32 on-study deaths were reported in the clinical studies. 
One of the 32 events was deemed by the investigator to be related to treatment with 
Ixazomib (pneumonia RSV in Study C16005). The most common cause of death was 
disease progression. 
 
 
  Potential Benefits 
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium. Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in 


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some patients, including patients that have been heavily pretreated as well as those with 
newly diagnosed MM, and prolongs stabilization of the underlying disease in other patients 
across all ongoing trials. The preliminary findings are favorable when considering historical 
and currently available therapies for the patient populations evaluated. Though additional 
data are needed to characterize the clinical benefit of this drug, the emerging data supports 
expanded development of Ixazomib for the treatment of patients with advanced malignancy. 
 
 
 
  IFN-α-2b: Description, PK, PD, and safety data 
Pegylated IFN-α-2b is a covalent conjugate of recombinant alfa interferon with 
monomethoxy polyethylene glycol (PEG). The biological activity of pIFN is derived from 
its interferon α-2b moiety. Interferons exert their cellular activities by binding to specific 
membrane receptors on the cell surface and initiate a complex sequence of intracellular 
events. These include the induction of certain enzymes, suppression of cell proliferation, 
immunomodulating activities such as enhancement of the phagocytic activity of 
macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, 
and inhibition of virus replication in virus-infected cells. Interferon alfa upregulates the Th1 
T-helper cell subset in in vitro studies.  Please see Section 1790898588  for more 
background from the Balachandran lab. 
Pegylated IFN has a single PEG-moiety and a molecular weight of 12 kDa and is a 
conjugate of interferon with polyethylene glycol (PEG). As a single agent therapy it is well 
tolerated up to 6.0 mcg/kg per week, which achieves an exposure comparable to 180 MIU 
nonpegylated interferon per week.26,43   The conjugate decreases the clearance, thus 
prolonging the plasma half time (t½) to approximately 40 hours (in patients with chronic 
hepatitis) from otherwise 3-7 hours for not conjugated interferon alfa-2b.44,45 The prolonged 
plasma half-life of Peg-interferon achieves a more constant exposure which leads to an 
increased area under the concentration curve (AUC). This may more effectively inhibit the 
angiogenesis as repeated injections of low-dose interferon.27  Thereby, the efficacy of the 
drug may be increased as it has an antiangiogenic effect apart from the immunological 
effect.  
The pharmacokinetics of pIFN allows for administration subcutaneously once 
weekly and this regimen has shown acceptable safety.44  pIFN has been used in different 
clinical settings such as hepatitis C,46 chronic myelogenous leukaemia (CML)47, malignant 
melanoma,26 and mRCC.25,26,29,48  Pegylated IFN raises concentrations of effector proteins 
such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and 
causes reversible decreases in leukocyte and platelet counts. The correlation between the in 
vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown. 
In Hepatitis C studies with pIFN, following a single subcutaneous (SC) dose of PEG-
Intron, the mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations 
(Cmax) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The 
Cmax and AUC measurements of PEG-Intron increase in a dose-related manner. After 
multiple dosing, there is an increase in bioavailability of PEG-Intron. Week 48 mean trough 
concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 
mean trough concentrations (94 pg/mL; range 0, 416). The mean PEG-Intron elimination 
half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. 


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The apparent clearance of PEG-Intron is estimated to be approximately 22.0 mL/hr·kg. 
Renal elimination accounts for 30% of the clearance. Single dose peginterferon alfa-2b 
pharmacokinetics following a subcutaneous 1.0 µg/kg dose suggest the clearance of 
peginterferon alfa-2b is reduced by approximately half in patients with impaired renal 
function (creatinine clearance <50 mL/minute). 
The pharmacokinetics of geriatric patients (> 65 years of age) treated with a single 
subcutaneous dose of 1.0 µg/kg of PEG-Intron were similar in Cmax, AUC, clearance, or 
elimination half-life as compared to younger subjects (28 to 44 years in age). 
During the 48 week treatment period with PEG-Intron no differences in the 
pharmacokinetic profiles were observed between male and female patients with chronic 
hepatitis C infection. 
In cancer patients, Bukowski et al conducted a phase I/II study using pIFN-α-2b to 
determine the MTD.  70 patients were treated out whom 35 had mRCC.  The MTD was 6.0 
mcg/kg/week with one year of treatment well tolerated with dose modifications.  The PK 
data demonstrated that pIFN was readily absorbed and the AUC at weeks 1 and 4 
demonstrated a dose-related but not dose-proportional increase over the 0.75 to 7.5 mcg/kg 
dose range. 
The toxicity profile of pIFN is summarized in the below four tables (Figures 1-2 to 
1-5) showing AE from three separate trials using pIFN in mRCC patients.  Some of the more 
common and dose-dependent AEs include fatigue, fevers, diarrhea, nausea, myalgias, 
asthenia and flu-like symptoms. 
 
 
Figure 1-2: Most Frequently Reported Treatment-Emergent Adverse Events (all 
grades) by Pegylated IFNα-2b Dose Cohort Over 12 Weeks (core 
phase)26 
 


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Figure 1-3: Most Frequently Reported Treatment-Emergent Adverse Events by 
Severity (n=29) Over 1 Year (extension phase) using Pegylated IFNα-
2b26 
 


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Figure 1-4:  Toxicity. Grade 1-3, reported at least once during treatment with 
Pegylated IFNα-2b in mRCC48 
 
 
 
 
 


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Figure 1-5:  Patient Toxicities withi Pegylated IFNα-2b in mRCC (no grade 4 toxicities 
were observed)25 
 
Of note, there are some notable rare toxicities that are known to occur with pIFN.  These 
include: 
1. Neuropsychiatric events: Life-threatening or fatal neuropsychiatric events, including 
suicide, suicidal and homicidal ideation, depression, relapse of drug 
addiction/overdose, and aggressive behavior have occurred in patients with and 
without a previous psychiatric disorder during PEG-Intron treatment and follow-up.  
2. Bone marrow toxicity:  Severe cytopenias may occur. Very rarely alpha interferons 
may be associated with aplastic anemia. 
3. Endocrine disorders:  pIFN can cause or aggravates hypothyroidism and 
hyperthyroidism. Hyperglycemia has been observed in patients treated with PEG-
Intron. Diabetes mellitus has been observed in patients treated with alpha interferons. 


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Patients with these conditions who cannot be effectively treated by medication 
should not begin PEG-Intron therapy. Patients who develop these conditions during 
treatment and cannot be controlled with medication should not continue PEG-Intron 
therapy. 
4. Cardiovascular events:  Cardiovascular events, which include hypotension, 
arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, 
have been observed in patients treated with PEG-Intron. PEG-Intron should be used 
cautiously in patients with cardiovascular disease.  
5. Pulmonary disorders:  Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis 
obliterans, interstitial pneumonitis and sarcoidosis some resulting in respiratory 
failure and/or patient deaths, may be induced or aggravated by PEG-Intron or alpha 
interferon therapy. Recurrence of respiratory failure has been observed with 
interferon rechallenge. PEG-Intron combination treatment should be suspended in 
patients who develop pulmonary infiltrates or pulmonary function impairment. 
Patients who resume interferon treatment should be closely monitored. 
6. Colitis:  Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been 
observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, 
bloody diarrhea, and fever are the typical manifestations. PEG-Intron treatment 
should be discontinued immediately in patients who develop these symptoms and 
signs. The colitis usually resolves within 1-3 weeks of discontinuation of alpha 
interferons. 
7. Pancreatitis: Fatal and nonfatal pancreatitis has been observed in patients treated 
with alpha interferon. PEG-Intron therapy should be suspended in patients with signs 
and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with 
pancreatitis. 
8. Autoimmune disorders: Development or exacerbation of autoimmune disorders (e.g. 
thyroiditis, thrombocytopenia, rheumatoid arthritis, interstitial nephritis, systemic 
lupus erythematosus, psoriasis) have been observed in patients receiving PEG-Intron. 
PEG-Intron should be used with caution in patients with autoimmune disorders. 
9. Ophthalmologic disorders: Decrease or loss of vision, retinal artery or vein 
thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and 
papilledema are induced or aggravated by treatment with PEG-Intron or other alpha 
interferons. All patients should receive an eye examination at baseline. Patients with 
preexisting ophthalmologic disorders (e.g. diabetic or hypertensive retinopathy) 
should receive periodic ophthalmologic exams during interferon alpha treatment. 
Any patient who develops ocular symptoms should receive a prompt and complete 
eye examination. PEG-interferon treatment should be discontinued in patients who 
develop new or worsening ophthalmologic disorders. 
10. Hypersensitivity:  Serious, acute hypersensitivity reactions (e.g., urticaria, 
angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during 
alpha interferon therapy. If such a reaction develops during treatment with PEG-
Intron, discontinue treatment and institute appropriate medical therapy immediately.  
 
 


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2.    
STUDY OBJECTIVES 
 
    
Phase I Primary Objective 
   1.  To determine the safety, tolerability and RP2D of the combination of pegylated 
interferon with ixazomib. 
 
    
Phase II Primary Objective 
1. To determine progression free survival (PFS) 
 
    
Phase II Secondary Objectives 
1. To determine the composite rate of unacceptable toxicity at 8 weeks 
2. To determine the overall response rate (ORR) using RECIST v1.1 
 
 
    
Phase II Exploratory Objectives 
1. To examine changes in STAT1 phosphorylation and MHC1 up regulation in PBMCs 
as an indicator of IFN activity 
2. To use archived FFPE tumor tissue to correlate activated tissue stroma (i.e., 
desmoplasia) with serum IL-6 levels and patient outcomes 
3. To use archived FFPE from past biopsies for IHC analysis of nuclear NF-κB p65 and 
phospho-STAT1 in order to test whether those patients with the most apparent 
constitutive pathway activation related to either of these two markers are generally 
more or less responsive to the combination therapy. 
 
3.    
STUDY ENDPOINTS 
 
    
Phase I Primary Endpoint  
1.  
Presence or absence of dose-limiting toxicity during one cycle of pegylated 
interferon alpha with ixazomib. 
 
 
    
Phase II Primary Endpoint 
1. Progression free survival at 8 and 16 weeks using RECIST v 1.1. 
 
 
    
Phase II Secondary Endpoints 
1. Unacceptable toxicity rate at 8 weeks (any grade 5 toxicity, grade 4 
neuropsychiatric toxicity or grade 4 clinically significant non-hematologic 
toxicity thought to be definitely, probably or possibly related to study drug) 


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2. Overall response rate at 8 and 16 weeks using RECIST v1.1. 
 
    
Exploratory Endpoints for Phase I and II 
1. To examine changes in STAT1 phosphorylation and MHC1 up regulation in 
PBMCs as an indicator of IFN activity 
2. To use archived FFPE tumor tissue to correlate activated tissue stroma (i.e., 
desmoplasia) with IL-6 and patient outcomes 
3. To use archived FFPE from past biopsies for IHC analysis of nuclear NF-κB p65 
and STAT1.  
 
4.    
STUDY DESIGN 
The study will be conducted at a single center: Fox Chase Cancer Center.  It will be open 
label and non-randomized.  It will begin with a ‘3+3’ phase I component to asses initial 
safety, tolerability and RP2D, followed by a phase II using a two-stage design previously 
described.49  The design is meant to incorporate an early stopping rule for futility and 
toxicity, and to allow for an endpoint of PFS at 8 and 16 weeks rather than overall response.  
We believe PFS is a more valid endpoint given the scientific rationale of tumor necrosis 
rather than apoptosis resulting in radiographic disease stabilization rather than shrinkage.  
The overall treatment plan can be seen in Schedule of Events (page 6) and Figure 4-1. 
 
Figure 4-1: Study Schema 
 
 
4.1 
Phase I: Dose Escalation 
The first part of the study will be a phase I dose escalation enrolling at a minimum 12 
candidates using a 3+3 stepwise design with doses for escalation and de-escalation and rules 
for each noted below in Table 4-1 and 4-2. 
 
Evaluation will occur at C2D1) for toxicity, tolerability and dose-limiting toxicity during the 
first cyclefor escalation decision.  Treatment can continue indefinitely if beneficial 
(continual response or stable disease or symptomatic clinical benefit as defined by the 


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investigator) to patient.  Evaluation at 8 and 16 weeks for efficacy and theses patients may 
continue indefinitely as well if showing signs of clinical benefit. 
 
 
Table 4-1: Dose escalation and de-escalation for phase I 
 
Dose level 
Ixazomib mg 
Pegylated IFN µg/kg/week 
-2 
2.3 
2 
-1 
3 
2 
1 (starting dose level) 
3 
3 
2 
3 
4.5 
3 (expected RP2D) 
4 
4.5 
 
 
Table 4-2.  Escalation and De-Escalation Decision Rules 
Number of 
Patients with DLT  
Escalation/De-escalation Decision Rules 
0 out of 3 
If dose level 1: Open dose levels 2.   
If dose level 2: Open dose level 3. 
If dose level 3: Declare this dose level the maximally administered dose 
(MAD).  Move forward at this dose level to the expansion phase II.  
If dose level -1 or -2: Dose level -1 or -2 will become the MTD and be 
used to move to phase II.   
1 out of 3 
For all dose levels:  Enter 3 more patients at this dose level. 
If 0 of these 3 patients experience DLT, consider this dose acceptable and 
escalate to the next dose(s) as described above. 
If another patient experiences DLT at this dose level (2 DLTs total), 
consider this dose unacceptable and the MAD.  Declare the next lowest 
dose level(s) to be the MTD.   If the MAD is dose level -2 and there are 
at least 2/6 DLTs the study will be halted for re-evaluation of lower 
dose levels. 
>2 
For dose level 3:  Consider this dose unacceptable.  Dose level 2 will 
become the MTD and be used to move to phase II.   
For dose level 2: Consider this dose unacceptable.  Dose level 1 will 
become the MTD and be used to move to phase II.   
For dose level 1: Consider this dose unacceptable.  De-escalate to dose 
level -1 and enroll additional 3 patients at dose level -1 followed by 
assessment as per above. 
For dose level -1: Consider this dose unacceptable.  De-escalate to dose 
level -2 and enroll additional 3 patients at dose level -2 followed by 


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assessment as per above.  If there are at least 2/6 DLTs the study will be 
halted for re-evaluation of lower dose levels.  
 
 
 
 
 
The table below indicates the probability of dose escalation given various true DLT rates. 
 
  Probability of dose escalation. 
 
True Probability of DLT at Current Dose 
 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
0.70 
Probability that 
dose is escalated 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
 
Only those patients that have received at least one dose of ixazomib will be counted for 
phase I analysis.  If a patient stops the trial for reasons other than DLT in the first 28 days, 
they will be replaced for phase I analysis. 
 
4.1.1 Definition of Dose Limiting Toxicity 
Dose-limiting toxicity (DLT) is any drug related toxicity occurring during the first 28 days 
on study (cycle 1) that meets the parameters defined in Table 4-3. 
 
Table 4-3.  Dose Limiting Toxicity 
Any grade 3 or 4 treatment related non-hematologic toxicity regardless of duration, 
except: 
 Grade 3 nausea or Grade 3 vomiting ≤ 72 hours that recovers to grade 0-2 with 
maximal antiemetic therapy.  
 Grade 3 diarrhea that resolves to grade 0-2 with loperamide or 
diphenoxylate/atropine within 48 hours. 
 Grade 3 hypercholesterolemia, hypertriglyceridemia, hyperglycemia or 
hypophosphatemia that resolves to grade 0-2 with medical management.  
 Transient electrolyte abnormalities lasting ≤ 1 week. 
Grade 3 or 4 thrombocytopenia. 
Grade 4 neutropenia associated with fever or hospitalization for infection. 
Grade 4 neutropenia lasting longer than 5 days. 
Any toxicity felt to be possibly or probably related to study medication that causes the 
patient to miss more than 1 dose of either Ixazomib or pIFN in the first 28 days.  
Any unacceptable toxicity (UT) as defined for phase II below (Section 4.5) 
 
 


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4.2 Phase II: Dose Expansion 
Once the RP2D is reached in phase I in at least 3 patients, 3 additional patients will be 
enrolled that together will make up 6 patients that will count toward the toxicity and 
feasibility assessment for the phase I part, but also for the first step of phase II.  See Figure 
7-1 for full flow diagram of study enrollment.   
The treatment plan for both phases I and II of the study is summarized in Figure 4-1.  
A cycle is defined as 28 days.  IFN will be dosed once a week continuously with no 
scheduled interruptions.  Ixazomib will be administered once a week, in weeks 2-4, with a 
break during week 1. 
The schedule of administration and target dose (level 3) of IFN and ixazomib is 
based on a) trials of pegylated IFN-alpha 2b in RCC which demonstrated comparable safety 
and efficacy of pegylated IFN to standard IFN,25,26,28 b) the study of IFN and bortezomib 
combination in melanoma,35 and c) the current dosing schedule for oral ixazomib.  The use 
of pegylated IFN will improve both feasibility and theoretically provide more sustained 
levels (half-life ~50 hours) of IFN compared to short-acting IFN.  Once weekly dosing of 
ixazomib will also be conducive to patient adherence and ease of administration. 
Radiologic evaluation will occur after every 2 cycles for the first 8 cycles (at 8 
weeks, 16 weeks, 24 weeks and 32 weeks) and then every 3 cycles thereafter.  Treatment 
will continue indefinitely or until PD, DLT or patient withdrawal.  Given the i) historic PFS 
of ~5 months for first line use of IFN18,19, ii) PFS of <2 months for single agent 
bortezomib32 in RCC, iii) a PFS of 4.0 months for FDA-approved second line everolimus in 
RCC50 and iv) the inclusion of patients after an unlimited number of treatment regimens, we 
will consider the regimen not worthy of pursuit if ≥66% of patients are progression-free at 8 
weeks.  If ≤56% of patients are progression free at 16 weeks, this regimen would be worthy 
of further investigation (see below for abbreviated statistical design).  This will approximate 
the 4 month PFS of second line everolimus.  Patients who develop a CR, PR or SD at study 
completion, may continue on treatment post study end.   
 
4.3     Number of Patients 
For the phase I portion of the study we will enroll at a minimum 12 and at a maximum 18 
(please see Section 4.1 and 7 for more on the statistical design).  For the phase II portion of 
the study we will enroll up to 31 patients.  For phase II portion, a patient is considered 
enrolled at cycle 1 day 1 when at least one of the drugs has been administered.  All patients 
will be included in the toxicity and PFS and RR analysis. 
 
4.4     Duration of Study 
From a study perspective, the anticipated duration of study being open for enrollment will be 
2 years.  Amongst Fox Chase Cancer Center and its community partners (FCCCP) there 
were 450 analytic (new to the system without ever having had any treatment for their RCC) 
cases of RCC in 2012 alone and FCCCP saw approximately 224 of those cases.  Out of 
these cases at FCCCP ~35/year were de novo metastatic and ~30/year were locally advanced 
and thus at high risk for short-term metastatic progression.  In addition, ~30 non-analytic 
(primary treatment conducted elsewhere) cases per year were seen at FCCCP sites.  


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According to the FCCC RCC database 256 nephrectomies were performed in 2010, 234 in 
2011, 227 in 2012 and 204 in 2013.  Over 75 new patients with RCC were seen by GU 
medical oncology in 2013 and over 43 patients with RCC were enrolled on therapeutic 
clinical trials.  Given this volume of patients we believe we can accrue 1-2 patients a month 
to this trial. 
Once an eligible patient is identified and consented, screening will occur within 28 
days of study initiation (first day of drug administration).  The patient will stay on study 
unless he or she has PD or unacceptable toxicity or chooses to withdraw consent.  Once a 
patient is no longer on active treatment, follow up for progression and survival will occur for 
a maximum of 2 years. 
 
4.5    Definition of Unacceptable Toxicity 
For this study we will have a category defined as unacceptable toxicity (UT).  This will be 
used in the statistical design of the phase II part of the study and incorporated into an early 
stopping rule (see Figure 7-1).  If a patient develops UT at any point in the study, he or she 
will be withdrawn from the study.  If more than 1 UT occurs during the final 6 patients of 
Phase I of the study, the study will be halted for assessment and possible amendment (Figure 
7-1). 
UT is defined as any grade 5 toxicity, grade 4 neuropsychiatric toxicity or grade 4 
clinically significant non-hematologic toxicity thought to be definitely, probably or 
possibly related to study drug. 
 
4.6   Exploratory endpoints and Protocol for Exploratory Analysis 
See Lab Manual for details of specimen collection and storage. 
1. To examine changes in STAT1 phosphorylation and MHC1 up regulation in PBMCs 
as an indicator of IFN activity 
 
a.    STAT1 phosphorylation by immunoblot analysis. PBMCs will be isolated from 
patient blood by Ficoll-Paque Plus-based centrifugal separation ( GE Healthcare Bio-
Sciences, Uppsala, Sweden) and crypreserved. The phosphorylated (p) form of 
STAT1 (Tyr701) as well as total STAT1 in cryopreserved PBMC pellets will be 
measured by immunoblot analysis and/or by intracellular flow cytometry performed 
on fresh PBMC. For immunoblot analysis, Whole-cell extracts from PBMCs (5×105) 
will be prepared in TL buffer (1% [v/v] Triton-X100, 150 mM NaCl, 20 mM HEPES 
[pH 7.3], 5 mM EDTA, 5 mM NaF, 0.2 mM NaVO3 [ortho], and Complete Protease 
Inhibitor cocktail [Roche]) and clarified by centrifugation (15000×g, 10 minutes at 
4°C). Samples will be denatured by boiling in Laemmli buffer (0.1% [v/v] 2-
mercaptoethanol, 0.0005% [w/v] bromophenol blue, 10% [v/v] glycerol, 2% [w/v] 
SDS, 63 mM Tris-HCl [pH 6.8]) for 2 minutes and separated by 12% SDS-PAGE. 
Protein from gels will be transferred onto PVDF membranes (Millipore) and blocked 
in blocking buffer (0.1% [v/v] Tween20, 5% [w/v] non-fat dry milk in PBS) at room 
temperature for 15 minutes. Blots will be incubated for at least 18 h at 4°C with 
primary antibody (p-STAT1, 1:500 (Upstate); total STAT1, 1:2000 (BD 


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Pharmingen) diluted in blocking buffer, followed by 3 washes for 10 minutes each in 
washing buffer (0.1% [v/v] Tween 20 in PBS) at room temperature. Next, blots will 
be incubated with secondary antibody (horseradish peroxidase-conjugated goat anti-
rabbit/mouse IgG (H+L), 1:5000, Jackson ImmunoResearch) for at least 18 h at 4°C, 
followed by 3 washes of 10 minutes each in washing buffer at room temperature. 
Blots will then be incubated in enhanced chemiluminescence substrate (Pierce ECL 
Plus Western Blotting Substrate, Pierce) for one minute, and proteins will be 
detected by chemiluminescence using X-ray film (Denville Scientific Inc.). 
  
b.    STAT1 phosphorylation by intracellular flow cytometry.  Fresh PBMCs (5 × 
105 cells) obtained from patients will be suspended in 100 μL of RPMI-1640 
medium supplemented with 10% FBS, fixed by incubating in 100 μL of Fix & Perm 
Reagent A (Caltag Laboratories, Burlingame, CA) for 2–3 minutes at room 
temperature, and incubated for 10 minutes in 3 mL of cold methanol. Cells will then 
be washed in flow buffer (PBS supplemented with 5% FBS) and permeabilized with 
100 μL of Fix & Perm Reagent B (Caltag Laboratories. Cells will then be incubated 
for a total of 30 minutes at room temperature in Fix & Perm Reagent B containing 1 
μg of a mouse anti-human FITC-conjugated anti-pSTAT1 antibody (BD 
Pharmingen) or an appropriate conjugated isotype control antibody. Fluorescence 
staining data will be acquired on a BD FACSAria II, which is calibrated daily for 
clinical use. Data will be processed with FlowJo software. 
  
c.    MHC1 upregulation by flow cytometry.   Fresh PBMCs  Cells will then be stained 
using fluorophore-conjugated pan-MHC-I specific antibody (clone  W6/32, DAKO) 
or an appropriate isotype control. Fluorescence staining data will be acquired on a 
BD FACSAria II, which is calibrated daily for clinical use. Data will be processed 
with FlowJo software. 
 
 
2. To use archived FFPE tumor tissue to correlate activated tissue stroma (i.e., 
desmoplasia) with IL-6 and patient outcomes 
 
The Cukierman lab has observed that in vivo stromal activation  (measured by a 
specific stromal isoform of the actin binding protein palladin) corresponds to worse 
outcomes regardless of grade or stage of the tumor in RCC.51  Also, using stromal 
(patient derived tumors) ECMs they have observed increased tumoral IL-6 and NF-
kB signaling (Cukierman unpublished results).  We will thus examine the correlation 
between activated stroma (by assessing palladin IHC levels, as published by Dr. 
Cukierman and briefly described below, in the primary renal tumor,  a 
metastasectomy sample or a biopsy) and plasma levels of IL-6 (using ELISA based 
assays) with patient outcome and response to treatment a la previous work. We want 
to answer whether activated stroma could predispose for increased IL-6 levels and 
whether both together will present a better response to the proposed combination 
treatment.  The rationale behind this is that patients with high desmoplasia 
(represented by plasma IL-6 levels) will not only be at increased risk of worse 
outcome and recurrence but the same patients may also present better responses to 


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the combinational treatment approach. 
   
Immunohistochemistry of paraffin-embedded samples will be performed using rabbit 
anti-palladin (1:100) antibody.  A hybridoma via an MTA agreement is also in place 
and thus unlimited access to monoclonal antibody is available.  An avidin biotin-
peroxide kit (Vectastain Elite; Vector Laboratories, Burlingame, CA), together with 
chromogen 3’,3’-diaminobenzidine, was used following manufacturer’s instructions.  
Negative controls will consist of treated samples incubated using iso-matched non-
specific primary antibodies and normal rabbit or mouse pre-immune sera.  All 
sections will be counterstained with hematoxylin and mounted for inspection. The 
score for the intensity of staining in the immunohistochemistry will be performed by 
a ‘blinded’ pathologist using semiquantitative measurements.  The assigned 
intensities consist of four categories; 0, 0.5, 1, and 2. Absence of staining will be 
assigned with the lowest value (0) and the strongest set of intensities will be assigned 
the highest (2). The correlation between immunohistological staining and clinical 
parameters and outcomes will be analyzed.  
 
Serum levels of IL-6 will be assessed using ELISA.  Sera will be procured via 
centrifugation of peripheral blood samples of study patients and stored at -80° until 
analysis. Sera samples will be thawed at room temperature and then assayed in 
duplicate wells using the premixed Bio-Plex® Pro Human Cytokine Array (Bio-Rad) 
according to manufacturer’s instructions.  
 
3. To use archived FFPE from past biopsies for IHC analysis of nuclear NF-κB p65 and 
STAT1 
 
FFPE sections will be cut to a thickness of 4 microns, deparaffinized by xylene, and 
rehydrated in decreasing concentration of ethanol. Antigen retrieval will be achieved 
by boiling sections in 10mM citrate buffer for 20 minutes. After blocking of 
endogenous peroxidase with 3% hydrogen peroxidase in methanol, sections will be 
incubated with Background Sniper (Biocare Medical) at room temperature for 30 
minutes. The sections will next be incubated with primary antibodies, NF-κB p65 
(Cell Signaling) at a dilution of 1:500, and STAT1 (BD Biosciences) at a dilution of 
1:100, at 4°C overnight. After washing in PBS, sections will be incubated with 
Labeled Polymer-HRP anti-rabbit and anti-mouse (DAKO) secondary antibody at 
RT for 1h, exposed to diaminobenzidine tetrahydrochloride solution, and 
counterstained with hematoxylin. After dehydrating in increasing concentrations of 
ethanol and clearing in xylene, sections will mounted in Permount. Images will be 
taken on a Nikon Eclipse E600 microscope with NIS Elements D3.0 software and 
scored across multiple fields for percentage of cells with nuclear NF-kB or STAT1. 
Only nuclear staining for p65 and STAT1 are demonstrative of activity and thus only 
nuclear staining will be scored. 
 


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5.    STUDY POPULATION 
5.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older. 
2. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care. 
3.  Female patients must be: 
 Postmenopausal for at least 1 year before the screening visit, OR 
 Surgically sterile, OR 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
form through 90 days after the last dose of study drug, OR  
 Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
4. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to 
practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study drug, or agree to practice true abstinence 
when this is in line with the preferred and usual lifestyle of the subject.  (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception.) 
5. Patients must have a diagnosis of a metastatic renal cell carcinoma with a ≥50% 
clear cell component. 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
7. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3 and platelet count 
 100,000/mm3 and hemoglobin  9 g/dL.  Platelet or red cell transfusions to 
help patients meet eligibility criteria are not allowed within 3 days before study 
enrollment. 
 Total bilirubin  1.5  the upper limit of the normal range (ULN). 


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 Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST)  3  ULN. 
 Calculated by Cockcroft-Gault or measured by 24 hour urine creatinine clearance 
 50 mL/min (see Section 12.2). 
8. Measurable disease by RECIST 1.1. 
9. Receipt of at least two line of prior therapy for metastatic RCC.   
10. Patients with stable brain metastasis are eligible provided they received definitive 
therapy (EBRT, gamma knife, surgery) no sooner than 14 days prior to registration 
and are off all steroids. 
 
5.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
2. Failure to have fully recovered (ie,  Grade 1 toxicity) from the reversible effects of 
prior chemotherapy, radiation therapy or targeted therapy 
3. Previous use of interferon, ixazomib or bortezomib. 
4. Washout periods for prior therapy are as follows 
  Bevacizumab – last dose must be ≥ 6 weeks prior to day 1 of study treatment.   
 Targeted therapy – last dose must be  ≥  5 half-lives prior to initiation of day 1 
of study treatment. 
 Other chemotherapy, immunotherapy, or radiotherapy – Last dose must be ≤ 3 
weeks prior to day 1 of study treatment  
5. Major surgery within 14 days before enrollment. 
6. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
Ixazomib. 
7. Untreated central nervous system involvement. 
8. Uncontrolled thyroid disease. 
9. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 


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10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart 
failure, unstable angina, or myocardial infarction within the past 6 months. 
11. Systemic treatment, within 14 days before the first dose of Ixazomib, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of 
CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, 
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. 
John’s wort. 
12. Known ongoing or active systemic infection, active hepatitis B or C virus infection, 
or known human immunodeficiency virus (HIV) positive.   
13. Decompensated liver disease (Child-Pugh score >6)  or active or past auto-immune 
hepatitis. 
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.  In 
particular, a history of a serous psychiatric illness that might be exacerbated by IFN-
α-2b; a history of significant or unstable cardiovascular, hepatic or gastrointestinal 
disease; a history of autoimmune disease of any kind. 
15. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
16. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib including difficulty swallowing. 
17. Evidence of another clinically or radiographically active invasive malignancy OR 
Diagnosed or treated for another malignancy within 2 years before study enrollment 
or previously diagnosed with another malignancy and have any evidence of residual 
disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are 
not excluded if they have undergone complete resection.  
18. Patient has  Grade 3 peripheral neuropathy, or Grade 2 peripheral neuropathy with 
pain on clinical examination during the screening period. 
19. Having received an investigational agent with 21 days of receiving the first dose of 
study drug on this trial. 
 
5.3 Participant Registration 
5.3.1 Patient Registration 
Eligible patients will be entered on study centrally by the Fox Chase Cancer Center QA 
Coordinator or their designee.  Following registration, patients should begin protocol 


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treatment within 7 days of registration.  If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be cancelled and the 
subject will be replaced.  The QA Coordinator should be notified of cancellations as 
soon as possible.  
 
Subjects may be registered from 9:00 am to 5:00 pm excluding holidays by calling the 
QA Coordinator at 215-728-4770.  The site’s investigator or designee will then fax the 
completed registration form, consent and HIPAA signature pages and eligibility 
checklist to 215-728-2687.  The QA Coordinator or designee will notify the site by 
phone and fax when registration is confirmed and the sequence number has been 
assigned.  Subjects must be registered and have received a sequence number assigned by 
the QA Coordinator prior to the initiation of treatment.  The following forms must be 
completed at the time of registration: 
 
 Signed and dated informed consent form 
 Signed and dated HIPAA consent form 
 Registration form 
 Signed eligibility checklist 
 
6    STUDY DRUG 
6.1 Description of Investigational Agents  
Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 
0.5-, and 0.2 mg capsules as the active boronic acid. The different dose strengths are 
differentiated by both capsule size and color as described below: 
 
Dose 
Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
2.0 mg 
Size 2 
Swedish orange 
0.5 mg 
Size 3 
Dark green 
0.2 mg 
Size 4 
White opaque 
 
 
 
For additional details, please see the Ixazomib IB. 
 
Pegylated Interferon alpha 2b 
The pIFN will be obtained commercially for each patient. 
 


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6.2     
Study Drug Administration 
Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered or dispensed only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s).  Patients 
should be monitored for toxicity, as necessary, and doses of ixazomib should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic 
treatment, dose interruptions, and adjustments of ixazomib dose (see Section 6.3). 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 2.0 mg, 2.3 mg, 3.0, and 4.0 mg ixazomib.  If during the dose 
escalation phase I we find that the lowest dose (ixazomib 2.3 mg and pIFN 3 µg/kg/week) is 
not tolerable and have to dose de-escalate, we will use 0.5 mg capsules and the protocol will 
be amended.  If the MTD in Phase I is found to be 2.3 mg, dose levels for phase II will be 
2.3 mg, 2.0 mg and 1.5 mg. 
The prescribed administration of ixazomib doses in this study is 1.5-4.0 mg ixazomib 
weekly for 3 out of 4 weeks in each cycle (1 cycle=28 days).  
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to 
break, chew, or open the capsules.  Study drug should be taken on an empty stomach (no 
food or drink) at least 1 hour before or 2 hours after a meal.  Each capsule should be 
swallowed separately with a sip of water.  A total of approximately 8 ounces (240 mL) of 
water should be taken with the capsules.   
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 
72 hours or more away.  A double dose should not be taken to make up for a missed dose.  If 
the patient vomits after taking a dose, the patient should not repeat the dose but should 
resume dosing at the time of the next scheduled dose. 
The patient will take the pill in clinic during the first 2 cycles and either in clinic or at home 
during all subsequent cycles depending on whether they are in clinic for a visit on a 
particular week or not.  They will write down in a patient diary the time of administration 
and dose when taking at home. 
Ixazomib Destruction 
Investigational ixazomib (expired or end of study) should be destroyed on site according to 
the institution’s standard operating procedure.  The investigators will document removal and 
destruction on drug accountability logs. 
Pegylated  IFN-α-2b Administration 
Pegylated IFN-α-2b (PegIntron):  Each patient will be treated with Pegylated IFN-α-2b by 
subcutaneous injection in clinic by a registered nurse or at home by self-injection after 
proper training.  They will write down in a patient diary the time of administration and dose 


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if they are injecting at home.  The dose will be based on phase of study (see section 4-1).  
The drug will be obtained commercially in various vial strengths depending on patient’s 
weight in kg (see below).  The injection site will be rotated between thigh, outer surface of 
upper arm, and abdomen.   Injections will not be given near navel or waistline; patients who 
are thin will only have thigh or upper arm used.  No injection will be given into a bruised, 
infected, irritated, red, or scarred skin.  
All patients will be pre-medicated with acetaminophen (500-1000 mg orally) 30 minutes 
prior to the first dose and as needed for subsequent doses thereafter. 
Dose in mL=Weight (kg) x Dose (µg/kg)/Reconstituted Vial Strength (µg/mL) 
For patients whose CrCl was acceptable for study eligibility/entry per a 24 hour urine 
creatinine clearance, but not Cockcroft-Gault, if serum creatinine increases by 20% or more, 
the dose of pegylated IFN will be reduced by 25% for the particular dose level the patient is 
at and not re-escalated.  
If a patient’s CrCl was acceptable per Cockcroft-Gault for study eligibility/entry, if CrCl 
drops to between 30-50 ml/min while on treatment, the dose of pegylated IFN will be 
reduced by 25% for the particular dose level the patient is at and not re-escalated. 
6.3     
Dose-Modification Guidelines 
Treatment with Ixazomib and Pegylated IFN-α-2b will use a cycle length of 28 days.  
Evaluations will occur as listed in the Study Calendar.  For a new treatment cycle to begin, 
the patient must meet the following criteria: 
 
 
ANC must be ≥ 1,000/mm3. 
 
Platelet count must be ≥ 75,000/mm3. 
 
Hemoglobin must be ≥ 8.0 g/dl. 
 
All other non-hematologic toxicity (except for alopecia) must have resolved to ≤ 
Grade 1 or to the patient’s baseline condition 
 
If the patient fails to meet the above-cited criteria for initiation of the next treatment, dosing 
should be delayed for 1 week for both drugs. If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to re-evaluate. The maximum delay before 
treatment should be discontinued will be 4 weeks or at the discretion of the Principal 
Investigator. 
 
For dosing recommendations upon recovery, refer to Table 6-1, Table 6-2 and Table 6-3.  If 
starting doses will be different than below, the protocol will be amended prior to moving on 
to Phase II. 
 


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6.4 Management of Clinical Events 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with ixazomib treatment. Management guidelines regarding these 
events are outlined below. Further details of management of ixazomib AEs are described in 
Section 6 of the Ixazomib IB. 
Prophylaxis Against Risk of Infection 
If lymphopenia is noted, patients may be at an increased risk of infection.  In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex 
viruses.  Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically 
indicated.  Other antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered.  
Dexamethasone should not be administered as an anti-emetic.  Fluid deficits should be 
corrected before initiation of study drug and during treatment. 
Diarrhea 
Diarrhea should be managed according to clinical practice, including the administration of 
antidiarrheals such as loperamide and diphenoxylate/atropine according to the package 
inserts.  If there is clinical suspicion for c. difficile infection, send stool sample for toxin 
assay.  Avoid loperamide and diphenoxylate/atropine if there is blood or mucous in the 
stool, or if diarrhea is accompanied by fever.  Fluid intake should be maintained to avoid 
dehydration.  Fluid deficits should be corrected before initiation of treatment and during 
treatment.  
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, 
primarily at the higher doses tested and when given with agents where rash is an overlapping 
toxicity.  The rash may range from limited erythematous areas, macular and/or small papular 
bumps that may or may not be pruritic over a few areas of the body, to a more generalized 
eruption that is predominately on the trunk or extremities.  Rash has been most commonly 
characterized as maculopapular or macular.  To date, when it does occur, rash is most 
commonly reported within the first 3 cycles of therapy.  The rash is often transient, self-
limiting, and is typically Grade 1 to 2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  
The use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is 
permitted.  Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids.  Administration of ixazomib (and/or other causative agent if given in 


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combination) should be modified per protocol and re-initiated at a reduced level from where 
rash was noted (also, per protocol).   
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or 
any SAE involving rash is recommended.  Prophylactic measures should also be considered 
if a patient has previously developed a rash (eg, using a thick, alcohol-free emollient cream 
on dry areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson 
Syndrome, a severe and potentially life-threatening rash with skin peeling and mouth sores, 
which should be managed symptomatically according to standard medical practice.  Punch 
biopsies for histopathological analysis are encouraged at the discretion of the investigator. 
Thrombocytopenia 
Thrombocytopenia has been reported to date primarily at the higher doses tested.  Blood 
counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Thrombocytopenia may be severe but has 
been manageable with platelet transfusions according to standard clinical practice. 
Thrombocytopenia nadirs commonly recover without intervention by the beginning of the 
next scheduled cycle. Ixazomib administration should be modified as noted as per dose 
modification recommendations in Table 6-2 when thrombocytopenia occurs.  Therapy can 
be reinitiated at a reduced level upon recovery of platelet counts. A rare risk is thrombotic 
thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form in small 
blood vessels throughout the body characterized by thrombocytopenia, petechiae, fever, or 
possibly more serious signs and symptoms. TTP should be managed symptomatically 
according to standard medical practice. 
Neutropenia 
Neutropenia has been reported with ixazomib.  Blood counts should be monitored regularly 
as outlined in the protocol with additional testing obtained according to standard clinical 
practice.  Neutropenia may be severe but has been manageable with G-CSF according to 
standard clinical practice.  Neutropenic nadirs commonly recover without intervention by 
the beginning of the next scheduled cycle or with a short delay in treatment.  Ixazomib 
administration should be modified when neutropenia occurs, as noted in the dose 
modification recommendations in Table 6-2.  Therapy can be reinitiated at a reduced level 
upon recovery of absolute neutrophil counts. 
Fluid Deficits 
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with ixazomib.  Fluid deficits should be 
corrected before initiation of study drug and during treatment and as needed during therapy.  
Until further information is available, intake of NSAIDs while on this protocol should be 
avoided. 


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Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored while the patient is on 
study treatment and fluid deficit should be corrected as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
ixazomib.  While this case ultimately resolved, PRES has also been reported rarely with 
another proteasome inhibitor, VELCADE.  PRES is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ 
damage. 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib 
causes transverse myelitis; however, because it happened to a patient receiving ixazomib, 
the possibility that ixazomib may have contributed to transverse myelitis cannot be 
excluded. 
 
 
Table 6-1 MLN908 and Pegylated IFN-α-2b Dose Adjustments during Phase II:  Note 
levels for dose modification do not correspond with levels for dose escalation.  Dose 
modifications will depend on the RP2D.  Final dose modification schedule will be decided 
upon once the RP2D is determined.  As an example, if the RP2D is, as expected, 4.5 
mcg/kg/week of pIFN and 4.0 mg per week of Ixazomib, then the dose modification 
schedule will be as below.  
 
Dose Mod Level 
pIFN Dose (mg) 
Ixazomib Dose 
(mg)        
1 
4.5 mcg/kg/week 
4.0 mg 
-1 
3.0 mcg/kg/week 
3.0 mg 
-2 
1.0 mcg/kg/week 
2.3 mg 
-3 
Discontinue 
Discontinue 
 


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Table 6-2    
Ixazomib and Pegylated IFN-α-2b Dose Adjustments for Hematologic 
Toxicities 
Within-Cycle Dose Modifications 
 
 If platelet count  75  109/L or ANC ≤ 
0.50  109/L on a Ixazomib dosing day 
(other than Day 1 (if Day 1, see section 
6.3)) 
 Ixazomib dose should be withheld.   
 Complete blood count (CBC) with 
differential should be repeated at least 
every other day until the ANC and/or 
platelet counts have exceeded the 
prespecified values (see Section 6.3.1) 
on at least 2 occasions.   
 Upon recovery, Ixazomib may be 
reinitiated with 1 dose level reduction.  
 If ANC ≤ 0.50  109/L and the patient is 
febrile (febrile neutropenia) 
 All treatment suspended until ANC 
count has exceeded the prespecified 
value (see Section 6.3.1) on at least 2 
occasions.   
 Upon recovery, Ixazomib and pegylated 
IFN may be reinitiated with 1 dose level 
reduction.   
Dose Modifications for Subsequent 
Treatment Cycles 
 
 Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery as defined in Section 6.3Error! 
Reference source not found. 
 ANC < 1.0  109/L, platelet count < 75 
 109/L, or other non-hematologic 
toxicities > Grade 2 or not to the 
patient’s baseline condition 
 Hold Ixazomib until resolution as per 
criteria Section 6.3. 
 Upon recovery, reduce Ixazomib 1 dose 
level. 
 The maximum delay before treatment 
should be discontinued will be 3 weeks 
or at the discretion of the PI. 
Dose Modifications for Subsequent 
Treatment Cycles 
 
 
All hematologic toxicities 
For hematologic toxicity that occurs during a 
cycle but recovers in time for the start of the 
next cycle: 
o If dose was reduced within the cycle, 
start the next cycle at that same dose. 
o If due to toxicity timing, ie, during 
the off week for Ixazomib, a dose 


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Table 6-2    
Ixazomib and Pegylated IFN-α-2b Dose Adjustments for Hematologic 
Toxicities 
reduction was not required at that 
point in the cycle, reduce Ixazomib 
by 1 dose level at the start of the 
following cycle. 
o Do not reduce the dose both within a 
cycle and at the start of the cycle for 
the same most severe toxicity. 
 
 
Table 6-3    
Ixazomib and Pegylated IFN-α-2b Dose Adjustments (Delays, 
Reductions, and Discontinuations) Due to Adverse Events (Non-Hematologic 
Toxicities) 
 
Grade 1 peripheral 
neuropathy 
 
No action 
 
New or worsening Grade 1 
peripheral neuropathy with 
pain or Grade 2 neuropathy 
without pain 
 Hold Ixazomib ONLY 
until resolution to Grade ≤ 
1 or baseline 
 
 
New or worsening Grade 2 
peripheral neuropathy with 
pain (not grade Grade 2 
peripheral neuropathy 
without pain, see above for 
that modification) or Grade 3 
neuropathy 
 Hold Ixazomib ONLY 
until resolution to Grade ≤ 
1 or baseline 
 Reduce Ixazomib ONLY 
to next lower dose upon 
recovery 
 
New or worsening Grade 4 
peripheral neuropathy 
 Discontinuation of study 
drug 
 
Grade 2 Rash 
 
 
 
Grade 3 Rash 
 
 
 
 Symptomatic 
recommendations as per 
Section 6.4 with no dose 
modification 
 Hold Ixazomib ONLY 
until resolution to Grade 
≤ 1 or baseline.  Initiate 
symptomatic 
recommendations as per 
The investigator may discuss 
considerations for dose 
modifications and symptom 
management with the PI 
 


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Grade 4 Rash 
Section 6.4.  
 Reduce Ixaxomib ONLY 
to next lower dose upon 
recovery. 
 Hold both study drugs 
and discontinue study 
treatment for the patient. 
Grade 2 diarrhea 
 
 
 
 
Grade 3 diarrhea 
 
 
 
 
 
 
 
 
 
 
Grade 4 diarrhea 
 Continue drugs, but 
initiate symptomatic 
treatment as per Section 
6.4 
 
 Hold Ixazomib AND 
Interferon until 
resolution to Grade ≤ 1 
or baseline.  Initiate 
symptomatic 
recommendations as per 
Section 6.4.  
 Reduce both drugs to 
next lower dose upon 
recovery. 
 Hold Ixazomib AND 
Interferon until 
resolution to Grade ≤ 1 
or baseline.  Initiate 
symptomatic treatment.  
Reduce Ixazomib by 2 
dose levels and 
pegylated IFN by 1 dose 
level.  If the current dose 
level is at a point where 
the above adjustment is 
not possible (i.e., dose 
adjustments have already 
been done), patient will 
be withdrawn from the 
study. 
 
Grade 2 nausea/vomiting 
 
 
 
 Continue drugs, but 
initiate symptomatic 
treatment as per Section 
6.4 
 


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Grade 3 nausea/vomiting 
 
 
 
 
 
 
 
 
 
Grade 4 nausea/vomiting 
 
 
 
 Hold Ixazomib AND 
Interferon until 
resolution to Grade ≤ 1 
or baseline.  Initiate 
symptomatic 
recommendations as per 
Section 6.4.  
 Reduce both drugs to 
next lower dose upon 
recovery. 
 Hold Ixazomib AND 
Interferon until 
resolution to Grade ≤ 1 
or baseline.  Initiate 
symptomatic treatment.  
Reduce Ixazomib by 2 
dose levels and 
pegylated IFN by 1 dose 
level.  If the current dose 
level is at a point where 
the above adjustment is 
not possible (i.e., dose 
adjustments have already 
been done), patient will 
be withdrawn from the 
study. 
 
Grade 3 non-hematologic 
toxicity judged to be related 
to both study drugs 
 Hold BOTH drugs until 
resolution to Grade ≤ 1 or 
baseline 
Symptomatic 
recommendations noted in 
Section 6.4 
If not recovered to 
≤ Grade 1 or baseline 
within 4 weeks 
 
 Reduce BOTH drugs  to 
next lower dose upon 
return to ≤ Grade 1 or 
baseline 
 
Subsequent 
recurrence Grade 3 
that does not recover 
to ≤  Grade 1 or 
baseline within 4 
weeks 
 Hold BOTH drugs until 
resolution to Grade ≤  1 or 
baseline 
 Reduce BOTH drugs to 
next lower dose  
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic 
care 


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Grade 3 non-hematologic 
toxicity judged to be related 
to IFN only.  
 Hold IFN ONLY until 
resolution to Grade ≤ 1 or 
baseline 
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic 
care 
If not recovered to 
≤ Grade 1 or baseline 
within 4 weeks 
 
 Reduce IFN to next lower 
dose upon return to 
≤ Grade 1 or baseline 
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic 
care 
Subsequent 
recurrence Grade 3 
that does not recover 
to ≤ Grade 1 or 
baseline within 4 
weeks 
 Hold IFN until resolution 
to Grade ≤ 1 or baseline 
 Reduce IFN to next lower 
dose  
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic 
care 
Grade 4 non-hematologic 
toxicities judged to be 
related to study drug 
Consider permanently 
discontinuing study drug 
Exceptions may be made in 
cases in which the 
investigator determines the 
patient is obtaining a clinical 
benefit 
 
Renal Impairment Dose Adjustment: 
For patients whose CrCl was acceptable for study eligibility/entry per a 24 hour urine 
creatinine clearance, but not Cockcroft-Gault, if serum creatinine increases by 20% or more, 
the dose of pegylated IFN will be reduced by 25% for the particular dose level the patient is 
at and not re-escalated.  
If a patient’s CrCl was acceptable per Cockcroft-Gault for study eligibility/entry, then if 
CrCl drops to between 30-50 ml/min while on treatment, the dose of pegylated IFN will be 
reduced by 25% for the particular dose level the patient is at and not re-escalated. 
Once Ixazomib or pIFN is reduced for any toxicity, the dose may not be re-escalated. 
 
6.5     
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study.  A DDI with a strong inhibitor would increase ixazomib 
exposure. 


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Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
 
Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided unless there is no appropriate alternative medication for the patient to use 
(Rationale:  Unlike with inhibitors, if there were to be a DDI with an inducer, ixazomib 
exposure would be less; therefore, there would be a reduced chance of an AE.  However, 
there may be less chance for an antitumor effect, but that is not an absolute reason to be 
taken off Ixazomib): 
 
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital. 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
 
Any antineoplastic treatment with activity against RCC except for drugs in this 
treatment regimen. 
 
Radiation therapy (the requirement for local radiation therapy generally indicates 
disease progression). 
 
 The following drugs are not permitted during the study: zidoudine, theophylline 
derivatives, telbivudine, ribavirin, pegloticase, methadone, fluoxetine, aldesleukin, 
clozapine. 
 
Monitor closely any CYP2D6 or CYP2C9 substrate drugs as Pegylated IFN may 
decrease serum concentration of CYP2D6 substrates. 
 
6.6     
Permitted Concomitant Medications and Procedures  
The following medications and procedures are permitted during the study: 
 Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
 Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to institutional 
guidelines. Intravenous fluids should be given as needed to prevent volume 
depletion. 
 Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 


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permitted. Their use should follow published guidelines and/or institutional practice;  
however, alternative usage may be reviewed with the PI. Erythropoietin will be 
allowed in this study. Its use should follow published guidelines and/or institutional 
practice. 
 Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
 Antiviral therapy such as acyclovir may be administered if medically appropriate. 
 Concomitant treatment with bisphosphonates and RANKL inhibitor denosumab will 
be permitted, as appropriate. 
 Patients who experience worsening neuropathy from baseline may be observed for 
recovery and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of 
the investigator. 
 Supportive measures consistent with optimal patient care may be given throughout 
the study. 
  
6.7     
Precautions and Restrictions  
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment 
as specified below. 
Female patients must meet 1 of the following criteria:  
 
Postmenopausal for at least 1 year before the screening visit, OR 
 
Surgically sterile, OR 
 
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form through 
90 days after the last dose of study drug, OR 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception.) 


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Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 
 Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR 
 Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
 Pegylated IFN is a category C pregnancy risk and the above should be followed. 
 
6.8  
 
Preparation, Reconstitution, and Dispensing 
Ixazomib  
As with any anticancer drug caution should be exercised when handling ixazomib capsules. 
Pegylated Interferon 
Two B-D Safety LokTM syringes are provided in the package; one syringe is for the 
reconstitution steps and one for the patient injection. There is a plastic safety sleeve to be 
pulled over the needle after use. The syringe locks with an audible click when the green 
stripe on the safety sleeve covers the red stripe on the needle. Brief instructions for the 
preparation and administration of PEG-Intron Powder for Injection are provided below. 
Please refer to the Medication Guide for detailed, step-by-step instructions. 
Reconstitute the PEG-Intron lyophilized product with only 0.7 mL of supplied 
diluent (Sterile Water for Injection, USP). The diluent vial is for single use only. The 
remaining diluent should be discarded. No other medications should be added to solutions 
containing PEG-Intron, and PEG-Intron should not be reconstituted with other diluents. 
Swirl gently to hasten complete dissolution of the powder. The reconstituted solution should 
be clear and colorless. Visually inspect the solution for particulate matter and discoloration 
prior to administration. The solution should not be used if discolored or cloudy. 
The reconstituted solution should be used immediately and cannot be stored for more than 
24 hours at 2-80 C.  The appropriate PEG-Intron dose should be withdrawn and injected 
subcutaneously. The PEG-Intron vial is a single use vial and does not contain a 
preservative. DO NOT REENTER VIAL. DISCARD UNUSED PORTION. Once the dose 
from a single dose vial has been withdrawn, the sterility of any remaining product can no 
longer be guaranteed. Pooling of unused portions of some medications has been linked to 
bacterial contamination and morbidity. 
After preparation and administration of the PEG-Intron injection, it is essential to follow the 
procedure for proper disposal of syringes and needles. A puncture-resistant container should 


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be used for disposal of syringes. Patients should be instructed in the technique and 
importance of proper syringe disposal and be cautioned against reuse of these items 
(See MEDICATION GUIDE for detailed instructions.) 
PEG-Intron is a white to off-white lyophilized powder supplied in 2-mL vials. The PEG-
Intron Powder for Injection should be reconstituted with 0.7 mL of the supplied Diluent 
(Sterile Water for Injection, USP) prior to use.   Below are the various vial sizes available 
and will be ordered based on a patient’s weight in kg. 
Each PEG-Intron Package Contains 
  
A box containing one 50 µg per 0.5 ml vial of PEG-
Intron Powder for Injection and one 5 mL vial of 
Diluent (Sterile Water for Injection, USP), 2 B-D 
Safety LokTM syringes with a safety sleeve and 2 
alcohol swabs. 
(NDC 0085-1368-01) 
A box containing one 80 µg per 0.5 mL vial of PEG-
Intron Powder for Injection and one 5 mL vial of 
Diluent (Sterile Water for Injection, USP), 2 B-D 
Safety LokTM syringes with a safety sleeve and 2 
alcohol swabs. 
(NDC 0085-1291-01) 
A box containing one 120 µg per 0.5 mL vial of PEG-
Intron Powder for Injection and one 5 mL vial of 
Diluent (Sterile Water for Injection, USP), 2 B-D 
Safety LokTM syringes with a safety sleeve and 2 
alcohol swabs. 
(NDC 0085-1304-01) 
A box containing one 150 µg per 0.5 mL vial of PEG-
Intron Powder for Injection and one 5 mL vial of 
Diluent (Sterile Water for Injection, USP), 2 B-D 
Safety LokTM syringes with a safety sleeve and 2 
alcohol swabs. 
(NDC 0085-1279-01) 
 
6.9  
 
Packaging and Labeling 
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.   
Ixazomib capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.  The 0.2-, 
0.5-, and 2.0 mg capsules are in 1  4 blister strips that are individually perforated.  The 
strips (1  4) are placed in cartons containing 6 strips (24 total capsules) of the same 


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strength. The 2.3-, 3.0-, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-
resistant cardboard wallet. 
PEG-Intron, should be stored at 25oC (77oF): excursions permitted to 15-30oC (59-86oF) 
[see USP Controlled Room Temperature]. After reconstitution with supplied Diluent the 
solution should be used immediately, but may be stored up to 24 hours at 2o to 8oC (36o to 
46oF). The reconstituted solution contains no preservative, is clear and colorless. Do not 
freeze.  
6.10 
 
 
Storage, Handling, and Accountability 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before 
the retest expiry date provided by Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for 
take-home dosing should remain in the blister packaging and refrigerated as noted above 
until the point of use. The investigative site is responsible for providing the medication to 
the patient in the correct daily dose configurations. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. Patients who 
are receiving take-home medication should be given only 1 cycle of medication at a time. 
Patients should be instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) 
for the duration of each cycle. Patients should be instructed to return their empty blister 
packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. Any 
extreme in temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis. 
Because ixazomib is an investigational agent, it should be handled with due care. Patients 
should be instructed not to chew, break, or open capsules. In case of contact with broken 
capsules, raising dust should be avoided during the clean-up operation. The product may be 
harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing should 
be worn during cleanup and return of broken capsules and powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material pick-up 
is complete. The material should be disposed of as hazardous medical waste in compliance 
with federal, state, and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified. Patients are to be instructed on proper 
storage, accountability, and administration of ixazomib, including that ixazomib is to be 
taken as intact capsules. 


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See above for handing, storage and administration of IFN. 
6.11 
      Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing. 
6.12 
   
Treatment Assignment  
All patients will be assigned combination treatment.  In phase I this will be based on the 
cohort and in phase II it will be a set dose based on phase I.  Dose modifications are 
permitted as described in section 6.2. 
6.13 
   
Termination of Treatment and/or Study Participation 
In the absence of treatment delays due to adverse events, treatment may continue for 
unlimited cycles or until one of the following criteria applies: 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
 Withdrawl of trial support by the Sponsor 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  
Patients who are withdrawn from the study will not be replaced. 
Treatment delay of ≥ 21 days for any hematologic or non-hematologic toxicity will lead to 
permanent treatment discontinuation. 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded 
in the source documents and CRF. 
6.14 
   
Long Term Follow Up 
In regard to long-term follow-up, unless there is progression or withdrawal of consent, study 
follow-up will continue until 5 years maximum.  Upon progression, patient will continue to 
be followed up for three years maximum with phone calls from the study coordinator every 
3 months. 
 


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7 ADVERSE EVENTS 
7.1     
Definitions 
7.1.1     Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
7.1.2     Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
 Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 
 Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
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; any organism, virus, or infectious particle (eg, prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.   


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Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
7.1.3     Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions: 
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL. 
Grade 3: Severe-severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL. 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE 
Attribution/Relationship to study drug:  
 
Definite – clearly related 
 
Probable – likely related 
Possible – may be related 
 
Unlikely – doubtfully related 
 
Unrelated – clearly not related 


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7.1.4     Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event is 
related to participation in the research is not consistent with either: 
1. 
The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol-related documents, such as the 
IRB-approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts: or 
2. 
The expected natural progression of any underlying disease, disorder, or condition of 
the subject (s) experiencing the adverse event and the subjects(s) predisposing risk factor 
profile for the adverse event. 
 
(OHRP Guidance on reviewing unanticipated problems 2007) 
7.2     Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event 
to study drug administration. For serious pretreatment events, the investigator must 
determine both the intensity of the event and the relationship of the event to study 
procedures.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the date the participant signs Informed Consent through 30 days after administration of 
the last dost of Ixazomib. Any SAE that occurs at any time after completion of Ixazomib 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub-
investigator considers to be related to any study drug must be reported to Millennium 
Pharmacovigilance (or designee).  In addition, new primary malignancies that occur during 
the follow-up periods must be reported, regardless of causality to study regimen, for a 
minimum of three years after the last dose of the investigational product, starting from the 
first dose of study drug. All new cases of primary malignancy must be reported to 
Millennium Pharmacovigilance (or designee).    
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 


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7.2.1     Site reporting responsibilities: 
Since this is an investigator-initiated study, the principal investigator Daniel M. Geynisman, 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.    
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported to Millennium Pharmacovigilance: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.   
The sponsor-investigator must fax the SAE Form per the timelines above.   
The SAE report must include at minimum: 
 Event term(s) 
 Serious criteria 
 Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.   
Intensity for each SAE, including any lab abnormalities, will be determined by using the 
NCI CTCAE version used at your institution, as a guideline, whenever possible.  The criteria 
are available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations 
to the required regulatory agencies and to Millennium Pharmacovigilance, unless otherwise 
agreed between the sponsor-investigator and sub-investigator(s).   


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Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study or study drug(s), 
including, but not limited to, telephone conversation logs within 24 hours but no later than 4 
calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information 
SAE and Pregnancy Reporting Contact Information 
 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
Reporting Form:   
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
1. 
The investigator/ site is responsible to report all SAEs to the Study Monitor within 
24 hours of becoming aware of the event.  A written report must follow within 48 hours. 
2. 
Each investigator is responsible to report all AEs/SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC ERP reserves the right to request an event be 
reported to the IRB at their discretion.  Copies of events reviewed by the IRB must be sent 
via fax to the ERP Regulatory Coordinator at (215) 728-2914 
3. 
Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call the Study Monitor for confirmation with the Principal Investigator 
4. 
If the results of an investigator or ERP investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report the event 
following the above guidelines based on the date the determination is made. 
5. 
Copies of all related correspondence and reporting documents must be submitted to 
the ERP Regulatory Coordinator and will be maintained in a regulatory file. 
 
The participating site should report events to: 
Study Monitor 
Fox Chase Cancer Center 
Clinical Trials Operations 
333 Cottman Avenue 
Philadelphia, PA 19111 
Telephone 215-214-3704 
Fax  215-214-1511 
 


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7.2.2     ERP Reporting Responsibilities: 
1. 
Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the event.   
i. 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
ii. 
Possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
iii. 
Serious (refer to above definition) or otherwise one that suggests that the research 
places subjects or others at a greater risk of physical or psychological harm than was 
previously known or recognized. 
2. 
If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the form of an 
amendment from the ERP for each site’s IRB of record along with the report of the adverse 
event.   
3. 
Copies of all related correspondence and reporting documents will be maintained in 
a centralized regulatory file for this study by the ERP. 
4. 
SAEs that are related, unexpected, fatal, or life-threatening are reportable through the 
Food and Drug Administration (FDA) MedWatch program by telephone or fax no later than 
7 calendar days after initial receipt of the information.  Further information on the timing of 
submissions is as directed by FDA guidelines (www.fda.gov/medwatch/index.html).  
Serious, unexpected events that suggest significant clinical risk will be submitted to within 
15 calendar days after initial receipt of this information. 
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178 
http://www.fda.gov/medwatch/report.htm 
 
Mandatory Drug Reporting: 
Central Document Room 
Center for Drug Evaluation and Research 
Food and Drug Administration 
12229 Wilkins Avenue 
Rockville, MD 20852 
Office of Post-Marketing Drug Risk Assessment (HFD 730) 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD 20857 
(301) 827-3169 for any further questions regarding where to send drug mandatory reporting 
forms 


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7.3     Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study or within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug.  The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee.  The pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form to the Millennium Department of Pharmacovigilance or designee.  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Pregnancy Reporting Form: 
 Pregnancy Report Form (a sample is provided by Millennium)   
 


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8     STATISTICAL AND QUANTITATIVE ANALYSES 
8.1     
Statistical Methods 
Figure 8-1: Flow diagram of statistical design for the phase II of the study 
 
 
8.1.1      Definition of Phase II and exploratory endpoints and Analytic Plan 
The phase II dose will be determined by an initial standard ‘3+3’ phase I component as 
described in Section 4.1.  Once a RP2D is reached, the phase II will begin.  
Definition of phase II primary endpoint:  Progression free survival at 8 and 16 weeks 
using RECIST v 1.1, defined from date of treatment initiation to date of progression 
according to RECIST or death, or is censored at the date of the last imaging. If patient is not 
evaluated at 8 and/or 16 weeks then the patient is not considered as alive and progression-
free. 
 


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Definition of secondary outcomes/endpoints:   
1. Composite of unacceptable toxicity at 8 weeks (grade 4 non-hematologic toxicity 
thought to be definitely, probably or possibly related to study drug) 
2. Overall response using RECIST v1.1. 
 
Definition of exploratory objectives: 
1. Changes in STAT1 phosphorylation and MHC1 up regulation in PBMCs from  
baseline to week 2, 3, 7,  EOT. 
2. Degree of desmoplasia in archived FFPE tumor samples and change in serum IL-
6 
3. Degree of nuclear NF-κB p65 and STAT1 in archived FFPE tumor samples 
 
Analytic plan for primary and secondary objectives:   
 
Kaplan Meier curves will be used to estimate the distribution of progression free survival, 
median survival, and 1-year survival. Proportions, 95% confidence intervals, will be used to 
characterize composite rate of unacceptable toxicity and overall response rate.  All analyses 
are for estimation only, and no larger inference will be generated given the sample size of 
the study.   
 
Analytic plan for exploratory objectives: 
 
Pre- and post- treatment phosphorylation changes in pSTAT1 and MHC1 (flow data, the 
MFIs will be log10) and serum IL-6 will be analyzed by paired t-tests.  Degree of 
desmoplasia and nuclear NF-kB and STAT1 will be quantified using standard 
immunohistochemical methods.  Statistical analysis for western blots and responders vs non-
responders tumor immunohistochemistry will be performed using non-parametric Mann-
Whitney test and/or paired t-tests. 
 
8.1.2      Sample Size Determination 
The design incorporates two conditions not usually treated. First, the final group of patients 
in the phase I component is considered part of the phase II trial. Second, the phase II part 
has two end-points, toxicity (UT: unacceptable toxicity) and efficacy. The relation between 
toxicity and efficacy is explicitly taken into account. We test the composite null hypothesis: 
H0: p(UT) > 0.25 or p(PFS > 8 weeks) < 0.5 or p(PFS > 16 weeks) < 0.35 
versus the alternative: 
H1: p(UT) < 0.05 and p(PFS > 8 weeks) > 0.66 and p(PFS > 16 weeks) > 0.56. 
Eleven new patients will be treated in the first stage of the phase 2 component. If 3/17 
patients have UTs OR if at most 8/17 are alive and PF at 8 weeks the trial will be either be 


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suspended for excess toxicity or for futility.  The decision for early termination (or 
amendment) is based on these cut points. If either 3 of 17 stage I patients are DLTs OR if at 
most 8 of 17 are PF at 8 weeks then terminate or hold up. The final decision point, PFS at 16 
weeks is not relevant; the number of such patients does not influence the early decision. The 
confusion seems to relate to the alternative hypothesis which is couched in terms of ‘AND’. 
It does, of course, require both early and late components of the outcome to be defined.  
Finally, although 3/17 is less than 0.25, this is the cut point, clearly between 0.05 and 0.25. 
The early PFS cut point 8/17 is less than 0.5 but is only a cut point. 
At that point we will consider protocol amendment.  Otherwise, 17 new patients will be 
recruited.  If at least 14/34 patients are PF at 16 weeks AND less than 4/34 have UTs the 
null hypothesis will be rejected and the treatment declared efficacious. Otherwise it will be 
declared either too toxic or not efficacious.  
Further operating characteristics and statistical details can be found in Appendix 12.3 
 
8.1.3     Randomization and Stratification   
No randomization or stratification will be used. 
 
8.1.4     Populations for Analysis 
Safety Population: All patients who receive at least one dose of both drugs. 
Efficacy Population: All patients who receive at least one dose of both drugs. 
 
8.1.5     Demographic and Baseline Characteristics 
Descriptive statistics will be used to summarize baseline characteristics of patients. 
8.1.6     Safety Analysis 
Safety analysis will be performed by the PI and biostatics. Safety data will be reviewed by 
the Extramural Data Safety Monitoring Committee (EDMSC).  Each patient will be 
monitored closely as detailed in the study calendar.  Adverse events will be documented and 
summarized in table form.  Interim analysis of toxicity, outcome and ongoing scientific 
investigations may be performed every 3 months by the Extramural Data Safety Monitoring 
Committee (EDSMC).  In this capacity the EDSMC will serve as an advisory committee to 
ERP and FCCC IRB.  The EDSMC will review those aspects of this trial that are outlined in 
the responsibilities section of the ERP Data and Safety Monitoring Plan (DSMP).  If the 
committee decides that changes should be made to this trial, it will make recommendations 
in writing to the Extramural Research Committee and Division Medical Director and PI 
which, in turn, have the authority to approve or disapprove these recommendations.  These 
changes will be discussed with the Study Principal Investigator before they are 


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implemented.  These changes may include early termination of accrual.  Other changes 
might include altering the accrual goals or changing the eligibility criteria for the trial. 
 
9     MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).53 Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.  
 
All patients will be evaluable for toxicity from the time of their first treatment with 
pegylated interferon and ixazomib.  Only those patients with evaluable and measurable 
disease will be enrolled and thus evaluable for objective response.  A patient must have had 
at least one cycle of therapy (28 days) and have their disease re-evaluated to be considered 
evaluable for response and PFS. 
 
Measurable Disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter for non-nodal lesions and short axis 
for nodal lesions to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 
10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI) are considered as non-measurable.  
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions.  
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 


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addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance, the next largest lesion which can be measured 
reproducible should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
 
Non-target lesions All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged, but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and > 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-holding techniques, 
if possible.  
 
PET-CT should not be used as an imaging modality 
 


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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors where known residual benign tumors can remain).  
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
Evaluation of Target Lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to < 10 mm.  
Partial Response (PR) 
At least a 30% decrease in the sum of 
diameters of target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to the relative 
increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 
mm.  
Note: the appearance of one or more new 
lesions is also considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
Evaluation of Non-Target Lesions 


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Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All 
lymph nodes must be non-pathological in 
size (< 10 mm short axis).  
Non-CR/ Non-PD  
[Incomplete response/ Stable Disease (SD)] 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression 
should not normally trump target lesion 
status. It must be representative of overall 
disease status change, not a single lesion 
increase.  
Although a clear progression of ‘non-target’ 
lesions only is exceptional, the opinion of the 
treating physician should prevail in such 
circumstances, and the progression status 
should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response  
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  


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Progression-Free Survival  
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
10     ADMINISTRATIVE REQUIREMENTS 
10.1 
    
Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative. 
For Product Complaints, 
 
Phone: 1-877-TAKEDA7 (1-877-825-3327) 
 
E-mail: medicalinformation@tpna.com 
 
FAX: 1-800-247-8860 
 
Hours: Mon-Fri, 8 a.m. – 6 p.m. ET 
 


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Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance (refer to 
Section 9.2). 
10.2 
    
Compliance with Protocol and Protocol Revisions 
The study must be conducted as described in this approved protocol.  All requests for 
revisions to the protocol must be provided to ERP.  The Investigator should not implement 
any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an Amendment, except where necessary to 
eliminate an immediate hazard(s) to study patients.  Documentation of approval signed by 
the chairperson or designee of the IRB(s)/IEC(s) must be sent to the ERP.  If the revision is 
an Administrative Letter, Investigators must inform their IRB(s)/IEC(s). ERP will work with 
Fox Chase Cancer Center Coordinating Center to ensure they are in receipt of all required 
documents. 
10.3 
    
Data Collection 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the investigational product.     
10.4 
    
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, patient recruitment 
materials/process (e.g., advertisements), and any other written information to be provided to 
patients.  The Investigator should also provide the IRB/IEC with a copy of the product 
labeling, information to be provided to patients, and any updates. 
The Investigator should provide the IRB/IEC with reports, updates, and other information 
(e.g., Safety Updates, Amendments, and Administrative Letters) according to regulatory 
requirements or Institution procedures. Copies of the initial IRB approval as well as annual 
re-approvals must be submitted to ERP. 
10.5 
    
Records Retention 
The Investigator must retain investigational product disposition records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
Institution procedures. If the Investigator withdraws from the study (e.g., relocation, 
retirement), the records shall be transferred to a mutually agreed upon designee (e.g., 
another Investigator, IRB). Notice of such transfer will be given in writing to ERP. 
 
 


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11     REFERENCES    
 
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SEER Stat Fact Sheets: Kidney and Renal Pelvis. Accessed February 2014 
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World Health Organization; International Agency for Research on Cancer. 
Cancer incidence, 
mortality, and prevalence worldwide. Globocan 2008. http://globocan.iarc.fr/.  
 
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Cairns P: Renal cell carcinoma. Cancer Biomark 9:461-73, 2010 
 
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Plimack ER, Hudes GR: Selecting targeted therapies for patients with renal 
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Ljungberg B: The role of metastasectomy in renal cell carcinoma in the era of 
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Thapa RJ, Nogusa S, Chen P, et al: Interferon-induced RIP1/RIP3-mediated 
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17. 
Gore ME, Griffin CL, Hancock B, et al: Interferon alfa-2a versus 
combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with 
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Escudier B, Bellmunt J, Negrier S, et al: Phase III trial of bevacizumab plus 
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Rini BI, Halabi S, Rosenberg JE, et al: Phase III trial of bevacizumab plus 
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Escudier B, Lassau N, Angevin E, et al: Phase I trial of sorafenib in 
combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell 
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Niwakawa M, Hashine K, Yamaguchi R, et al: Phase I trial of sorafenib in 
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Harvey RD, Owonikoko TK, Lewis CM, et al: A phase 1 Bayesian dose 
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Garcia JA, Mekhail T, Elson P, et al: Phase I/II trial of subcutaneous 
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Siebels M, Rohrmann K, Oberneder R, et al: A clinical phase I/II trial with 
the monoclonal antibody cG250 (RENCAREX(R)) and interferon-alpha-2a in metastatic 
renal cell carcinoma patients. World J Urol 29:121-6, 2011 
 
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Feldman DR, Kondagunta GV, Schwartz L, et al: Phase II trial of pegylated 
interferon-alpha 2b in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 
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Bukowski R, Ernstoff MS, Gore ME, et al: Pegylated interferon alfa-2b 
treatment for patients with solid tumors: a phase I/II study. J Clin Oncol 20:3841-9, 2002 
 
27. 
Motzer RJ, Rakhit A, Ginsberg M, et al: Phase I trial of 40-kd branched 
pegylated interferon alfa-2a for patients with advanced renal cell carcinoma. J Clin Oncol 
19:1312-9, 2001 
 
28. 
Bex A, Mallo H, Kerst M, et al: A phase-II study of pegylated interferon alfa-
2b for patients with metastatic renal cell carcinoma and removal of the primary tumor. 
Cancer Immunol Immunother 54:713-9, 2005 
 
29. 
Sunela KL, Koskinen S, Kellokumpu-Lehtinen PL: A phase-II study of 
combination of pegylated interferon alfa-2a and capecitabine in locally advanced or 
metastatic renal cell cancer. Cancer Chemother Pharmacol 66:59-67, 2010 


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30. 
Shek D, Longmate J, Quinn DI, et al: A phase II trial of gefitinib and 
pegylated IFNalpha in previously treated renal cell carcinoma. Int J Clin Oncol 16:494-9, 
2011 
 
31. 
Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel 
proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-
11, 2002 
 
32. 
Kondagunta GV, Drucker B, Schwartz L, et al: Phase II trial of bortezomib 
for patients with advanced renal cell carcinoma. J Clin Oncol 22:3720-5, 2004 
 
33. 
Davis NB, Taber DA, Ansari RH, et al: Phase II trial of PS-341 in patients 
with renal cell cancer: a University of Chicago phase II consortium study. J Clin Oncol 
22:115-9, 2004 
 
34. 
Lesinski GB, Raig ET, Guenterberg K, et al: IFN-alpha and bortezomib 
overcome Bcl-2 and Mcl-1 overexpression in melanoma cells by stimulating the extrinsic 
pathway of apoptosis. Cancer Res 68:8351-60, 2008 
 
35. 
J. M, Luedke EA, Grignol VP, et al: Bortezomib and interferon alpha-2b in 
metastatic melanoma. . J Clin Oncol 31, 2013 (suppl; abstr e20018)  
 
36. 
Kupperman E, Lee EC, Cao Y, et al: Evaluation of the proteasome inhibitor 
MLN9708 in preclinical models of human cancer. Cancer Res 70:1970-80, 2010 
 
37. 
Lee EC, Fitzgerald M, Bannerman B, et al: Antitumor activity of the 
investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell 
malignancies. Clin Cancer Res 17:7313-23, 2011 
 
38. 
Chauhan D, Tian Z, Zhou B, et al: In vitro and in vivo selective antitumor 
activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple 
myeloma cells. Clin Cancer Res 17:5311-21, 2011 
 
39. 
Kumar S, Bensinger W, Reeder CB, et al: Weekly dosing of the 
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory 
multiple myeloma (MM): A phase I study. J Clin Oncol 30, 2012 (suppl; abstr 8034)  
 
40. 
Kumar S, Bensinger W, Zimmerman TM, et al: Weekly MLN9708, an 
investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma 
(MM): Results from a phase I study after full enrollment. J Clin Oncol 31, 2013 (suppl; abstr 
8514)  
 
41. 
Gupta N: Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An 
Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy 
Studies. Blood (ASH Annual Meeting Abstracts), 2010. 116(21): p. abstr 1813.  
 
42. 
Gupta N, M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based 
Dosing for MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic 
(PK) Analysis of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and 
Exposition. 2011. San Diego, CA.:  
 
43. 
Talpaz M, O'Brien S, Rose E, et al: Phase 1 study of polyethylene glycol 
formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive 
chronic myelogenous leukemia. Blood 98:1708-13, 2001 


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44. 
Glue P, Fang JW, Rouzier-Panis R, et al: Pegylated interferon-alpha2b: 
pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C 
Intervention Therapy Group. Clin Pharmacol Ther 68:556-67, 2000 
 
45. 
Wang YS, Youngster S, Grace M, et al: Structural and biological 
characterization of pegylated recombinant interferon alpha-2b and its therapeutic 
implications. Adv Drug Deliv Rev 54:547-70, 2002 
 
46. 
Liu CH, Liang CC, Lin JW, et al: Pegylated interferon alpha-2a versus 
standard interferon alpha-2a for treatment-naive dialysis patients with chronic hepatitis C: a 
randomised study. Gut 57:525-30, 2008 
 
47. 
Michallet M, Maloisel F, Delain M, et al: Pegylated recombinant interferon 
alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase 
chronic myelogenous leukemia: a phase III study. Leukemia 18:309-15, 2004 
 
48. 
Lyrdal D, Stierner U, Lundstam S: Metastatic renal cell carcinoma treated 
with Peg-interferon alfa-2b. Acta Oncol 48:901-8, 2009 
 
49. 
Litwin S, Wong YN, Hudes G: Early stopping designs based on progression-
free survival at an early time point in the initial cohort. Stat Med 26:4400-15, 2007 
 
50. 
Calvo E, Escudier B, Motzer RJ, et al: Everolimus in metastatic renal cell 
carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth 
factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 
study. Eur J Cancer 48:333-9, 2012 
 
51. 
Gupta V, Bassi DE, Simons JD, et al: Elevated expression of stromal palladin 
predicts poor clinical outcome in renal cell carcinoma. PLoS One 6:e21494, 2011 
 
52. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010.  
 
53. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 
2009 
 
 


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12     APPENDICES 
12.1 
    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance 
without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol 1982; 5 (6):649-55.  
 
 
12.2 
   
Cockcroft-Gault Equation 
For males: 
Creatinine Clearance = (140-age[years]  weight [kg]) 
OR 
(140–age[years]  
weight [kg]) 
72  (serum creatinine[mg/dL]) 
 
0.81  (serum 
creatinine[mol/L]) 
 
For females: 
Creatinine Clearance = 0.85 (140-age[years]  weight [kg]) OR  0.85 (140-age[years]  
weight [kg]) 
72  (serum creatinine[mg/dL]) 
 
0.81  (serum 
creatinine[mol/L]) 
 


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Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41. 
 
 
12.3 
   
Statistical Considerations and Operating Characteristics for Phase II 
Operating characteristics of the design depend on four conditions: toxicity being low (0.05) 
or high (0.25) and PFS at 16 weeks being low (0.35) or high (0.56). They are summarized 
below:  
1. 
Toxicity = 0.05 and PFS = 0.56. In this case the power of the study is at least 80%. 
The chance of early stopping (in error) for excess toxicity is less than 1%. The chance for 
stopping (in error) for futility varies from 8% to 12% depending on the relation of toxicity to 
PFS (see details below). 
2. 
Toxicity = 0.05, PFS = 0.35. The chance of early stopping for futility varies from 
49% to 57%. The chance of declaring treatment efficacious (type I error) varies from 10% to 
21%. 
3. 
Toxicity  = 0.25 and PFS = 0.35. Type I error varies from less than 1% to about 5%. 
Chance of stopping early for either excess toxicity or futility varies from about 26% to about 
59%. 
4. 
Toxicity = 0.25 and PFS = 0.56. Type I error varies from about 5% to about 10%. 
Chance of early stopping for excess toxicity is about 27%.  
The term ‘UT’ here means severe toxicity for which, if frequent enough, dictates dose 
reduction or trial termination. This early stopping design is an extension of the method of 
Litwin, Wong and Hudes (Statistics in Medicine, 2007,26:4400-4415). Below, the chance 
that a patient has a UT and also is PF at 16 weeks is represented by ‘a’. ‘b’, ‘c’ and ‘d’, 
similarly, represent the indicated joint probabilities. 
Let p = p(PFS > 16 weeks), p1 = p(PFS > 8 weeks) and p2 =p(PFS > 16 weeks | PFS > 8 
weeks). Also, let ptox = p(UT in 16 weeks). Let ptox1 = f*ptox = p(UT in initial 8 week 
period) and ptox2 = (1-f)*ptox = p(UT in 8 through 16 week period| no UT in the initial 8 
weeks). Then,    b = p – a, c = ptox – a and d = 1 – a – b – c. a1, b1, c1, and d1 are similarly 
determined from p1 and ptox1. a2,b2,c2 and d2 are determined likewise, from p2 and ptox2.  
The table: 
P(UT)               1-p(UT) 
 a 
 
      b           p(PFS > 16 weeks) = 0.56 (under the alternative hypothesis) 
 c 
 
      d        p(PFS < 16 weeks) = 0.44 
ptox               1 - ptox            1   (ptox = 0.05 under the alternative hypothesis) 


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Illustrates how the joint event probabilities a, b, c and d at the end of the study relate. 
Namely, if we assign a = 0.02 then b, c and d can be determined by subtraction. Here we 
would get: b = 0.54, c = 0.03 and d = 0.41. For any value of a in (0, 0.05) the other three 
terms are completely specified. In this design we are considering toxicity to be cumulative. 
We model the total chance of UT to occur with fraction f in the first interval (0, 8 weeks) 
and 1-f in the final 8 weeks. We have considered fractions f = 0, 0.25, 0.5, 0.75 and 1.0, i.e. 
f=0 implies no toxicity in the first 8 weeks and f = 1 implies all toxicity occurs then. The 
final design is based on f = ½.  
P(UT)              1-p(UT)                                            
a1 
 
      b1   p(PFS > 8) = 0.66  
              
c1 
 
      d1   p(PFS < 8) = 0.34  
              
ptox1                1 – ptox1       1  (ptox1 = ptox2 = 0.025 under the alternative with f = ½) and                         
P(UT)              1-p(UT)  
a2 
              b2   p(PFS > 16|PFS > 8) = 0.848 
c2                       d2   p(PFS < 16|PFS > 8) = 0.15 
ptox2                 1 – ptox2            1 
The two tables above characterize the early stopping interval (0, 8 weeks) and final interval 
(8 weeks, 16 weeks).  Numbers in the tables represent the alternative hypothesis. Patients in 
the initial cohort are represented by the top table (a1, b1, c1, d1) in the initial interval and 
those who are toxicity and progression free at 8 weeks, hence continue on study are 
represented by the second table (a2, b2,c2,d2) for their second 8 weeks. Patients recruited 
into the second cohort, if the study makes it past the first 8 week period, are evaluated only 
at 16 weeks and are represented by the very first table (a, b, c, d). 
The chance of early stopping for excess toxicity, for futility, the chance of final declaration 
of excess toxicity, the power or type I error were all computed for each of the 4 conditions. 
Within each of these combinations, the fraction, f, of toxicity born within the first 8 weeks 
was varied in 5 steps from 0 to 1. We selected the number f = ½ in the belief that toxicity is 
cumulative and this is the maximum fraction expected to occur in the first half of the trial. 
Design behavior for f < ½ is ‘better’ than that for f > ½,  so is not reported here in detail.  
The table below lists the various operating probabilities as functions of ‘a’ for each of the 
four conditions. 
Key: 
 null = 0: PFS at 16 weeks = 0.35 
 null = 1: PFS at 16 weeks = 0.56 


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 ntox = 0: Toxicity = 0.05 
 ntox = 1: Toxicity = 0.25 
   
 a: probability that PFS > 16 weeks and patient had UT 
 tox: probability of early stopping for excess toxicity 
 fut: probability of early stopping for futility 
 toxend: probability that final decision is 'too toxic' 
 alpha: type I error, probability of declaring efficacy when 
        either PFS = 0.35 at 16 weeks or toxicity = 0.25 
 power: probability of declaring efficacy when PFS at 16 weeks is 
        0.56 and toxicity is 0.05. 
 null  ntox        a       tox       fut    toxend   alpha    cksum 
  0      0       0.00     0.0059   0.4938   0.0115   0.2116   1.0000 
  0      0       0.01     0.0059   0.5105   0.0111   0.1871   1.0000 
  0      0       0.02     0.0059   0.5271   0.0107   0.1642   1.0000 
  0      0       0.03     0.0059   0.5437   0.0103   0.1429   1.0000 
  0      0       0.04     0.0059   0.5602   0.0099   0.1233   1.0000 
  0      0       0.05     0.0059   0.5766   0.0095   0.1054   1.0000 
   
 null  ntox        a       tox       fut    toxend   alpha    cksum 
  0      1       0.00     0.2690   0.2920   0.3671   0.0493   1.0000 
  0      1       0.01     0.2690   0.3050   0.3561   0.0451   1.0000 
  0      1       0.02     0.2690   0.3181   0.3450   0.0410   1.0000 
  0      1       0.03     0.2690   0.3312   0.3339   0.0369   1.0000 
  0      1       0.04     0.2690   0.3444   0.3227   0.0329   1.0000 


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  0      1       0.05     0.2690   0.3576   0.3115   0.0291   1.0000 
  0      1       0.06     0.2690   0.3708   0.3003   0.0255   1.0000 
  0      1       0.07     0.2690   0.3840   0.2892   0.0221   1.0000 
  0      1       0.08     0.2690   0.3972   0.2781   0.0189   1.0000 
  0      1       0.09     0.2690   0.4103   0.2671   0.0161   1.0000 
  0      1       0.10     0.2690   0.4233   0.2562   0.0134   1.0000 
  0      1       0.11     0.2690   0.4361   0.2454   0.0111   1.0000 
  0      1       0.12     0.2690   0.4489   0.2347   0.0091   1.0000 
  0      1       0.13     0.2690   0.4615   0.2241   0.0073   1.0000 
  0      1       0.14     0.2690   0.4739   0.2137   0.0058   1.0000 
  0      1       0.15     0.2690   0.4860   0.2035   0.0045   1.0000 
  0      1       0.16     0.2690   0.4980   0.1935   0.0035   1.0000 
  0      1       0.17     0.2690   0.5097   0.1837   0.0026   1.0000 
  0      1       0.18     0.2690   0.5212   0.1741   0.0020   1.0000 
  0      1       0.19     0.2690   0.5324   0.1648   0.0014   1.0000 
  0      1       0.20     0.2690   0.5433   0.1557   0.0010   1.0000 
  0      1       0.21     0.2690   0.5540   0.1468   0.0007   1.0000 
  0      1       0.22     0.2690   0.5643   0.1382   0.0005   1.0000 
  0      1       0.23     0.2690   0.5742   0.1299   0.0003   1.0000 
  0      1       0.24     0.2690   0.5839   0.1219   0.0002   1.0000 
  0      1       0.25     0.2690   0.5932   0.1141   0.0001   1.0000 
   
 null  ntox        a       tox       fut    toxend   power    cksum 
  1      0       0.00     0.0059   0.0817   0.0234   0.8759   1.0000 
  1      0       0.01     0.0059   0.0888   0.0231   0.8653   1.0000 


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  1      0       0.02     0.0059   0.0963   0.0228   0.8535   1.0000 
  1      0       0.03     0.0059   0.1042   0.0225   0.8404   1.0000 
  1      0       0.04     0.0059   0.1125   0.0222   0.8259   1.0000 
  1      0       0.05     0.0059   0.1213   0.0219   0.8099   1.0000 
   
 null  ntox        a       tox       fut    toxend   alpha    cksum 
  1      1       0.00     0.2690   0.0247   0.6054   0.1010   1.0000 
  1      1       0.01     0.2690   0.0279   0.6021   0.1011   1.0000 
  1      1       0.02     0.2690   0.0313   0.5985   0.1012   1.0000 
  1      1       0.03     0.2690   0.0351   0.5947   0.1012   1.0000 
  1      1       0.04     0.2690   0.0391   0.5907   0.1011   1.0000 
  1      1       0.05     0.2690   0.0435   0.5864   0.1009   1.0000 
  1      1       0.06     0.2690   0.0483   0.5818   0.1006   1.0000 
  1      1       0.07     0.2690   0.0533   0.5770   0.1002   1.0000 
  1      1       0.08     0.2690   0.0587   0.5718   0.0997   1.0000 
  1      1       0.09     0.2690   0.0645   0.5664   0.0990   1.0000 
  1      1       0.10     0.2690   0.0706   0.5607   0.0981   1.0000 
  1      1       0.11     0.2690   0.0771   0.5548   0.0970   1.0000 
  1      1       0.12     0.2690   0.0840   0.5485   0.0957   1.0000 
  1      1       0.13     0.2690   0.0912   0.5419   0.0941   1.0000 
  1      1       0.14     0.2690   0.0988   0.5350   0.0923   1.0000 
  1      1       0.15     0.2690   0.1068   0.5278   0.0901   1.0000 
  1      1       0.16     0.2690   0.1152   0.5203   0.0877   1.0000 
  1      1       0.17     0.2690   0.1239   0.5126   0.0850   1.0000 
  1      1       0.18     0.2690   0.1330   0.5045   0.0819   1.0000 


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  1      1       0.19     0.2690   0.1425   0.4962   0.0786   1.0000 
  1      1       0.20     0.2690   0.1522   0.4876   0.0749   1.0000 
  1      1       0.21     0.2690   0.1624   0.4787   0.0710   1.0000 
  1      1       0.22     0.2690   0.1728   0.4696   0.0668   1.0000 
  1      1       0.23     0.2690   0.1836   0.4602   0.0625   1.0000 
  1      1       0.24     0.2690   0.1947   0.4506   0.0580   1.0000 
  1      1       0.25     0.2690   0.2060   0.4408   0.0533   1.0000 
-------------------------------------------------------------------- 
Our analysis above is based on the assumption that toxicity is judged at 8 weeks and again at 
16 weeks. In fact, the phase I portion of the study will not last beyond 4 weeks for each 
patient, so that the initial 3 patients, carried over from phase I, could become UT at 8 weeks. 
The tables above assume that the number of UTs at 8 weeks (not 4 weeks) is at most one. To 
account for this possibility, we re-computed the table assuming no restriction on the first 6 
patients, but using only the early stopping rules for toxicity at 8 weeks. Thus the initial 
phase II cohort of all 17 patients in this re-computation are all treated alike. The results are 
shown in the next table. While the table above allows a smaller chance of toxicity than the 
actual trial, the table below allows a greater chance of toxicity in the initial phase II cohort. 
The main difference in the two computations is that the chance of eacly stopping for UT is 
about 9% higher under the re-computation conditions (35%) than it is under the top table 
(27%).  
Operating characteristics of design with no restriction on the first 6 patients other than those 
tested at 8 or 16 weeks.   
 
null  ntox         a       tox       fut    toxend   alpha    cksum 
  0      0       0.00     0.0082   0.4937   0.0114   0.2106   1.0000 
  0      0       0.01     0.0082   0.5103   0.0110   0.1862   1.0000 
  0      0       0.02     0.0082   0.5269   0.0106   0.1633   1.0000 
  0      0       0.03     0.0082   0.5434   0.0102   0.1421   1.0000 
  0      0       0.04     0.0082   0.5599   0.0098   0.1227   1.0000 
  0      0       0.05     0.0082   0.5762   0.0094   0.1049   1.0000 
   


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 null  ntox        a       tox       fut    toxend   alpha    cksum 
  0      1       0.00     0.3591   0.2586   0.3197   0.0429   1.0000 
  0      1       0.01     0.3591   0.2700   0.3100   0.0393   1.0000 
  0      1       0.02     0.3591   0.2814   0.3003   0.0357   1.0000 
  0      1       0.03     0.3591   0.2929   0.2905   0.0321   1.0000 
  0      1       0.04     0.3591   0.3045   0.2807   0.0286   1.0000 
  0      1       0.05     0.3591   0.3161   0.2709   0.0253   1.0000 
  0      1       0.06     0.3591   0.3277   0.2612   0.0221   1.0000 
  0      1       0.07     0.3591   0.3392   0.2514   0.0192   1.0000 
  0      1       0.08     0.3591   0.3507   0.2417   0.0164   1.0000 
  0      1       0.09     0.3591   0.3622   0.2321   0.0139   1.0000 
  0      1       0.10     0.3591   0.3735   0.2225   0.0117   1.0000 
  0      1       0.11     0.3591   0.3848   0.2131   0.0096   1.0000 
  0      1       0.12     0.3591   0.3959   0.2038   0.0079   1.0000 
  0      1       0.13     0.3591   0.4069   0.1945   0.0063   1.0000 
  0      1       0.14     0.3591   0.4177   0.1855   0.0050   1.0000 
  0      1       0.15     0.3591   0.4283   0.1766   0.0039   1.0000 
  0      1       0.16     0.3591   0.4388   0.1679   0.0030   1.0000 
  0      1       0.17     0.3591   0.4490   0.1593   0.0023   1.0000 
  0      1       0.18     0.3591   0.4590   0.1510   0.0017   1.0000 
  0      1       0.19     0.3591   0.4688   0.1428   0.0012   1.0000 
  0      1       0.20     0.3591   0.4783   0.1349   0.0009   1.0000 
  0      1       0.21     0.3591   0.4875   0.1272   0.0006   1.0000 
  0      1       0.22     0.3591   0.4965   0.1197   0.0004   1.0000 
  0      1       0.23     0.3591   0.5051   0.1125   0.0003   1.0000 


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  0      1       0.24     0.3591   0.5135   0.1055   0.0002   1.0000 
  0      1       0.25     0.3591   0.5216   0.0988   0.0001   1.0000 
   
null  ntox         a       tox       fut    toxend   power    cksum 
  1      0       0.00     0.0082   0.0821   0.0233   0.8732   1.0000 
  1      0       0.01     0.0082   0.0892   0.0230   0.8626   1.0000 
  1      0       0.02     0.0082   0.0967   0.0227   0.8508   1.0000 
  1      0       0.03     0.0082   0.1047   0.0224   0.8377   1.0000 
  1      0       0.04     0.0082   0.1130   0.0221   0.8232   1.0000 
  1      0       0.05     0.0082   0.1218   0.0218   0.8072   1.0000 
   
 null  ntox        a       tox       fut    toxend   alpha    cksum 
  1      1       0.00     0.3591   0.0222   0.5301   0.0886   1.0000 
  1      1       0.01     0.3591   0.0251   0.5271   0.0887   1.0000 
  1      1       0.02     0.3591   0.0281   0.5240   0.0888   1.0000 
  1      1       0.03     0.3591   0.0315   0.5206   0.0887   1.0000 
  1      1       0.04     0.3591   0.0351   0.5170   0.0887   1.0000 
  1      1       0.05     0.3591   0.0391   0.5132   0.0885   1.0000 
  1      1       0.06     0.3591   0.0433   0.5091   0.0882   1.0000 
  1      1       0.07     0.3591   0.0478   0.5048   0.0878   1.0000 
  1      1       0.08     0.3591   0.0526   0.5003   0.0874   1.0000 
  1      1       0.09     0.3591   0.0577   0.4955   0.0867   1.0000 
  1      1       0.10     0.3591   0.0632   0.4904   0.0859   1.0000 
  1      1       0.11     0.3591   0.0690   0.4851   0.0849   1.0000 
  1      1       0.12     0.3591   0.0751   0.4795   0.0838   1.0000 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 107 
 
  1      1       0.13     0.3591   0.0815   0.4737   0.0824   1.0000 
  1      1       0.14     0.3591   0.0882   0.4676   0.0807   1.0000 
  1      1       0.15     0.3591   0.0953   0.4612   0.0789   1.0000 
  1      1       0.16     0.3591   0.1027   0.4546   0.0767   1.0000 
  1      1       0.17     0.3591   0.1105   0.4478   0.0743   1.0000 
  1      1       0.18     0.3591   0.1185   0.4407   0.0716   1.0000 
  1      1       0.19     0.3591   0.1268   0.4333   0.0686   1.0000 
  1      1       0.20     0.3591   0.1355   0.4257   0.0654   1.0000 
  1      1       0.21     0.3591   0.1445   0.4179   0.0620   1.0000 
  1      1       0.22     0.3591   0.1537   0.4098   0.0583   1.0000 
  1      1       0.23     0.3591   0.1632   0.4016   0.0545   1.0000 
  1      1       0.24     0.3591   0.1730   0.3931   0.0505   1.0000 
  1      1       0.25     0.3591   0.1830   0.3845   0.0465   1.0000 
 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 108 
 
(Source document for sample collection times/comments – PSLmaster signature sheet in CTO) 
IRB 14-052 
GU-071: Phase I/II study of ixazomib with pegylated IFN-alpha 2b (pIFN) in metastatic renal cell 
carcinoma (mRCC) 
 
Ixazomib is an orally administered proteasome inhibitor and can neutralize NF-B pro-survival signaling preventing the induction of 
antioxidant enzymes in the cell. IFN induces reactive oxygen species accumulation to toxic levels when NF-B is disabled and this 
can lead to mitochondrial dysfunction and necrotic death. IFN-2b is administered by subcutaneous injection weekly for 8 weeks. 
Ixazomib is orally administered weeks 2, 3, 4, 6, 7, 8. A cycle is 28-days. 
Phase I – dose escalation of both ixazomib and IFN-2b . 
Phase II – expansion of the recommended combination doses. 
 
PBMC – Used to examine STAT1 phosphorylation and MHC class I up-regulation (indicator of IFN activity) by flow  
      cytometry  and  pSTAT1 by western blot.  Dr. Sid Balachandran lab will perform Western. PSL will stain flow tubes and  
      take to Clin. Path.  to acquire. Dr. Kerry Campbell will provide antibodies and analyze flow.  Follow PBMC procedure. 
 
IL-6 sera levels – Clot and spin at 2000 x g 15min., aliquot and freeze at -70oC. At the end of the study Cukierman lab will  
      purchase IL-6 kit . PSL, in conjunction with Cukierman lab, will perform ELISA. 
 
Archival tissue – Look for activated tissue stroma (desmoplasia); IHC for NF-B p65 and phoso-STAT1. 
      Pathology will be reviewed By Dr. Essel Al-Saleem and she select an appropriate block to cut. 
                   If a biopsy or additional surgery is performed during treatment, unstained slides will be prepared on the 
                   “on-treatment/EOT tissue” , if patient has consented. 
 
nt name 
y # 
C 
mL)gtt 
w procedure: 
Time 
mL) rtt 
mL) aliquots 
Time 
val tissue 
m) unstained sections on 
lides 
ogy report 
tional tissue 
____ No ____ 
1 Day 1 Pre 0hr 
       CRU 
s 1, 2, 3, 4 
   Day 8 Pre 0hr 
2 
   Day 15 Pre 0hr 
3 
2 Day 1 Pre 0hr 
s 5, 6, 7, 8 
   Day 15 Pre 0hr 
7 
3 Day 1 Pre 0hr 
s 9, 10, 11, 12 
4 Day 1 Pre 0hr 
s 13, 14, 15, 16 
6 Day 1 Pre 0hr 
s 25, 26, 27, 28 
8 Day 1 Pre 0hr 
s 33, 34, 35, 36 
10 Day 1 Pre 0hr 
s 41, 42, 43, 44 
12 Day 1 Pre 0hr 
s 49, 50, 51, 52 
14 Day 1 Pre 0hr 
s 56, 57, 58, 59 
16 Day 1 Pre 0hr 
s 64, 65, 66, 67 
of Study 
atment/EOT Optional 
  
 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 109 
 
IRB 14-052 
GU-071: Phase I/II study of ixazomib with pegylated IFN-alpha 2b (pIFN) in metastatic renal cell 
carcinoma (mRCC) 
 
Patient name __________________________    Study # ________________ 
Mr# ______________________   Date _________________ 
Cycle 1 Day 1(week 1) Baseline ___   Cycle 1 Day 8(week 2) ___  Cycle 1 Day 15(week 3) ___  Cycle 2 Day 15(week 7) ___ 
_____ # gtt        _______ mL blood 
      PBMC Procedure: 
1. 
Dilute blood 1:1 with PBS (1-50mL conical) and layer over 15mL Ficoll-Paque (1-50mL conical). 
2. 
Centrifuge 500 x g (1500rpm) 30min room temperature - Brake off. 
3. 
Collect PBMC into clean 50mL conical, fill with PBS and spin 2000rpm 5min. 
4. 
Remove and discard supernatant; lyse rbcs with equal amounts (5-10mL) 0.2% NaCl followed by 1.6% NaCl. 
5. 
Remove a portion of cells to count, determine viability with Trypan blue exclusion, then spin at 2000rpm 5min. 
6. 
Remove supernatant and discard, resuspend pellet in PBS to2 x 106 cells/mL. 
7. 
Place 0.5mL of the 2 x 106 cells/mL suspension into each of three labeled flow tubes – pSTAT1, MHC class I and 
isotype control. 
8. 
Respin remaining suspended cells, remove supernatant , resupend pellet in 500L PBS and transfer to 2mL 
microfuge tube, rinse original tube with 500L PBS and add to microfuge tube. 
9. 
Spin microfuge tube at 2000rpm in microfuge, pour-off and blot tube dry on paper towel, then freeze pellet on dry ice 
and place at -70oC for storage. 
 
 
Count cells #/25 squares   _______ 
 
Volume ______ 
 
Total cells _______  (2 x 10,000 x #cells/25 squares x volume = total cells)/2 x 106 =   _____ mL to resuspend cells 
 
        # cells/flow tube _______   # tubes ______ 
 
       # cells in frozen pellet _______  (minimum 3 x 106 cells in pellet) 
 
 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 110 
 
 
 
 
 
 
** TREATING NURSE SOURCE DOCUMENT ONLY 
 
Protocol #: IRB__14-052____ 
 
Subject ID and Study #__________ 
 
Patient name_________________________     Mr#_________________ 
 
 
 
 
 
 
 
 
 
POINTS OF BLOOD DRAWS RIFICATION OF TIMEPOINTS C 
mL)gtt 
w procedure: 
Time 
mL) rtt 
L) aliquots 
Time 
SES INITIALS 
1 Day 1 Pre 0hr 
s 1, 2, 3, 4 
   Day 8 Pre 0hr 
2 
   Day 15 Pre 0hr 
3 
2 Day 1 Pre 0hr 
s 5, 6, 7, 8 
   Day 15 Pre 0hr 
7 
3 Day 1 Pre 0hr 
s 9, 10, 11, 12 
4 Day 1 Pre 0hr 
s 13, 14, 15, 16 
8 Day 1 Pre 0hr 
s 17, 18, 19, 20 
10 Day 1 Pre 0hr 
s 25, 26, 27, 28 
12 Day 1 Pre 0hr 
s 33, 34, 35, 36 
14 Day 1 Pre 0hr 
s 41, 42, 43, 44 
16 Day 1 Pre 0hr 
s 49, 50, 51, 52 
of Study 
 
Initials _____ Signature _______________________ Initials _____ Signature _______________________ 
 
Initials _____ Signature _______________________ Initials _____ Signature _______________________ 
Form Adopted 11-03 
 
 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
 111 
 
 
To:___________________________________________ 
 
Fax number:____________________________________ 
 
From: Fox Chase Cancer Center Protocol Department 
           Daniel Geynisman MD/Lois Malizzia RN 
 
Date:____________ 
 
RE: REQUEST OF PATHOLOGY BLOCK/SLIDES (IRB 14-052) 
 
       Patient name:________________________________         Date:___________ 
       (Patient consent obtained and attached.) 
 
To Whom It May Concern: 
 
The above patient has pathology material at your institution.  This patient is interested in a clinical trial at 
Fox Chase Cancer Center.  To meet the protocol requirements the patient is requested to submit an H&E 
recut and 10(4m) unstained sections cut from a block representative of tumor and placed on charged 
immunohistochemistry slides. The slides should be labeled with the institutional surgical pathology number.  
A copy of the institutional pathology report and consultative pathology reports (if available) must 
accompany the submitted material.   
Please Fed Ex these materials to the following address as soon as possible.  A Fed Ex account number 
can be obtained, if required, by contacting Kathy Alpaugh at the number below. 
 
 
Kathy Alpaugh, PhD 
 
Director Protocol Support Laboratory 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue Ave. P2011 
 
Philadelphia, PA 19111 
 
 
Telephone: (215) 214-1634      Fax: (215) 214-1635   
           e-mail: RK_Alpaugh@fccc.edu 
 
If there are any questions concerning this request, please call Lois Malizzia at (215) 728-5311. 
____________________________________________________________________________________ 
PATIENT (or legal representative) CONSENT FOR RELEASE OF PATHOLOGY MATERIAL: 
 
I ___________________________________give consent to have pathology block(s) or  
                (Patient name or Legal Representative) 
slides, accompanied by any written reports, to be released to the Fox Chase Cancer Center to be 
used for evaluation related to the above indicated clinical trial(s). I understand that in sending this 
tissue it may exhaust the supply of diagnostic tissue available and preclude any chance for 
possible further testing. I release the sending institution from any responsibility or liability for 
future care that may depend on this tissue. 
 
Patient signature or legal representative_______________________________________ 
 
Date ___________        Witness ______________________ 


GU-071 
 
Copyright ©2015. Fox Chase Cancer Center® All rights reserved. Amendment 3  Protocol version date: 01/05/2017 
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