Clinical trial NCT01833143
Conditions: Non-Small Cell Lung Cancer
Keywords: KRAS-Mutant Bortezomib KRAS G12D 12-222
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2013-04-11; Completion date: 2019-08-28
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the drug Bortezomib to see how well it works. The investigators want to find out what effects, good or bad, it has on patients with a limited smoking history or who have a specific mutation associated with their lung cancer.

Detailed description:

Arms: arm 1: Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay \> 2 weeks, or at the discretion of the treating physician or patient.
Interventions: intervention 1: Bortezomib intervention 2: Acyclovir
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase 2 Trial of Bortezomib in KRAS-Mutant 
Non-Small Cell Lung Cancer in Never Smokers or Those with KRAS G12D 
 
PROTOCOL FACE PAGE FOR 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Gregory Riely, MD, PhD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Paul Paik, MD 
Medicine 


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Investigator(s)/Department: 
Charles Rudin, MD 
Mark G. Kris, MD 
Naiyer Rizvi, MD 
Lee M. Krug, MD 
Maria C. Pietanza, MD 
Jamie Chaft, MD 
Marjorie Zauderer, MD 
Alexander Drilon MD 
Stephen Veach, MD 
Helena Yu, MD 
 
Leslie Tyson, RN, NP 
Anne Haughney Siller, RN 
Grace Monger, RN, NP 
Melanie Albano, NP 
Dorothy Dulko, NP 
Clare M. Moran, NP 
 
Ephraim Casper, MD 
  
 
Arlyn Apollo, MD 
Pamela Drullinsky,  MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Han Xiao, MD 
Tina Passalaris, MD 
 
Camelia Sima. MD 
Joanne Chou, MPH 
Michelle Ginsberg, MD 
Medicine 
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Medicine: All Regional 
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Medicine: Basking Ridge 
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Biostatistics 
Biostatistics 
Radiology 


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Consenting 
Professional(s)/Department: 
Charles Rudin, MD 
Gregory Riely, MD 
Paul Paik, MD, PhD 
Mark G. Kris, MD 
Naiyer Rizvi, MD 
Lee M. Krug, MD 
Maria C. Pietanza, MD 
Jamie Chaft, MD 
Marjorie Zauderer, MD 
Stephen Veach, MD 
Alexander Drilon, MD 
Helena Yu, MD 
 
Ephraim Casper, MD 
 
 
 
Arlyn Apollo, MD 
Pamela Drullinsky,  MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Han Xiao, MD 
Tina Passalaris, MD 
Shilen N. Patel, MD 
Medicine 
Medicine 
Medicine 
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Medicine: All Regional 
Network Sites 
 
Medicine: Rockville Centre 
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Medicine: Basking Ridge 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 6 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 7 
 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 7 
 
3.1 Proteasome Inhibition in KRAS-Mutant Lung Cancer .............................................................. 7 
 
3.2 Bortezomib: Mechanism of Action ........................................................................................... 9 
 
3.3 Bortezomib: Clinical Experience.............................................................................................. 9 
 
3.3.1 Intravenous Administration .............................................................................................. 10 
 
3.3.2. Subcutaneous Administration ......................................................................................... 10 
 
3.3.3 Potential Risks with Bortezomib....................................................................................... 11 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................................. 11 
 
4.1 
Design............................................................................................................................... 11 
 
4.2 
Intervention ....................................................................................................................... 12 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 12 
 
5.1. Preparation, Handling, Storage, and Destruction .................................................................. 12 
 
5.2. Dispensing and Administration.............................................................................................. 13 
 
5.3. Precautions for Subcutaneous Administration ....................................................................... 13 
 
5.4. Binding, Packaging, Labeling ................................................................................................ 14 
 
5.5. Product Complaints............................................................................................................... 14 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 14 
 
6.1 
Subject Inclusion Criteria................................................................................................... 14 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 15 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 16 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 16 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 17 
 
9.1 Schedule and Dose Administration ........................................................................................ 17 
 
9.2 Toxicity-Based Dose and Schedule Modifications .................................................................. 17 
 
9.2.1. General Algorithm .......................................................................................................... 17 
 
9.2.2.  Neurologic Toxicities ..................................................................................................... 18 
 
9.2.3.  Hepatic Impairment ....................................................................................................... 19 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................. 19 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 21 
 
11.1. Anticipated Toxicities .......................................................................................................... 21 


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11.2. Adverse and Serious Adverse Event Definitions ................................................................. 22 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 23 
 
12.1. Objective Response ............................................................................................................ 23 
 
12.2. “Best” Response ................................................................................................................. 23 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 23 
 
14.0 BIOSTATISTICS .................................................................................................................. 24 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES... 25 
 
15.1 Research Participant Registration ..................................................................................... 25 
 
15.2 Randomization .................................................................................................................. 25 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 25 
 
16.1 Quality Assurance ............................................................................................................. 25 
 
16.1.2. Protocol Compliance .................................................................................................... 26 
 
16.2 Data and Safety Monitoring ............................................................................................... 26 
 
16.3. On-Site Audits..................................................................................................................... 26 
 
16.4. Premature Closure of Study ................................................................................................ 27 
 
16.5. Record Retention ................................................................................................................ 27 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 27 
 
17.1 Privacy .............................................................................................................................. 27 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 28 
 
17.2.1. Adverse Event Reporting to Millenium Pharmacovigilance ........................................... 28 
 
17.2.2. Reporting Drug Exposure: Pregnancy and Birth Events ................................................... 30 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 30 
 
19.0 REFERENCES ..................................................................................................................... 31 
 
20.0 APPENDICES ...................................................................................................................... 35 
 
APPENDIX A: Anticipated Side-Effects of Bortezomib ................................................................. 35 
 
APPENDIX B: Common Terminology Criteria for Adverse Events ............................................... 40 
 
APPENDIX C: Karnofsky Performance Status Scale ................................................................... 41 
 
APPENDIX D: Body Surface Area and Creatinine Clearance Calculations .................................. 42 
 
APPENDIX E: New York Heart Association Classification of Cardiac Disease............................. 43 
 
APPENDIX F: Pregnancy and Effective Methods of Contraception............................................. 44 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title:  A Phase 2 Trial of Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never 
Smokers or Those with KRAS G12D 
 
Objectives 
 
The primary objective of this study is: 
 
to determine the efficacy of single-agent subcutaneous bortezomib in patients with 
advanced (stage IIIB/IV) KRAS-mutant non-small cell lung cancer (NSCLC) in never- 
smokers (<100 lifetime cigarettes) or patients with a G12D mutation. The primary 
endpoint will be best objectiveresponse rate (CR+PR) at any time prior to progression by 
RECIST v1.1. 
 
The secondary objectives of this study are to evaluate: 
 
1.  progression-free survival 
2.  overall survival 
3.  8-week stable disease 
4.  toxicity (NCI-CTCAE v4.0) 
 
Patient Population: patients with advanced (stage IIIB/IV) KRAS-mutant non-small cell lung 
cancer (NSCLC) who either are never-smokers (<100 lifetime cigarettes) or have a G12D 
mutation 
 
Number of Patients:  25 patients evaluable for response. 
 
Study Design and Methodology:  This will be a single-institution, open label, two-stage, 
single agent trial of subcutaneous bortezomib in patients with advanced (stage IIIB/IV) 
KRAS-mutant NSCLC with a never-smoking history or a G12D mutation. 
 
Treatments Administered:  Bortezomib (1.3 mg/m2/dose) will be administered by 
subcutaneous injection on days 1, 4, 8, and 11 of a 21-day cycle.  Cycles will be repeated 
until disease progression or unacceptable toxicity. 
 
Efficacy Data Collected: The following evaluations will be conducted to assess the efficacy 
of bortezomib - radiographic response rate by RECIST v1.1, progression-free survival, and 
overall survival. 
 
Safety Data Collected: The following evaluations will be conducted to assess the safety of 
bortezomib - toxicity assessments by NCI-CTCAE v4.0. 
 
Statistical Design: Stage II minimax design testing the null hypothesis of 10% objective 
response rate (ORR) against alternative of 30% ORR. In the first stage, 16 evaluable 
patients will be accrued- if 2/16 have a response, 9 additional patients will be accrued in the 
second stage. Bortezomib will be considered worthy of further study if 5/25 patients respond. 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
The primary objective of this study is: 
 
To determine the efficacy of single-agent subcutaneous bortezomib in patients with advanced 
(stage IIIB/IV) KRAS-mutant non-small cell lung cancer (NSCLC) who either are never-
smokers (<100 lifetime cigarettes) or have a G12D mutation. The primary endpoint will be 
best objective response rate (ORR,= PR+CR) at any time prior to progressionby RECIST 
v1.1. 
 
HYPOTHESIS: The use of subcutaneous bortezomib in patients with advanced (stage 
IIIB/IV) KRAS-mutant non-small cell lung cancer (NSCLC) who either are never-smokers 
(<100 lifetime cigarettes) or have a G12D mutation will result in improved efficacy in this 
patient population, as determined by overall response rates. 
 
The secondary objectives of this study are to evaluate: 
 
1.  progression-free survival 
2.  overall survival 
3.  8-week stable disease 
4.  toxicity (NCI-CTCAE v4.0). 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Proteasome Inhibition in KRAS-Mutant Lung Cancer 
Lung Cancer and KRAS Mutations:  Lung cancer is the most common cause of cancer death in the 
U.S. and worldwide. Approximately 215,020 new lung cancer cases are diagnosed in the U.S. each 
year,1 and approximately 1.44 million new lung cancer cases are diagnosed worldwide. 2 Of patients 
who are diagnosed with lung cancer, more than 80% eventually succumb to the disease. 
Histologically, the vast majority of patients with lung cancer have non-small cell lung cancer 
(NSCLC). Platinum doublet chemotherapy is the standard first-line treatment for NSCLC, and single 
agent chemotherapy or erlotinib provides clinical benefit in second-line patients.3   The overall 
survival for patients with lung adenocarcinomas who receive standard first line therapy is 
approximately 12 months with an overall survival of 2% and 13% at 5 years for clinically-staged and 
pathologically-staged disease, respectively.  Thus, despite the advances in the treatment of NSCLC 
over the past decade, there remains a high unmet medical need for new treatments for lung cancer. 
 
Point mutations in KRAS are the most common oncogene driver mutations in NSCLC, and occur in 
approximately 25% of adenocarcinomas of the lung.  In the United States alone, this molecularly 
selected cohort accounts for an approximate incidence of 22,000 patients a year.  KRAS mutations 
have been shown to confer resistance to epidermal growth factor receptor (EGFR)-targeted 
therapies in colorectal cancer4 and emerging data suggest that lung cancer patients with mutations 
of the KRAS oncogene are similarly resistant to the EGFR-tyrosine kinase inhibitors (TKIs), erlotinib 
and gefitinib.5   Some data also suggest that NSCLC patients with KRAS mutations may not respond 
to adjuvant platinum-based chemotherapy,6 although subsequent analyses have shown conflicting 
results.  Finally, some studies have shown that the presence of KRAS mutations represents a 
negative prognostic factor for patients with NSCLC.7 Taken together, there is a need for new 
medical treatments for patients with KRAS-mutant NSCLC. 


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Never-smokers and KRAS G12D:  Although KRAS mutations were classically thought to occur in 
smokers, an evaluation of nearly 500 patients from Memorial Sloan Kettering noted a 15% incidence 
of KRAS mutations in lung adenocarcinomas from never-smokers.8   Furthermore, KRAS transition 
mutations were noted more commonly in never-smokers, compared to transversions that occurred 
more frequently in former or current smokers. In this cohort, G12D was the most common KRAS 
mutation in never-smokers and the second most common mutation overall.  Never-smokers on the 
whole, are thought to have tumors that are genetically less complex than tumors in smokers9, 
making the use of targeted therapy in the former more attractive. 
 
KRAS Mutants Rely on NF-kB: NF-kB forms a 
family of transcription factors that participates in 
a number of essential biological processes such 
as inflammation, the immune response, 
development, cell growth, and survival.10 
Preclinical evidence suggests that patients with 
KRAS mutations are highly dependent on the 
NF-kB pathway.  Barbie et al11 employed a 
systematic RNA interference (RNAi) screen to 
detect synthetic lethal partners of oncogenic 
KRAS.  Knockdown of the non-canonical IkB 
kinase, TKB1, resulted in apoptosis in KRAS 
mutant human cell lines. TKB1 was found to 
activate NF-kB signaling and subsequent pro- 
survival signals such as BCL-XL and cREL. In a 
separate paper, Meylan et al demonstrated that 
the introduction of a nonphosphorylatable NF-kB 
super repressor, IkB, in KRAS G12D-mutant 
murine tumors resulted in loss of cell viability 
secondary to apoptosis.12 
 
Proteasome Inhibition Downregulates NF-kB and Induces KRAS-Mutant Tumor Regression: The 
fact that KRAS mutant tumors are dependent on NF-kB signaling provides a strong rationale for the 
use of targeted therapy with proteasome inhibitors. These drugs have been shown to result in 
downregulation of the NF-kB pathway via prevention of the degradation of NF-kB inhibitory proteins 
such as IkB.13   In a separate genome-wide RNAi screen, Luo et al demonstrated a diverse set of 
proteins with synthetic lethal interactions with oncogenic KRAS.  Among these, knockdown of 
proteasome subunits such as PSMA5, PSMB5, and PSMB6 was shown to result in accumulation of 
KRAS mutant cells in prometaphase and subsequent death.  Furthermore, two structurally distinct 
small molecule inhibitors of the proteasome, bortezomib and MG132 exhibited synthetic lethality in 
RAS mutant cells in the study, again secondary to a profound prometaphase block.14   In KRASLSL- 
G12D/wt;p53flox/flox mice (G12D-mutant), bortezomib induced in-vivo tumor regression of lung 
adenocarcinoma. Taken together, these observations provide a strong biologic rationale for the use 
of proteasome inhibition with bortezomib in the treatment of KRAS-mutant NSCLC. 
 
Our clinical experience at MSKCC supports the hypothesis that proteasome inhibition results in 
synthetic lethality in KRAS-mutant lung cancers. We have seen impressive reductions in tumor 
volume (near complete responses) with bortezomib in two patients at our center, one in each of two 


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subjected their tumors to mutational analysis.  Genotyping revealed that both samples harbored a 
KRAS G12D mutation 
 
At MSKCC, an average of 2-3 patients with G12D-mutant advanced adenocarcinoma alone are 
seen per month based on LC-MAP data. In addition, 64 patients with G12D mutations have already 
been identified at MSKCC as of 2011. The target accrual for this protocol is 25 patients. Based on 
our KRAS G12D volume alone (not taking into account our never-smoker KRAS-mutant population 
which represents 15% of all KRAS mutations), we expect to fully accrue within 12-18 months of 
study initiation. 
 
3.2  Bortezomib: Mechanism of Action 
 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  Bortezomib is 
currently approved by the United States Food and Drug Administration (US FDA) for the treatment of 
patients with multiple myeloma (MM).  It is also indicated for the treatment of patients with mantle 
cell lymphoma (MCL) who have received at least 1 prior therapy. 
 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways.  The antineoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of 
expression of genes that control cellular adhesion, migration, and angiogenesis. Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the 
extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. 
Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo 
assays.15   In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both 
as a single agent and in combination with chemotherapy and radiation.16,17, 18,19,20, 21,22, 23,24, 25,26, 27, 28 
Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers 
unregulated growth and resistance to conventional chemotherapeutics.29 
 
The mechanisms of action leading up to apoptosis have been more clearly defined and include 
initiation of the unfolded protein response and direct/indirect effects on various molecular targets 
including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, transcription 
factors c-jun and HIF1-α, tumor suppressor protein p53, angiogenesis factors, and many others. 
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor κB 
(NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic 
effect, and possibly anti-angiogenic and other effects.30,31, 32,33, 34,35, 36, 37 
 
3.3  Bortezomib: Clinical Experience 
 
 
It is estimated that as of June 2011, more than 300,000 patients have been treated with bortezomib, 
including patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, 
the US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available drug. 
Bortezomib has been commercially available since 13 May 2003.  For further details regarding the 
drug, please refer to the Investigator’s Brochure. 


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3.3.1 Intravenous Administration 
 
In a phase 1 trial in patients with refractory hematologic malignancies, the MTD for a twice weekly 
dosing for 4 weeks of a 42-day cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, 
hyponatremia, hypokalemia, fatigue, and malaise.38   The toxicity was greatest during the third and 
fourth weeks of therapy.  In the 3-week schedule of bortezomib monotherapy (4 doses, given on 
Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects 
with Grade 3 diarrhea and 1 with peripheral sensory neuropathy). Therefore, the MTD at this 
schedule was 1.3 mg/m2/dose.  Antitumor activity was reported in subjects with Non-Hodgkin’s 
Lymphoma (NHL), MM, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate 
cancer.
39,40, 41, 42 
 
The safety and efficacy of bortezomib in subjects with MM were investigated in two phase 2 clinical 
studies, studies M34100-024 (subjects with first relapse)43 and M34100-025 (subjects with second or 
greater relapse and refractory to their last prior therapy).44   In M34100-025, 202 heavily pretreated 
subjects with refractory MM after at least 2 previous treatments received bortezomib, 1.3 mg/m2 on 
Days 1, 4, 8, and 11 of a 21-day treatment cycle.  Complete responses (CRs) were observed in 4% 
of subjects, with an additional 6% of patients meeting all criteria for CR but having a positive 
immunofixation test.  Partial response (PR) or better was observed in 27% of subjects, and the 
overall response rate (CR, PR, and minor response [MR] combined) was 35%.  Seventy percent of 
subjects experienced stable disease or better. 
 
The phase 3 study (M34101-039)45, also referred to as the APEX study, was designed to determine 
whether bortezomib provided benefit (time to progression [TTP], response rate, and survival) to 
patients with relapsed or refractory MM relative to treatment with high-dose dexamethasone. The 
study was also designed to determine the safety and tolerability of bortezomib relative to high-dose 
dexamethasone, and whether treatment with bortezomib was associated with superior clinical 
benefit and quality of life relative to high-dose dexamethasone.  A total of 669 patients were enrolled 
and 663 patients received study drug (bortezomib:  331; dexamethasone: 332).  Bortezomib 
resulted in an increase in response rates, TTP, and OS. Updated response rates and survival data 
were reported for M34101-039.46   The phase 3 study (MMY 3002) known as the VISTA study, 
evaluated the safety and efficacy of the combination of bortezomib, melphalan, and prednisone in 
previously untreated multiple myeloma patients who were not candidates for stem cell transplant.47 
The study was designed to determine the benefit of adding bortezomib to melphalan and prednisone 
as assessed by TTP. The addition of bortezomib resulted in improvements in response rate, TTP, 
time to next therapy, treatment-free interval, and OS with a higher incidence of peripheral sensory 
neuropathy and GI symptoms in the VMP group despite similar hematologic toxicities. 
 
3.3.2. Subcutaneous Administration 
 
After a randomized Phase 1 trial demonstrated similar drug exposure, proteasome inhibition, and 
efficacy and safety profiles between VELCADE IV and SC, a Phase 3 study compared the efficacy 
and safety of subcutaneous versus intravenous bortezomib at the approved 1.3 mg/m2 dose and 
twice per week schedule in patients with relapsed multiple myeloma.33   Subcutaneous bortezomib 
was shown to offfer non-inferior efficacy to standard intravenous administration, with an improved 
safety profile. 


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222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) 
bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous 
group and 73 in the intravenous group. Patients received a median of eight cycles in both groups. 
ORR after four cycles was 42% in both groups showing non-inferiority (p=0·002). After a median 
follow-up of 11.8 months in the subcutaneous group and 12.0 months in the intravenous group, 
there were no significant differences in time to progression and 1-year overall survival. 
 
Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group 
versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 
14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral 
neuropathy of any grade (56 [38%] vs 39 [53%]; p=0.044), grade 2 or worse (35 [24%] vs 30 [41%]; 
p=0.012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0.026) was significantly less common 
with subcutaneous than with intravenous administration. Subcutaneous administration was locally 
well tolerated. In conclusion, the SC administration of VELCADE has good local tolerance. The 
systemic safety profile for the SC administration of VELCADE was associated with a lower incidence 
of Grade ≥3 adverse events, and treatment modifications (discontinuations and dose reductions). In 
particular, there was a lower incidence of peripheral neuropathy reported. Additional information 
regarding bortezomib is available in the current Investigator’s Brochure. 
 
3.3.3 Potential Risks with Bortezomib 
 
To date, more than 300,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib.  The known anticipated risks of bortezomib therapy 
are presented in  Appendix A.  These risks are grouped according to the combined frequency 
observed in an integrated analysis of AEs in sponsored clinical studies of single-agent bortezomib 
dosed at 1.3 mg/m2 twice weekly on a 21-day schedule, in patients with multiple myeloma and 
mantle cell lymphoma. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a single-institution, open label, one-arm Simon minimax two-stage phase II clinical 
trial of subcutaneous bortezomib in patients with advanced (stage IIIB/IV) KRAS-mutant non- 
small cell lung cancer (NSCLC) who either are never-smokers (<100 lifetime cigarettes) or 
have a G12D mutation. 
 
A maximum of 25 patients will be enrolled in this trial in a two-stage design. Stage 1 involves 
a preliminary determination of efficacy of the drug in a total of 16 patients.  If zero to one 
responses are observed , the drug would be considered unworthy of study with consequent 
trial termination. 
 
However, if 2 or more responses are observed in this cohort by RECIST v1.1 criteria, the trial 
would then proceed to an expanded cohort in Stage 2.  Stage 2 involves accrual of an 
additional 9 patients.  Bortezomib would be considered worthy of further study in this 
population if 5 or more patients out of the total 25 enrolled have an objective response. 


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4.2 
Intervention 
 
Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 
4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle.  Dose 
modifications are permitted as per a prescribed algorithm.  Acyclovir at 400mg daily is 
recommended as prophylaxis for herpes zoster. 
 
Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of 
treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable 
toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. Preparation, Handling, Storage, and Destruction 
 
Bortezomib (VELCADE) is available in sterile, single use vials containing 3.5 mg of 
VELCADE with a 1:10 ratio of bortezomib to mannitol. 
 
SUBCUTANEOUS: Each vial of VELCADE for Injection should be reconstituted under 
a laminar flow biological cabinet (hood) within eight hours before dosing with 1.4 mL 
of normal (0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted 
solution contains VELCADE at a concentration of 2.5 mg/mL for subcutaneous 
administration. For injection site reactions, a more dilute concentration of 1 mg/mL 
can be used. 
 
Vials containing lyophilized VELCADE® (bortezomib) for Injection should be stored 
according to the label requirements.  For the United States, store at USP Controlled 
Room Temperature which is 25ºC (77ºF); for Europe, do not store above 30ºC (86ºF); 
excursions permitted from 15 to 30ºC (59-86ºF). To date, stability data indicate that 
the lyophilized drug product is stable for at least 18 months when stored under the 
recommended conditions.  Stability studies are ongoing, and Millennium 
Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study. 
 
INTRAVENOUS (used ONLY in the event of intolerable subcutaneous toxicity e.g. 
injection site reactions, see Section 5.3): Prior to IV administration, the contents of 
each vial must be reconstituted with 3.5 mL of normal (0.9%) saline (sodium chloride 
injection). The reconstituted product should be a clear and colorless solution. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. If any 
discoloration or particulate matter is observed, the reconstituted product should not 
be used. 
 
Bortezomib contains no antimicrobial preservative. When reconstituted as directed, 
bortezomib may be stored at 25ºC (77ºF). Reconstituted VELCADE should be 
administered within 8 hours of preparation. The reconstituted material may be stored 
in the original vial and/or the syringe prior to administration. The product may be 
stored for up to 8 hours in a syringe; however, total storage time for the reconstituted 
material must not exceed 8 hours when exposed to normal indoor lighting. 


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Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling bortezomib solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations. The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area 
immediately and thoroughly with soap and water for at least 15 minutes. If product contacts 
eye, immediately flush eye thoroughly with water for at least 15 minutes. Always contact a 
physician after any form of body contact.  All materials that have been used for preparation 
should be disposed of according to standard practices.  A log must be kept of all disposed 
materials. 
 
Prior to reconstitution the vials should remain in the cartons to protect them from light. 
Dissolution is completed in approximately 10 seconds. The reconstituted solution is clear 
and colorless, with a final pH of 5 to 6.  Reconstituted bortezomib should be administered 
promptly and in no case more than 8 hours after reconstitution. 
 
5.2. Dispensing and Administration 
 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified subinvestigator(s).  Patients may be treated on an outpatient basis, if possible.The 
drug will be prepared under the supervision of a pharmacist, or appropriately qualified and 
trained personnel. The amount (in mg) of drug to be administered will be determined based 
on body surface area.  Body surface area is to be calculated based on body weight using a 
standard nomogram or calculation (Appendix D). The dose should be calculated prior to 
Cycle 1 Day 1 based on weight measured at screening. Dose should be recalculated at the 
start of a cycle only if a significant change in weight has occurred (>10%). If a patient 
experiences a notable change in weight within a cycle, as determined by an unscheduled 
weight assessment, then the patient’s dose should be recalculated at that time based on 
clinical judgment.  There must be at least 72 hours between each dose of bortezomib. 
 
IMPORTANT NOTE: Intravenous and subcutaneous route of administration have different 
reconstituted concentrations.  Caution should be used when calculating the volume to be 
administered. For administration: 
 
SUBCUTANEOUS: Administer subcutaneously – for subsequent doses, administer at 
least 1 inch from an old site and never administer to tender, bruised, erythematous, or 
indurated sites. If injection site reaction occurs, the more dilute 1 mg/mL 
concentration may be used subcutaneously (Section 5.1). 
 
INTRAVENOUS (used ONLY in the event of intolerable subcutaneous toxicity e.g. 
injection site reactions, see Section 5.3): Administer the appropriate dose via rapid 
I.V. push (approximately 3-5 seconds). 
 
5.3. Precautions for Subcutaneous Administration 
 
• The drug quantity contained in one vial (3.5 mg) may exceed the usual dose 
required.  Caution should be used in calculating the dose to prevent overdose. 
 
• When administered subcutaneously, sites for each injection (thigh or abdomen) should 
be rotated. If local injection site reactions occur following VELCADE administration 


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subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) 
may be administered subcutaneously.  Alternatively, the IV route of administration can be 
considered at the investigator’s discretion. In clinical trials of VELCADE IV, local skin 
irritation was reported in 5% of patients, but extravasation of VELCADE was not 
associated with tissue damage. In a clinical trial of subcutaneous VELCADE, a local 
reaction was reported in 6% of patients as an adverse event, mostly redness. Should IV 
bortezomib be used, the dosing and monitoring schedule for patients is identical to that of 
SQ administration (Section 9.1 and Section 9.2.1 for dose reductions) 
 
5.4. Binding, Packaging, Labeling 
 
Bortezomib will be supplied in vials as open-label stock.  Both the box label and vial label will 
fulfill all requirements specified by governing regulations. 
 
5.5. Drug Destruction 
For commercially-labeled VELCADE for IND-exempt studies, please contact your Millennium 
Clinical Operations representative to arrange for return of study drug procedures. Any 
unused or expired VELCADE must be returned to Millennium. Be sure to document drug 
return on your drug accountability logs. 
 
5.6. Product Complaints 
 
A product complaint is a verbal, written, or electronic expression which 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 the following) 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, call MedComm 
Solutions at: +1-866-835-2233 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
1.  Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC) 
 
2.  Documented KRAS mutation 
 
3.  History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D 
 
mutation regardless of smoking history 
 
4.  Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC 
 
5.  Age ≥ 18 years 
 
6.  Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation 
therapy and recovered from treatment 
7.  Karnofsky performance status ≥ 70% 
 
8.  Adequate hematologic and/or hepatic function 


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a.  WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul 
b.  Hemoglobin ≥ 9.0 g/dl 
c.   Platelet count ≥ 100,000/ul 
 
d.  AST ≤ 2.0 X ULN (upper limit of normal) 
 
e.  Total bilirubin ≤1.5 x ULN 
 
9.  Measurable indicator lesions by RECIST v1.1 criteria. 
 
10. Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent may 
be withdrawn by the subject at any time without prejudice to future medical care. 
11. Female subject is either postmenopausal for at least 1 year before the screening visit, 
is surgically sterilized or if they are of childbearing potential, agree to practice 2 
effective methods of contraception from the time of signing the informed consent form 
through 30 days after the last dose of bortezomib, or agree to completely abstain 
from heterosexual intercourse. 
 
12. Male subjects must agree to 1 of the following:  practice effective barrier 
contraception during the entire study treatment period and through a minimum of 30 
days after the last dose of study drug, or completely abstain from heterosexual 
intercourse. 
 
 
6.2 
Subject Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
1.  Uncontrolled central nervous system metastases defined as any lesion which is either 
a.  symptomatic, or 
b.  requiring escalating doses of corticosteroids 
 
2.  Significant medical history or unstable medical condition such as 
a.  uncontrolled diabetes 
b.  myocardial infarction within 6 months prior to enrollment 
 
c.   New York Heart Association Class III or IV heart failure (Appendix E) 
 
d.  severe uncontrolled ventricular arrythmias 
e.  uncontrolled angina 
f. ECG evidence of acute ischemia or active conduction system abnormalities 
 
3.  Baseline ≥ grade 2 peripheral neuropathy by CTCAE v 4.0 (Appendix B) 
 
4.  Known hypersensitivity to boron or mannitol 
 
5.  Female patients who are pregnant/lactating or have a positive serum or urine β-hCG 
 
pregnancy test 


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6.  Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
7.  No active concurrent malignancy, with the exception of 
a.  in-situ malignancy 
b.  completely resected basal cell carcinoma or squamous cell carcinomas of the 
skin 
c.   low-risk prostate cancer after curative therapy 
 
8.  Participation in clinical trials with other investigational agents not included in this trial, 
within 14 days of the start of this trial and throughout the duration of this trial 
 
7.0 
RECRUITMENT PLAN 
 
Eligible patients with KRAS-mutant advanced NSCLC will be recruited from the Thoracic 
Oncology Service at MSKCC.  Testing for KRAS mutations is performed routinely for all 
adenocarcinomas of the lung.  Every attempt will be made to recruit women and minorities in 
this study.  Participation is voluntary.  The consenting physician will inform patients of their 
diagnosis and current treatment options including standard treatment, and the risks, benefits 
and experimental nature of this treatment program. There are no gender or racial 
restrictions.  Patients under the age of 18 are excluded because this disease rarely affects 
patients in this age group. 
 
8.0 
PRETREATMENT EVALUATION 
 
Patients will undergo baseline screening after informed consent is obtained. This includes 
the following, to be completed within 14 days of starting treatment, except for imaging which 
can be completed within 30 days of treatment initiation, unless otherwise stated: 
 
(1) medical history 
(2) baseline evaluation of symptoms and detailed medication list 
(3) physical examination 
(4) evaluation for weight loss and performance status (Appendix C) 
(5) height (anytime prior to treatment), weight, and vital signs 
(6) blood work 
(a) complete blood count 
(b) comprehensive metabolic panel 
(7) pregnancy test (for women of child-bearing potential, pregnancy testing is not 
required for postmenopausal or surgically-sterilized women) 
(8) baseline electrocardiogram 
(9) baseline imaging (within 30 days of treatment initiation) 
(a) computed tomography and/or MRI of the chest, abdomen, and pelvis 
(b) MRI of the brain only if judged by investigator to be indicated 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Schedule and Dose Administration 
 
 
Bortezomib is to be administered subcutaneously in 21-day cycles at a dose of 1.3 
mg/m2/dose on days 1, 4, 8, and 11. Treatment will only be initiated once eligibility criteria 
have been met and the appropriate pretreatment evaluations performed. 
 
 
Antiviral prophylaxis with 400 mg of acyclovir daily is recommended for all patients as herpes 
zoster can occur commonly in patients who receive bortezomib without prophylaxis.  For 
sexually-active patients, it is recommended that either 1 highly effective method of 
contraception or 2 effective methods of contraception be used as detailed in  Appendix F. 
Bortezomib will be continued until: 
(1) disease progression 
(2) unacceptable toxicity 
(3) treatment delay >2 weeks, or 
(4) at the discretion of the patient or treating physician 
 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified subinvestigator(s). The pharmacist will maintain records of drug receipt (if 
applicable), drug preparation, and dispensing, including the applicable lot numbers, patients’ 
height, body weight, and body surface area, total drug administered in milliliters and 
milligrams, and date and time of administration. Any discrepancy between the calculated 
dose and dose administered and the reason for the discrepancy must be recorded in the 
source documents. 
 
9.2 Toxicity-Based Dose and Schedule Modifications 
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s). Toxicities are to be assessed according to the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE v4.0, Appendix B). Should significant 
local reaction occur due to subcutaneous administration, a switch to the IV formulation at the 
same dose and schedule can be considered but only at the investigator’s discretion. 
 
9.2.1. General Algorithm 
 
 
In general, all previously established or new toxicities observed any time are to be managed 
as described in the following table: 


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Table  9.1. 
Toxicity Management 
Toxicity 
Grade 
Action 
Lymphopenia 
Any 
None 
Nonhematological toxicity* 
3 
Hold bortezomib up to 2 weeks or until 
toxicity returns to grade 1 or better 
4 
Discontinue bortezomib 
Hematological Toxicity 
4 
Hold bortezomib up to 2 weeks or until 
all of the following: 
• Hgb ≥ 8g/dL(grade 2 or better) 
• Platelets ≥ 75 K/mcL(grade 1 or better) 
• ANC ≥ 1000 K/mcL(grade 2 or better) 
*excludes neuropathy & hepatic toxicities: management of these toxicities discussed subsequently 
 
DOSE MODIFICATION LEVELS FOR BORTEZOMIB 
all doses given on D1, 4, 8, and 11 of a 21-day cycle 
 
Starting dose 
1.3 mg/m2 
Dose Level -1 
1.0 mg/m2 
Dose Level -2 
0.7 mg/m2 
 
 
If bortezomib has been held: 
 
 
i) If the toxicity does not resolve within ≤ 2 weeks, bortezomib must be discontinued 
ii)   If the toxicity resolves as described in the table above, bortezomib can be restarted, 
however dose must be reduced by approximately 25% as follows: 
(1) If the patient was receiving 1.3 mg/m2, reduce to Dose Level -1. 
(2) If the patient was receiving 1 mg/m2, reduce to Dose Level -2 
(3) if the patient was receiving 0.7 mg/m2, discontinue drug unless patient is responding, 
in which case, drug continuation at the discretion of the principal investigator. 
 
If the drug is discontinued, every effort will be made to have patients evaluated for response at 
the planned time. If this is not possible, the patient will be considred a non-responder. Please 
refer to the Investigator’s Brochure for information regarding the rationale behind the dose for 
each dose modification level as based on previous experience with bortezomib. 
 
Once bortezomib is reduced for any toxicity, the dose may not be re-escalated. 
 
9.2.2.  Neurologic Toxicities 
  
Patients who experience bortezomib-related neuropathic pain or peripheral sensory 
neuropathy are to be managed as presented in the following table: 


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Table 9.2. 
Management of Patients With Bortezomib-Related Neuropathic Pain 
and/or Peripheral Sensory or Motor Neuropathy 
Severity of Peripheral Neuropathy Signs 
and Symptoms 
Modification of Dose and Regimen 
Grade 1 without pain or loss of function 
No action 
Grade 1 with pain or Grade 2 
Reduce bortezomib by one dose level; if 
already at at Dose Level -2, discontinue drug 
Grade 2 with pain or Grade 3 
Withhold bortezomib therapy until toxicity 
resolves. When toxicity resolves reinitiate at 
Dose Level -2 and change treatment 
schedule to once per week.  If already at 
Dose Level -2, discontinue drug. 
Grade 4 
Discontinue bortezomib 
Source:  VELCADE (bortezomib) for Injection Investigator’s Brochure Edition 14. 
Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 
 
9.2.3.  Hepatic Impairment 
 
Patients with bilirubin ≤ 1.5 × ULN (grade 1) do not require a starting dose adjustment.  Please 
note that patients with bilirubin levels > 1.5 ULN (grade 2 or worse) are excluded from 
enrollment. 
 
 
If a patient develops grade 2 or worse hyperbilirubinemia (>1.5 ULN) while on study, the 
investigator should hold bortezomib for 2 weeks or until the toxicity returns to grade 1 or better. 
 
Restarting bortezomib at the next lower dose level (see DOSE MODIFICATION LEVELS 
above) could be considered at the investigator’s discretion and following exclusion careful 
consideration of liver disease due to other causes, such as, but not limited to, active infection 
and lung cancer-related liver disease.  If already at Dose Level -2, discontinue drug. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
  
Treatment will be initiated once criteria for study inclusion have been fully met.  Restaging 
scans, with evaluation of response, will be done every 2 cycles (during week 3 of second cycle, 
± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, 
treatment delay > 2 weeks, or at the discretion of the treating physician or patient. 


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Table 10.1.  Study Treatment Schedule and Evaluations 
 
 
CYCLE 1 
CYCLE 2 
CYCLES 3 and 4, and onw ards… 
 
Base 
line 
Wk* 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
W 
k 
3 
Wk 
1 
Wk 
2 
Wk 
1 
Wk 
2 
W 
k 
3 
Off 
Study
d 
 
D 
1 
D 
4 
D 
8 
D 
11 
D 
1 
D 
4 
D 
8 
D 
11 
D 
1 
D 
4 
D 
8 
D 
11 
D 
1 
D 
4 
D 
8 
D 
11 
Bortezomib 
IV (1.3 
mg/m2/day) 
X** 
X** 
X** 
X** 
X** 
X** 
X** 
 
X** 
X** 
 
X** 
X** 
X** 
X** 
X** 
X** 
X** 
Informed 
Consent 
X 
 
 
Obtain 
pathology 
specimen 
for KRAS 
X 
 
 
Medical 
History 
X 
 
 
Physical 
Exam 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X  
* 
X  
* 
X 
* 
X 
* 
X 
X 
Concurrent 
medications 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X  
* 
X  
* 
X 
* 
X 
* 
X 
X 
Vital signs 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
X 
Performanc 
e status 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X  
* 
X  
* 
X 
* 
X 
* 
X 
X 
CBC 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X 
X 
CMP 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X  
* 
X  
* 
X 
X 
EKG 
X 
Adverse 
event 
evaluation 
X 
* 
X 
* 
X 
* 
X 
* 
X 
* 
X  
* 
X  
* 
X 
* 
X 
* 
X 
X 
Radiologic 
tumor 
assessment 
s 
c 
X 
 
X 
a 
 
X 
a 
MRI 
X 
 
 
Pregnancy 
test 
Xb 
 
 
Wk: week, D: day 
*: ± 3 day window for on-study evaluations (Physical exam, concurrent medications, vital signs, performance 
status, CBC, CMP, EKG, adverse event evaluation 
**: ± 1 day window for treatment with Bortezomib 
a: ± 7 days, imaging will be performed after every 2 cycles of therapy 
b: ± 7 days, serum qualitative/urine, not required for postmenopausal or surgically-sterilized women 
c: ± 30 days of Week 1 Day 1. 
d: The off-study visit should be completed 30 days after the end of treatment (+/- 14 days) 


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11.0  TOXICITIES/SIDE EFFECTS 
 
11.1. Anticipated Toxicities 
 
 
A detailed list of anticipated side-effects from bortezomib treatment are included in  Appendix 
A and discussed in the Investigator’s Brochure. In general, the risks and side-effects of 
bortezomib as detailed in the informed consent include those which are: 
 
Likely (occurring in ≥30% of patients) 
• Fatigue 
• Constipation, diarrhea, nausea, vomiting, and loss of appetite (may result in 
dehydration or weight loss) 
• Fever commonly with shaking chills 
• Pain or numbness and tingling in the hands and feet 
• Low platelets increasing the likelihood of bleeding 
• Low red blood cell count leading to fatigue 
 
Less Likely (occurring in 10-29% of patients) 
• Low white cell count increasing the likelihood of infections (such as those of the upper 
and lower respiratory tract including sinusitis, bronchitis and pneumonia) 
• Flu-like symptoms such as sore throat, runny nose, and chills 
• Abdominal pain 
• Aches and pains in the muscles, joints, and arm and leg bones 
• Fluid retention with swelling in the arms and legs (may result in weight gain and 
dizziness with standing) 
• Cough or shortness of breath 
• Headache 
• Skin rash with itching and redness 
• Herpes virus infections such as shingles 
• Anxiety and insomnia 
 
Rare but serious (<10% of patients) 
• Low blood pressure with light-headedness or fainting 
• Irregular heart beat and cardiac arrest 
• New or worsening heart failure 
• Fluid build-up in the lungs and respiratory failure 
• Gastrointestinal bleeding or obstruction 
• Bleeding in the brain 
• Infections in the blood or sepsis 
• Allergic reactions 
• Confusion and/or seizures from a brain syndrome called reversible posterior 
encephalopathy 
• Loss of vision or hearing 


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11.2. Adverse and Serious Adverse Event Definitions 
Adverse event (AE): any untoward medical occurrence in a patient or subject administered 
subcutaneous bortezomib. 
• The untoward medical occurrence does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of bortezomib whether or not it is related to 
the bortezomib. 
• This includes any newly occurring event, or a previous condition that has increased in 
severity or frequency since the administration of study drug. 
• For this protocol 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. 
 
Serious Adverse Event (SAE): any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening 
o refers to an AE in which the patient was at risk of death at the time of the event 
o 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 
• Results in persistent or significant disability or incapacity 
o 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. 
o 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 one of the outcomes listed 
above, or 
▪ 
involves suspected transmission via a medicinal product of an infectious agent 
(any organism, virus, or infectious particle e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy, whether pathogenic or non- 
pathogenic) 
o examples 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 
 
 
As far as possible, each adverse event should be evaluated to determine: 
• severity grade via CTCAE v4.0 
• relationship to study drug 
• duration (start and end dates) 
action taken 
• whether or not it constitutes an SAE 


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12.0  CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary endpoint of the study is tumor response; this will be evaluated according to the 
RECIST v1.1 criteria.  Secondary endpoints of progression free survival, 8-week stable 
disease, and overall survival will be evaluated according to RECIST v.1.1 criteria as well. 
 
Once patients discontinue study treatment secondary to progression of disease, overall 
survival (OS) status will be followed by standard death registries and by calling the patient 
and/or his or her primary care physician twice a year.  For patients who continue to receive 
care at MSKCC, biannual chart reviews will be conducted by the research staff.  For patients 
who choose to receive further care at an outside facility, every attempt to contact the patient 
and/or his/her treating physician will be made on a biannual basis as well. OS will be 
measured from the time of study treatment initiation. Patients who discontinue treatment 
secondary to toxicity will continue to be followed on study until evidence of resolution of 
toxicity to grade 1 or better and evidence of disease progression. The 
 
12.1. Objective Response 
 
 
Objective responses are defined according to RECIST v1.1 criteria. 
 
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 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. 
 
12.2. “Best” Response 
 
The Best Objective Response is recorded from the start of treatment until disease 
progression. In general, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. Note that Objective Response 
and progression free survival (PFS) are clinical endpoints. 
 
13.0   CRITERIA FOR REMOVAL FROM STUDY 
 
Patients must be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care. The investigator also has the right to 
withdraw, and in some cases is required to withdraw, patients from the study for any of the 
following reasons that represent grounds for study discontinuation: 


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• Progressive disease at any time 
• Occurrence of an unacceptable adverse event 
• A significant treatment cycle delay or bortezomib interruption, at the investigator’s 
discretion (as detailed in Section 9.1). 
• Intercurrent illness 
• Protocol violations 
• Noncompliance 
• Administrative reasons 
• Failure to return for follow-up 
• General or specific changes in the patient’s condition unacceptable for further 
treatment in the judgment of the investigator 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for a patient’s withdrawal from the study is to be recorded in 
the source documents. 
 
14.0   BIOSTATISTICS 
 
The primary endpoint of this single-arm phase II trial will be best objective response rate 
(ORR) to Bortezomib (partial+complete responses) by RECIST criteria v1.1, evaluated at any 
time between treatment initiation and documented progression of disease. A Simon two- 
stage minimax design will be used to test the null hypothesis of 10% response rate against 
the desired alternative of a 30% ORR, with a one-sided type I error (probability of falsely 
accepting a non-promising therapy) of 10% and power of 90%. The null hypothesis is based 
on historical data of best objective response of non-small cell lung carcinomas to cytotoxic 
chemotherapy after failure of first-line chemotherapy (range from 8-10%). In the first stage of 
this design, 16 patients will be accrued. If zero to one responses are observed, then the 
study will be terminated and declared negative. If at least 2 responses are observed, then an 
additional 9 patients will be accrued to the second stage. At the end of the study, if 5 or more 
patients respond out of a total of 25 patients enrolled, the treatment will be considered worthy 
of further investigation in this patient population. Under this design, the expected sample size 
is 25, and the probability of early termination is 51%. 
 
Patients who receive at least one dose of the drug will be evaluable for response. For 
patients who discontinue the drug before the documented progression via RECIST v1.1, 
every effort will be made to have a final evaluation scan. If this is not possible, they will be 
considered non-responders. 
 
With an expected accrual rate at MSKCC of 1-2 patients a month for this selected cohort, we 
expect to complete accrual within 8 months (if study will be stopped after the first stage) or 
12-18 months (if patients will be accrued for both stages). 
 
Progression-Free (PFS) and overall survival (OS) will be calculated using Kaplan-Meier 
estimators starting from the time of treatment initation. Patients will be followed-up until 
progression of disease or death (for PFS) or until death (for OS). Patients who do not 
experience the event of interest during the study time will be censored at the time of the last 
available follow-up. 


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Eight-week stable disease will be summarized using descriptive statistics. 
 
Toxicities will be assessed through the NCI-Common Terminology Criteria for Adverse 
Events version 4.0 and presented individuall and using descriptive statistics.  Dose 
modifications will be permitted as per a prescribed algorithm. 
 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
Randomization is not performed in this study. 
 
16.0   DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. The data collected for this study will be entered into the Clinical 
Research Database (CRDB). 
 
16.1 
Quality Assurance 
 
There are several different mechanisms by which clinical trials are monitored for data safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 


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16.1.2. Protocol Compliance 
 
 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies). 
Changes to the protocol will require approval from Millennium and written IRB 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients. The IRB may provide, if applicable 
regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval /favorable opinion of the IRB. The 
investigator will submit all protocol modifications to Millennium and the regulatory 
authority(ies) in accordance with the governing regulations.  Any departures from the 
protocol must be fully documented in the source documents. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. 
 
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qualit 
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p 
df 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level or risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
16.3. On-Site Audits 
 
Regulatory authorities and/or Millennium may request access to all source documents, data 
capture records, and other study documentation for on-site audit or inspection.  Direct access 
to these documents must be guaranteed by the investigator, who must provide support at all 
times for these activities. 


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16.4. Premature Closure of Study 
 
This study may be prematurely terminated, if in the opinion of the sponsor-investigator or 
Millennium, there is sufficient reasonable cause. Written notification documenting the reason 
for study termination will be provided to the sponsor-investigator or Millennium by the 
terminating party. 
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend, or discontinue the development of the drug 
 
16.5. Record Retention 
The sponsor-investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). 
 
17.0   PROTECTION OF HUMAN SUBJECTS 
 
Good Clinical Practice: The study will be conducted in accordance with the International 
Conference on Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate 
regulatory requirement(s). The investigator will be thoroughly familiar with the appropriate 
use of the drug as described in the protocol and Investigator’s Brochure. Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected.  Master files should be established at the beginning of the study, maintained 
for the duration of the study, and retained according to the appropriate regulations. This is 
the responsibility of the sponsor-investigator. 
 
Ethical Considerations: The study will be conducted in accordance with ethical principles 
founded in the Declaration of Helsinki. The Institutional Review Board (IRB) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of 
the patients. The study will only be conducted at sites where IRB approval has been 
obtained. The protocol, Investigator’s Brochure, informed consent, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, 
annual progress reports, and any revisions to these documents will be provided to the IRB by 
the investigator.  Millennium requests that the protocol and informed consent documents be 
reviewed by Millennium prior to IRB submission. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports, and communications will identify the patient by initials and the assigned patient 
number. The investigator will grant monitor(s) and auditor(s) from Millennium or its 


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designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection 
process. The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1. Adverse Event Reporting to Millenium Pharmacovigilance 
 
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 must be reported to Millennium Pharmacovigilance (or designee).  SAEs will be 
reported using the Clinical Research Database (CRDB) reporting form. 
 
SAEs must be reported to Millennium Pharmacovigilance (or designee) from first dose of 
bortezomib up to and including 30 days after administration of the last dose of bortezomib. 
When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.  Any SAE that occurs at any time after completion of 
bortezomib treatment or after the designated follow-up period that the investigator and/or 
sub-investigator considers to be related to any study drug must be reported to the Millennium 


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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). 
 
This is an investigator-initiated study. The principal investigator Gregory J. Riely, MD, PhD 
(who may also sometimes be referred to as the sponsor-investigator), is conducting the study 
and acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator 
include both those of a sponsor and those of an investigator. 
 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with 
any study drug, to Millennium Pharmacovigilance (or designee) as soon as possible, but no 
later than 5 calendar days of the sponsor-investigator’s observation or awareness of the 
event.  Subinvestigators must report all SAEs to the sponsor-investigator so that the 
sponsor-investigator can meet his/her foregoing reporting obligations to Millennium 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
subinvestigator(s).  Millennium Pharmacovigilance (or designee) may request follow-up 
information to a reported SAE, which the sponsor-investigator will be responsible for 
providing to Millennium Pharmacovigilance (or designee). 
 
The SAE report must include event term(s), serious criteria, and the investigator’s or sub- 
investigator’s determination of both the intensity of the event(s) and the relationship of the 
event(s) to study drug administration. Intensity for each SAE, including any lab abnormality, 
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.  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, as soon as possible but no later 
than 5 calendar days of such communication. 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America, PPD, Inc., Safety and Medical Management, US 
Fax:  +1 888-488-9697, Hotline number (available 24/7):  1-800-201-8725 
 
 
Millennium Pharmaceuticals will send to the sponsor-investigator VELCADE safety letters 
(real-time safety letters and/or the quarterly safety updates). All safety letters pertaining to 
the VELCADE program will be sent to the Investigator-Sponsor via an electronic distribution 
using Mercury, the Millennium Secure File Transfer (MFT) system. For each safety letter 
distributed, Sponsor-Investigator will receive an e-mail inviting to download the Adobe/PDF 
document from Mercury. 


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To meet GCP requirements, Millennium is required to send Sponsor-Investigators the safety 
letters within 15 days after the world-wide receipt date of the safety event.  Sponsor- 
Investigators responsibility is to read the safety letter, and provide the safety letter to the 
Institutional Review Board per institution’s policy. Sponsor-investigator will be responsible for 
forwarding such reports to any sub-investigator(s). 
 
17.2.2. Reporting Drug Exposure: Pregnancy and Birth Events 
  
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and must permanently discontinue study 
drug(s).  All pregnancies and suspected pregnancies must be reported to Millennium 
Pharmacovigilance (or designee). The pregnancy must be followed for the final pregnancy 
outcome (ie, delivery, still birth, miscarriage) and Millennium Pharmacovigilance will request 
this information from the investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation 
in this study, this must be reported to Millennium Pharmacovigilance (or designee) 
immediately. 
 
18.0   INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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19.0   REFERENCES 
 
 
1 Jemal A, Siegel R, Ward E, Muray T, Xu J, Thun, MJ.Cancer Statistics,2007. CA:Cancer for 
Clin.2007; 57:43-66. 
 
2 Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer Statistics 2002. CA:Cancer for Clin. 2005; 
55:74-108. 
 
3 NCCN: National Comprehensive Cancer Network 13. NCCN clinical practice guidelines in oncology™: 
non-small cell lung cancer 
 
4 Amado RG, Wolf M, Peeters M, VanCutsem E, Siena S, Freeman D, et al. Wild-type KRAS is 
required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol.2008; 
26:1626-1634. 
 
5 Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, 
Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler 
K, Demmy T, Shepherd F. Vinorelbine plus cisplatin vs observation in resected non-small cell lung 
cancer. NEJM 2005:23;352(25)2589-97. 
 
6 Zhu C-Q, Santos G, Ding K, Sakurada A, Cutz JC, Liu N. Role of KRAS and EGFR as biomarkers of 
response to erlotinib in national cancer institute of Canada clinical trials group study BR.21. J Clin 
Oncol. 2008; 26:4268-4275. 
 
7 Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M et al. The role of RAS 
oncogene in survival of patients with lung cancer: a systematic review of the literature with meta- 
analysis. Brit J of Cancer. 2005: 92:131-139. 
 
8 Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in 
never smokers with lung adenocarcinoma. Clin Cancer Res. Sep 15 2008;14(18):5731-5734. 
 
9 Powell CA, Spira A, Derti A, et al. Gene expression in lung adenocarcinomas of smokers and 
nonsmokers. Am J Respir Cell Mol Biol. Aug 2003;29(2):157-162. 
 
10 Sun SC. Non-canonical NF-kappaB signaling pathway. Cell Res. Jan 2011;21(1):71-85. 
 
11 Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS- 
driven cancers require TBK1. Nature. Nov 5 2009;462(7269):108-112. 
 
12 Meylan E, Dooley AL, Feldser DM, et al. Requirement for NF-kappaB signalling in a mouse model of 
lung adenocarcinoma. Nature. Nov 5 2009;462(7269):104-107. 
 
13 Escobar M, Velez M, Belalcazar A, Santos ES, Raez LE. The role of proteasome inhibition in 
nonsmall cell lung cancer. J Biomed Biotechnol. 2011;2011:806506. 
 
14 Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal 
interactions with the Ras oncogene. Cell. May 29 2009;137(5):835-848. 
 
15 Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome 
inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59(11):2615-22. 
 
16 Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in cancer 
therapy. Clin Cancer Res 1999;5(9):2638-45. 


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myeloma cells. Cancer Res 2001;61(7):3071-6.
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17 Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor- 
kappaB inhibition. Cancer Res 2001;61(9):3535-40. 
 
18 LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. Proteasome 
inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. 
Cancer Res 2002;62(17):4996-5000. 
 
19 Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential effects of 
the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor 
xenografts. Mol Cancer Ther 2003;2(9):835-43. 
 
20 Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. Effects of the 
proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor 
xenografts. Mol Cancer Ther 2002;1(14):1243-53. 
 
21 Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome inhibitor, 
bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia 
2004;18:1357-63. 
 
22 Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor bortezomib 
in cancer therapy. Cancer Cell Int 2005;5:18. 
 
23 Goel A, Dispenzieri A, Geyer SM, Greiner S, Peng KW, Russell SJ. Synergistic activity of the 
proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy 
in an orthotopic model of multiple myeloma. Blood 2006;107(10):4063-70. 
 
24 Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The proteasome 
inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic 
agents: therapeutic applications. Blood 2003;101(6):2377-80. 
 
25 Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al. The proteasome inhibitor PS-341 
sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 
2003;102(1):303-10. 
 
26 Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib 
interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells 
sensitive and resistant to STI571. Blood 2003;102(10):3765-74. 
 
27 O'Connor OA, Smith EA, Toner LE, Teruya-Feldstein J, Frankel S, Rolfe M, et al. The combination of 
the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B- 
cell lymphomas to cyclophosphamide. Clin Cancer Res. 2006;12(9):2902-11. 
 
28 David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the farnesyl transferase 
inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human 
myeloma cells that is associated with down-regulation of p-AKT. Blood 2005;106(13):4322-9. 
 
29 McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL, et al. The proteasome as 
a new drug target in metastatic prostate cancer. In: 7th Annual Genitourinary Oncology Conference; 
1999 February 1999; Houston, TX. 
 
30 Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The proteasome 
inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple 


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31 Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors 
induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006;107(12):4907-16. 
 
32 Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al. PS-341, a novel proteasome inhibitor, 
induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol 
Cancer Ther 2002;1(10):841-9. 
 
33 Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H. Proteasome inhibitor PS-341 
induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 
signaling. Cancer Sci 2004;95(2):176-80. 
 
34 Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional activity of 
hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. 
Mol Cell Biol 2006;26(15):5895-907. 
 
35 An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: 
accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of 
proteasome inhibition. Leukemia 2000;14(7):1276-83. 
 
36 Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib mediates 
antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 
2006;66(1):184-91. 
 
37 Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular sequelae of 
proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002;99(22):14374- 
9. 
 
38 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I Trial of the 
Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. J Clin Oncol 
2002;20(22):4420-7. 
 
39 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I Trial of the 
Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. J Clin Oncol 
2002;20(22):4420-7. 
 
40 Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I Trial of the Novel 
Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin Cancer Res 2002;8(8):2505- 
11. 
 
41 Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the 
proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen- 
independent prostate cancer. J Clin Oncol 2004;22(11):2108-21. 
 
42 Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, Pangalis GA. 
Treatment of relapsed or refractory Waldenström's macroglobulinemia with bortezomib. Haematologic. 
2005;90(12):1655-8. 
 
43 Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study of 
two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004;127(2):165-72. 
 
44 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 2 Study of 
Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 2003;348(26):2609-17. 


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45 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or 
High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med 2005;352(24):2487-98. 
 
46 Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Bortezomib 
Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in Relapsed 
Multiple Myeloma: Updated Results of the APEX Trail. Blood 2005;106(11):Abstract 2547. 
 
47 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib 
plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 
2008;359(9):906-17. 
 
48Moreau P, Coiteux V, Hulin C, Leleu X, van de Velde H, Acharya M, Harousseau JL. Prospective 
comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple 
myeloma. Haematologica. 2008 Dec;93(12):1908-11. Epub 2008 Sep 2. 


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20.0   APPENDICES 
 
APPENDIX A: Anticipated Side-Effects of Bortezomib 
 
Known Anticipated Risks of bortezomib by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
System Organ Class Observed Incidence 
Preferred Term 
 
 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anemia* 
Very common 
Neutropenia* 
Common 
Lymphopenia, pancytopenia*, leukopenia*, 
febrile neutropenia 
Cardiac Disorders 
Common 
Tachycardia, atrial fibrillation, palpitations, 
cardiac failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac 
tamponade*±, bradycardia, atrioventricular 
block complete, arrhythmia, cardiac 
arrest∗, cardiac failure, arrhythmia, 
pericardial effusion, pericarditis, pericardial 
disease±, cardiopulmonary failure± 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common 
Blurred vision, conjunctivitis, conjunctival 
hemorrhage 
Gastrointestinal Disorders 
Most common                                                     Constipation, diarrhea*, nausea, vomiting* 
Very common                                                      abdominal pain (excluding oral and throat) 
Common                                                             Dyspepsia, pharyngolaryngeal pain, 
gastroesophageal reflux, abdominal 
distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal 
hemorrhage*, lower gastrointestinal 
hemorrhage*± rectal hemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue 
ulceration, retching, upper gastrointestinal 
hemorrhage*, hematemesis*, oral mucosal 
petechiae, ileus paralytic*, ileus, 
odynophagia, enteritis, colitis, esophagitis, 
enterocolitis, diarrhea hemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common                                                     Fatigue, pyrexia 
Very common                                                      Chills, edema peripheral, asthenia 
Common 
Neuralgia, lethargy, malaise, chest pain, 
mucosal inflammation* 
 
Uncommon                                                         Injection site pain, injection site irritation, 


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Known Anticipated Risks of bortezomib by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
 
 
System Organ Class Observed Incidence 
Preferred Term 
 
injection site phlebitis, general physical 
health deterioration*, catheter-related 
complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinemia, hepatitis*± 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common 
Upper respiratory tract infection, 
nasopharyngitis, pneumonia*, Herpes 
zoster* 
Common 
Lower respiratory tract infection*, sinusitis, 
pharyngitis, oral candidiasis, urinary tract 
infection*, sepsis∗, bacteremia*, cellulitis∗, 
Herpes simplex, bronchitis, gastroenteritis*, 
infection 
Uncommon 
Septic shock*, catheter-related infection*, 
skin infection*, Herpes zoster 
disseminated*, lung infection∗, infusion site 
cellulitis, catheter site cellulitis, infusion site 
infection, urosepsis*, Aspergillosis*, tinea 
infection, Herpes zoster ophthalmic, 
Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, 
empyema±, fungal esophagitis± 
Injury, Poisoning, and 
Procedural Complications 
Common 
Fall 
Uncommon 
Subdural hematoma 
Investigations 
Common 
Weight decreased, alanine 
aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) 
increased, blood alkaline phosphatase 
increased, liver function test abnormal, 
blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) 
increased, oxygen saturation decreased*, 
blood albumin decreased, ejection fraction 
decreased* 
Metabolism and Nutritional Disorders 
Very common 
Decreased appetite, anorexia, dehydration* 
Common 
Hyperglycemia, hypoglycaemia, 
hyponatremia, hypokaliemia, 
hypercalcemia* 


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Known Anticipated Risks of bortezomib by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
 
 
System Organ Class Observed Incidence 
Preferred Term 
 
Musculoskeletal and 
Connective Tissue Disorders 
Very common 
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and 
Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all 
preferred terms under the MedDRA High- 
level term Peripheral neuropathy NEC) 
Very common 
Paresthesia, dizziness excluding vertigo, 
headache 
Common 
Polyneuropathy, syncope, dysesthesia, 
dysgeusia, postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, 
ageusia, encephalopathy, 
paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy 
syndrome± 
Psychiatric Disorders 
Very common                                                      Anxiety, insomnia 
Common                                                             Confusional state 
Uncommon                                                         Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, 
hematuria 
Uncommon                                                         Micturition disorder 
Respiratory, Thoracic, and 
Mediastinal Disorders 
Very common                                                      Cough, dyspnea 
Common 
Epistaxis, dyspnea exertional, pleural 
effusion*, rhinorrhea, hypoxia*, pulmonary 
edema∗ 
Uncommon                                                         Hemoptysis*, acute respiratory distress 
syndrome*, respiratory failure*, 
pneumonitis*, lung infiltration, pulmonary 
alveolar hemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, 
pleurisy, pleuritic pain 
Skin and Subcutaneous 
Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, 
petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic 


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Known Anticipated Risks of bortezomib by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
 
 
System Organ Class Observed Incidence 
Preferred Term 
vasculitis± 
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral hemorrhage* 
 
Source: VELCADE® Investigator’s Brochure Edition 14. 
Most common = ≥ 30%, Very common = 10% to 29%, Common = 1% to 9%, 
Uncommon = < 1%. 
* 
Fatal outcomes have been reported. 
± Indicates a Preferred term not listed in the source table, however the event is deemed 
medically important and so is included. 
 
 
 
Reports of Adverse Reactions From Postmarketing Experience 
 
System Organ Class 
Preferred Term 
Blood and lymphatic system disorders 
Observed 
Incidencea 
Disseminated intravascular coagulation 
Rare 
Cardiac Disorders 
Atrioventricular block complete 
Rare 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
Deafness bilateral 
Rare 
Eye Disorders 
Ophthalmic herpes                                                        Rare 
Optic neuropathy                                                        Rare 
Blindness                                                                    Rare 
Gastrointestinal Disorders 
Acute pancreatitis 
Rare 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
Hepatitis 
Uncommon 
Liver failure 
Unknown 
Infections and infestations 
Herpes meningoencephalitis 
Rare 
Septic shock 
Rare 
Immune System Disorders 
Angioedema 
Rare 
Nervous System Disorders 
Autonomic neuropathy 
Rare 
Dysautonomia 
Unknown 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
Acute diffuse infiltrative pulmonary diseaseb 
Rare 


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Reports of Adverse Reactions From Postmarketing Experience 
 
Acute respiratory distress syndrome (ARDS)               Rare 
Interstitial pneumonia                                                    Rare 
Lung infiltration                                                             Rare 
Pneumonitis                                                                  Rare 
Pulmonary hypertension                                               Rare 
Skin and subcutaneous system disorders 
Acute febrile neutrophilic dermatosis                            Unknown 
Toxic epidermal necrolysis                                           Unknown 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 14. 
a 
Incidence is assigned using the following convention:  very common (≥ 1/10); 
common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and 
< 1/1000 ); very rare (< 1/10,000, including isolated reports). 
b 
Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term 
which corresponds to a Preferred Term of Interstitial lung disease. 
 
ADDITIONAL NOTES: 
 
Other medical events of interest that are considered not causally related to bortezomib 
include hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib. Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
 
Additional details on the potential risks of bortezomib may be found in the current 
Investigator’s Brochure. 


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APPENDIX B: Common Terminology Criteria for Adverse Events 
  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting: 
http://ctep.cancer.gov/reporting/ctc.html 


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APPENDIX C: Karnofsky Performance Status Scale 
  
 
The following table presents the Karnofsky performance status scale. 
 
Points 
Description 
 
100 
Normal, no complaints, no evidence of disease 
 
90 
Able to carry on normal activity 
 
80 
Normal activity with effort; some signs or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or to do active work 
 
60 
Requires occasional assistance but is able to care for most of his/her 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
 
20 
Very sick; hospitalization necessary; active support treatment necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
Sources:  Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an 
examination of its reliability and validity in a research setting. Cancer 1984;53:2002-2007. 
 
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative 
treatment of cancer. Cancer1948; 1(4):634-656. 
 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod 
CM, ed. Evaluation of Chemotherapeutic Agents. New  York: Columbia University Press, 1949, I9 1-205. 


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APPENDIX D: Body Surface Area and Creatinine Clearance Calculations 
 
 
 
 
 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
 
BSA = (W 0.425 x H 0.725) x 0.007184 
where the weight is in kilograms and the height is in centimeters. 
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height 
and weight be known. Arch Intern Medicine. 1916; 17:863-71 
 
 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
CrCl (ml/min) = (140 - age) (actual wt in kg) 
 
72 × serum creatinine (mg/dl) 
 
For females, use 85% of calculated CrCl value. 
 
Note:  In markedly obese patients, the Cockroft-Gault formula will tend to overestimate 
the creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring 
renal clearance.) 


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APPENDIX E: New York Heart Association Classification of Cardiac Disease 
 
 
 
 
 
The following table presents the NYHA classification of cardiac disease. 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994:253-256. 


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APPENDIX F:  Pregnancy and Effective Methods of Contraception 
 
 
It is not known what effects bortezomib 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.  Non sterilized 
female patients of reproductive age 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: 
• 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 from the time of signing the informed consent form through 30 days after 
the last dose of bortezomib, or agree to completely abstain from heterosexual 
intercourse. 
 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see 
examples below). 
 
Highly effective methods 
Other effective methods 
(barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, or 
contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at 
the same time is recommended. 
 
 
Male patients, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the 
following: 
• Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain 
from heterosexual intercourse. 


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APPENDIX G:Pregnancy Reporting Form 
 
 
INA\ 
MILLENNIUIM 
THE TAK5CA ONr.OLO GY C<OMPAN'i 
 
 
Pre,gnan·CY Form v03Nov2008(llS) 
Pagel of 4 
 
 
 
 
 
Report Type:    IJIInitial D Follow-up 
Date of Report: 
I 
DO MM 
Yr 
 
REPORTERlNFORMATION:(PI'ease forw ard rf an alternative IPhysiicia·n is more appropriate! 
Reporter name: 
nue:   
 
Address: 
Te ephone No.: 
Fax No_ 
Cily, State{Pr•ovince: 
Postal Code: 
Country: 
 
FATHER'S INFORMA TION  
0 Father Unknown 
Initials: 
Date of Birth:_/_/ 
or  Age: 
years 
DO MM 
Yr 
Participatni g in an MPIclinical  study?   0 No    0 Yes 
If no, w hat company product w as taken: 
If yes, please provide:  Study drug: 
ProtocolNo: 
Center No:   
 
Patient No:  
 
Medical/ Famliial / Soc alHistory 
Qe. .Include chron c illnesses:specify,fami tialbirth defeclslgenetic/chromosom:ldisorders;habitualexposure: 
specify, alcoholllobacco;drug exposur e:specify,substance abuse and med cation use. Please include drug 
treatment 
prior to or around the time of conception and/or duringpregnancy) 
Race: 
Occupation: 
Number of children: 


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    /AVA\ 
MILLENNIUIM 
THE TAK50A OHCXlLOCW t.OMPAN'II' 
 
MOTHE R' S INFORMA TION: 
 
 
Plregnancy Form v03Nov200S (llS)  
Page2of 4 
 
Initials: 
Date of Birth:_/_/ 
or Age: 
years 
DO MM 
Yr 
Participating in an MPI clinical study?   0 No    D Yes 
Race:   
 
If no, w hat company product w as taken:   
 
Occupation: 
If yes,please provide: Study drug: 
ProtocolNo: 
Center No:  
  Patient No:  
 
 
 
Medical / Familial / SocialHistory 
Number of previous pregnancies: Full term   
 
Pre-term -- 
(i _e_ Include alcoflolltoOOcc o and substance abuse;complicati ons of past      Outcomes of previous pregnancei s: 
pregnancy,labor/deliver y,fel usl baby;llnesses dumg this pregnancy; 
assisted conception:specify; other disorder-s inc ud ng famial birth  
(Please indicate number of occurrences) 
defects/geneticl chrcmosomal 
disorder.;;;method of diagnosis 
consanguinity,etc_) 
• Spontaneous abortion: 
• Normal live birth: 
• Therapeutic abortion: 
• Chlidren bam w ith defects: -- 
• Elective abortion: 
• Stillbirth: 
  
 
• Other: 
• Outcome unknow n: 
 
 
MOTHER'S DRUG EXPOSURE INFORMA TION 
Please include medical prescnptions, vaccinations, medical devices, OTC products, pregnancy supplements (such as 
folic acid, multivitamins) 
Product 
Name 
Dosage 
Route 
administered 
to patient 
Date of first 
use 
{DD MM/Yr) 
Date of end 
treatment 
(DD MM!Yr) 
Indication 
Contraindicated 
to pregnancy 
( 
I 
I 
) 
( 
I 
I 
) 
DYes ONo DUnk 
(  
I  
I  
) 
( 
I 
I 
) 
DYes ONo DUnk 
( 
I 
I 
) 
( 
I 
I 
) 
DYes ONo DUnk 
(  
I  
I  
) 
( 
I 
I 
) 
DYes ONo DUnk 


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'
Tab.da 
11\YA\ 
MELLENNIUM 
THE TAKEillA ON('.OI.OGY ('J'>MPANY 
 
 
Pregnancy Form v03Nov2008 (US) 
Page 3 of 4 
 
 
CURRENT PIREGNA NCY 11\JIFORIMA TION 
 
Period at exposure: 
w eeks  
Trimester    (1) (2)   (3) 
IFet.altNeonatalStatus 
Date of last mensbl.Jal period:  
/  
/  
 
t:J Unknown 
DO 
IMM 
Yr  
a Norma'l 
g  · IJiJD·  Slilt·u·   
LJ  Birth defect (strucwral/chromos omal d'isorder)* 
[] Pregnancy Ongoing  
LJ  Other (non-struct ura , premat ure birth,int raut erine 
Estimated date •Of delive,ry: 
I 
death/stil birth)* 
LJ Live Birth 
[)!)   MM  
':t'r 
LJ  StiDbirth 
"If box is cheCked. please note  tails ,;,. "Additional 
LJ Early Tem1nation 
derails" ection beklw 
t:J Spontaneous abortion* 
t:J Therapeutic abortion* 
t:J Elective abortion• 
t:J Other': 
"ff box is checked . ple-ase nor;eason  m '"Additional Deu11s:" section below 
A·dditi  llill c·lili! i: 
Is there evidence of a defect from a prenatal test?  
t:JYes  
LlNo 
If yes,indicate w hich test(s) show ed evidence of birth detect: 
t:JUltrasound 
OAmn ocentes s 
LlMaternal Serum-Aipha-
Fetoprotein []Chorionic ViJiSampling   c:JHuman Chorionic 
Gonadotropin 
f::JOther: P ease specify  detas •of defecf{s)•,disorder(s), 
and/or ofher arnoma.ly(i es): 
 
What are the defed(s) attributed t.o: 


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/AVA\ 
MILLENNIUIM
" THIE TAKEDA <mr.O LOG V ('.OMPANY 
  
Pregnancy Form  v03Nov200S (DS) 
Page 4 of 4 
 
 
 
 
Infant lnfonnat jgn; 
 
Gestationalw eeks at birth or at termination:  
w eeks  
Sex:0 Male D Female  D Unk 
 
Date of birtf'l or termfnation:  I 
/--:=--- 
Ill>   MM 
Yr 
If multiple birtlls (e.g. twins), ndicate number:   
 
Length:   
D em D in 
Weight   
D g  
D lbs 
Head circumference: 
D em D in 
(Please complete separate· form for each child) 
Birth Order (1, 2,3, etc.)   
 
Apgar S()ore (0-11 0) at 1mmute:   
 
Apgar S()ore (0-11 0) at 5 minute:   
 
D Unk 
a Unk 
Breast-fed: 
DYes D No  
D Unk 
Method of delivery: D Normalvaginal  a Caesarean section 
 
(j mher: ----- 
 
AdcUt jonall Nptes; 
Resuscitation required: 0 Yes D No   a Unk 
Admiss1on tointensive care requ red:. 
 
D Yes D No   D Unk 
 
 
 
 
 
 
 
 
 
Pleas e attach RELEVANT LABORATORY TESTS A:ND PROCEDURES (e.g.results of  ullrasounds, amniocentesis, cllorionic vii 
b mpfing, or misceOa. neous testing a.s appl cable). In the· case of an abnorm al ev olulion •or 0\Jtcome.pleas e send co p es. of  results of  
aDI 
reev antlaborat ory  te-sit ng and procedu re -s. includ ng  p.alhology results of  produas of  conception and or autopsy  reportsif 
app!Jcable. Pleas e submit 1311Y  additional relev antinf orm ation on a separat e sheet. 
 
 
 
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- Investigator Name: -------------------
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