Efficacy and Tolerability of Nanoparticle Albumin Bound Paclitaxel (Abraxane) in Patients 65 and Older With Locally Advanced or Metastatic Breast Cancer
Phase: PHASE2
Conditions: Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Recurrent Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: City of Hope Medical Center

IRB # 11139 
09/23/19 
Packet: 18 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:      Efficacy and Tolerability of Nanoparticle Albumin Bound Paclitaxel (Abraxane) in patients  
                   65 and older with Locally Advanced or Metastatic Breast Cancer 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: 
IRB # 11139 
PROTOCOL DATE: 09/23/19 
DATE(S)/OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Submission [Protocol Dated 05/25/12] 
 
 
   Version 00 
COH Amendment 01 (Protocol Dated 06/15/12)                                                                                    Version 01 
COH Amendment 02 Title Page dated 08/08/12                                                                                     Version 02 
COH Amendment 03 Title Page dated 08/17/12                                                                                     Version 03 
COH Amendment 04 (Protocol Dated 10/19/12)                                                                                    Version 04 
COH Amendment 05 (Protocol dated 11/28/12)                                                                                     Version 05 
COH Amendment 06 (Protocol dated 03/14/13)                                                                                     Version 06 
COH Amendment 07 Title Page dated 05/31/13                                                                                     Version 07 
COH Amendment 08 (Protocol dated 10/15/13)                                                                                     Version 08 
COH Amendment 09 (Protocol dated 01/17/14)                                                                                     Version 09 
COH Amendment 10 (Protocol dated 06/23/14) 
Version 10 
COH Amendment 11 (Protocol dated 05/04/15) 
Version 11 
COH Amendment 12 (Protocol dated 08/10/15) 
Version 12 
COH Amendment 13 (Personnel Updates 12/30/15)  
                                                           Version 13 
COH Amendment 14 (Protocol dated 09/16/16) 
                                                           Version 14 
COH Amendment 15 (Personnel Updates 10/11/18) 
                                                           Version 15 
COH Amendment 16 (Title Page and Protocol dated 09/23/19)                                                          Version 16 
COH Amendment 17 (Personnel Updates) 
                                                            Packet 17 
COH Amendment 18 (Personnel Updates) 
                                                            Packet 18 
 
 
SITE: 
Breast  
HISTOLOGY: 
All 
STAGE: 
All 
MODALITY: 
All 
TYPE: 
All 
 
 
PRINCIPAL INVESTIGATOR: 
Mina Sedrak, MD 

IRB # 11139 
09/23/19 
Packet: 18 
 
(Former National PI: Arti Hurria, M.D.) 
COLLABORATING INVESTIGATOR: 
Medical Oncology:  Joanne Mortimer, M.D., Joseph Chao, M.D., Warren 
Chow, M.D., Jana Portonow, M.D, Yuan Yuan, M.D,  
Radiology: 
Arnold Rotter, M.D. 
Biostatistics: 
Suzette Blanchard, Ph.D. 
 
Heeyoung Kim, Ph.D.  
 
PARTICIPATING CLINICIAN: 
Marianna Koczywas, M.D., Christina Yeon, MD, James Waisman, MD, 
Daneng Li M.D.,  
 
PARTICIPATING INSTITUTIONS: 
City of Hope, Duarte 
 
City of Hope, South Pasadena 
 
City of Hope, Antelope Valley 
 
Ohio State University, Columbus, OH 

IRB # 11139 
09/23/19 
Packet: 17 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:      Efficacy and Tolerability of Nanoparticle Albumin Bound Paclitaxel (Abraxane) in patients  
                   65 and older with Locally Advanced or Metastatic Breast Cancer 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: 
IRB # 11139 
PROTOCOL DATE: 09/23/19 
DATE(S)/OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Submission [Protocol Dated 05/25/12] 
 
 
   Version 00 
COH Amendment 01 (Protocol Dated 06/15/12)                                                                                    Version 01 
COH Amendment 02 Title Page dated 08/08/12                                                                                  Version 02 
COH Amendment 03 Title Page dated 08/17/12                                                                                     Version 03 
COH Amendment 04 (Protocol Dated 10/19/12)                                                                                    Version 04 
COH Amendment 05 (Protocol dated 11/28/12)                                                                                     Version 05 
COH Amendment 06 (Protocol dated 03/14/13)                                                                                     Version 06 
COH Amendment 07 Title Page dated 05/31/13                                                                                     Version 07 
COH Amendment 08 (Protocol dated 10/15/13)                                                                                     Version 08 
COH Amendment 09 (Protocol dated 01/17/14)                                                                                     Version 09 
COH Amendment 10 (Protocol dated 06/23/14) 
Version 10 
COH Amendment 11 (Protocol dated 05/04/15) 
Version 11 
COH Amendment 12 (Protocol dated 08/10/15) 
Version 12 
COH Amendment 13 (Personnel Updates 12/30/15)  
                                                           Version 13 
COH Amendment 14 (Protocol dated 09/16/16) 
                                                           Version 14 
COH Amendment 15 (Personnel Updates 10/11/18) 
                                                           Version 15 
COH Amendment 16 (Title Page and Protocol dated 09/23/19)                                                          Version 16 
COH Amendment 17 (Personnel Updates) 
                                                            Packet 17 
 
 
SITE: 
Breast  
HISTOLOGY: 
All 
STAGE: 
All 
MODALITY: 
All 
TYPE: 
All 
 
 
PRINCIPAL INVESTIGATOR: 
Mina Sedrak, MD 
 
(Former National PI: Arti Hurria, M.D.) 

IRB # 11139 
09/23/19 
Packet: 17 
COLLABORATING INVESTIGATOR: 
Medical Oncology:  Joanne Mortimer, M.D., Joseph Chao, M.D., Warren 
Chow, M.D., Jana Portonow, M.D, Yuan Yuan, M.D,  
Radiology: 
Arnold Rotter, M.D. 
Biostatistics: 
Suzette Blanchard, Ph.D. 
 
 
 
Heeyoung Kim, Ph.D.  
 
PARTICIPATING CLINICIAN: 
Samuel Chung, M.D, Marianna Koczywas, M.D., Christina Yeon, MD, 
James Waisman, MD, Daneng Li M.D.,  
 
PARTICIPATING INSTITUTIONS: 
City of Hope, Duarte 
 
City of Hope, South Pasadena 
 
City of Hope, Antelope Valley 
 
Ohio State University, Columbus, OH 

  
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Efficacy and Tolerability of Nanoparticle Albumin Bound Paclitaxel 
(Abraxane) in Patients 65 and Older with Locally Advanced or 
Metastatic Breast Cancer 
 
 
Principal Investigator (COH):  
Mina Sedrak, MD 
 
 
 
 
 
1500 E. Duarte Road 
Duarte, CA 91010 
Phone: 626-218-9200 
FAX: 626-301-8898 
e-mail: msedrak@coh.org 
Co-Investigators (COH):  
Medical Oncology:  
Joanne Mortimer, MD 
Joseph Chao, MD 
Warren Chow, MD 
Jana Portnow, MD 
Yuan Yuan, MD 
Peggy Burhenn, RN 
Radiology: 
 
 
Arnold Rotter, MD 
Biostatistics:  
 
Suzette Blanchard, PhD 
 
 
 
 
Can-Lan Sun, PhD 
 
 
 
 
Heeyoung Kim 
 
Participating Clinicians (COH): 
Medical Oncology: 
James Waisman 
Marianna Koczywas 
Daneng Li M.D. 
 
City of Hope-South Pasadena:  
Christina Yeon, MD    
Samuel Chung, MD 
City of Hope-Antelope Valley: 
 
 
 
 
 
 
PARTICIPATING SITES: 
 
Ohio State University Comprehensive Cancer Center 
Anne Noonan, MD 
A445 Starling Loving Hall 
320 W. 10th Avenue  
Columbus, OH 43210 
Email: Anne.Noonan@osumc.edu 
 
 
Study Sponsor, Monitor and Data Coordinating Center:   
 

  
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City of Hope Comprehensive Cancer Center 
 
Protocol :  
 
Initial: 5/25/12 
 
 
 
 
Amend 01: 6/15/12 
 
Amend 02: 8/8/12 (COH title page only) 
Amend 03: 8/17/12 (COH title page only) 
Amend 04: 10/19/12 
Amend 05: 11/28/12    
Amend 06:  03/14/13 
Amend 07: 5/31/13 (COH title page only) 
Amend 08: 10/15/13 (COH Title Page only) 
Amend 09: 01/17/14 (COH Title Page only) 
Amend 10: 06/23/14 
Amend 11: 05/04/15 
Amend 12: 08/10/15 
Amend 13: 12/30/15 (Personnel updates) 
Amend 14: 09/16/16 (Personnel updates) 
Amend 15: 10/11/18 (Personnel updates) 
Amend 16: 09/23/19 (Personnel updates) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In Memory of Dr. Arti Hurria 

  
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SYNOPSIS 
 
Study Objectives 
 
The primary objective of the study is to evaluate the tolerability (grade 2-5 toxicity, need 
for dose reductions, or delays) of weekly nab- paclitaxel (abraxane) in older adults with 
locally advanced or metastatic breast cancer. In addition, we will capture neuropathy 
(grade 2 or higher).  The secondary objectives are (1) to determine efficacy (response and 
time to progression) of weekly nab-paclitaxel in older adults with locally advanced 
metastatic breast cancer, and (2) to explore predictors of the need for dose reduction, dose 
delays, or grade 2-5 toxicity and neuropathy grade 2 or higher based on a cancer-specific 
geriatric assessment. 
 
Eligibility:  
 
Locally advanced or metastatic breast cancer, first or second line chemotherapy treatment 
for metastatic disease, age >65 years., KPS >70%, resolution of grade > 2 toxicity from 
prior therapy (other than alopecia), peripheral neuropathy < grade 1, hematologic 
inclusion (absolute neutrophil count >1,500/mm3, platelets >100,000cells/mm3, and Hb > 
9.0g/dl), hepatic and renal inclusion (AST and ALT < 2.5 x institutional upper limit of 
normal, alkaline phosphatase  < 2.5 x upper limit of normal unless bone metastasis are 
present in the absent of liver metastases, bilirubin < 1.5mg/dl, CrCl > 30ml/min), ability 
to understand and the willingness to sign a written informed consent document. 
 
Exclusion criteria:  
 
KPS < 70%, patients may not be receiving any other investigational agents, untreated 
CNS metastases or symptomatic CNS metastases requiring escalating doses of 
corticosteroids, peripheral neuropathy of severity greater than grade 1, known history of 
allergic reactions to paclitaxel, presence of any serious or uncontrolled infection 
 
Treatment regimen: 
 
Nab-paclitaxel 100mg/m2 3 weeks on +/- 1 day from indicated dates, 1 week off 
 
Response evaluation: 
 
Radiological studies will be conducted after every 2 cycles to assess response to therapy. 
Toxicity will be evaluated utilizing the NCI CTC version 4.0. 
 
Sample size: 40 patients

  
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TABLE OF CONTENTS 
 
 
 
SCHEMA 
 
1. OBJECTIVES ................................................................................................................5 
1.1 
Primary Objective .............................................................................................5 
1.2 
Secondary Objective .........................................................................................5 
 
2. BACKGROUND ...........................................................................................................5 
 
2.1  
Pharmacology and Aging ...................................................................................5 
2.2       Age-Related Changes in the Pharmacokinetics of Taxane Chemotherapy ........6 
2.3        COH IRB 07157: Age-related changes in the pharmacokinetics (pK), 
response, and toxicity of weekly nab-paclitaxel in patients with metastatic 
breast cancer.....................................................................................................17 
2.4  
Rationale and Goals of this Study: Pharmacokinetics of Nab-Paclitaxel  .......17 
 
2.5       Evaluating Factors Other than Chronological Age Which May Affect 
 
           Treatment Tolerance .........................................................................................17 
 
3. PATIENT SELECTION ..............................................................................................18 
 
3.1       Inclusion Criteria..............................................................................................19 
 
3.2  
Exclusion Criteria ............................................................................................19 
 
3.3  
Inclusion of Women and Minorities ................................................................20 
 
4. RECRITMENT AND REGISTRATION PROCEDURES .........................................21 
 
4.1  
Subject Identification and Recruitment ...........................................................21 
4.2       Registration Process .........................................................................................21 
4.3       Procedures for On-Study and Treatment Deviations .......................................22 
 
 
5. TREATMENT PLAN ..................................................................................................22 
 
5.1  
Guidelines for Nab-Paclitaxel Administration ................................................22 
 
5.2       Duration of Therapy .........................................................................................23 
 
6. DOSE DELAYS/DOSE 
MODIFICATIONS
 
23 ...................................................................................................................................... 
 
6.1       Administration of Study Drug to Patients with Abnormal Hematologic  
 
 
Function ...........................................................................................................23 
 
6.2       Administration of Study Drug to Patients with Abnormal Hepatic Function ..24 
 
6.3  
Dose Modification  ..........................................................................................24 
 
6.4  
Dose Reductions and Guidelines for Use of Growth Factors for Hematologic 
Toxicity ............................................................................................................24 
 
 
7.  PHARMACEUTICAL INFORMATION .....................................................................26 
7.1 
Availability/ Distribution .................................................................................26 

  
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7.2 
Storage and Stability ........................................................................................27 
7.3 
Study Medication Administration ....................................................................27 

  
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8.      QUESTIONNAIRES ................................................................................................28 
8.1      Data to be Gathered by the Research Interviewer ............................................29 
8.2      Data to be Gathered by the Study Participant ...................................................29 
8.3      Data to be Collected at Each Clinic Visit While on Treatment ........................30 
8.4      Description of Questionnaire Measures ............................................................30 
 
9.      STUDY CALENDAR ..............................................................................................33 
 
10.    MEASUREMENT OF EFFECT ...............................................................................34 
10.1    Eligibility ..........................................................................................................34 
10.2    Method of Measurement ...................................................................................35 
10.3    Baseline Measurement of “Target” and “Non-Target Lesions” .......................36 
10.4.   Response Criteria ..............................................................................................37 
10.5.   Reporting of Results .........................................................................................39 
 
11.  REGULATORY AND REPORTING REQUIREMENTS ........................................39 
11.1    Identification, Recording, and Handling Adverse Events ................................39 
11.2    Definitions and Types of Adverse Events ........................................................39 
11.3    Additional Criteria for COH Data and Safety Monitoring  ..............................42 
11.4.   Safety Reporting Requirements and Timelines – City of Hope Process ..........43 
11.5.   Safety Reporting Requirements and Timelines – Participating Sites ...............43 
11.6.   Human Subjects Issues .....................................................................................44 
 
12. STATISTICAL CONSIDERATIONS .........................................................................44 
 
13. REFERENCES ............................................................................................................46 
 
 
INFORMED CONSENT  
APPENDICES 
 
 
APPENDIX I 
 
APPENDIX II 
 
APPENDIX III 
 
APPENDIX IV 
 
APPENDIX V 
 
  
 

  
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1.0. OBJECTIVES 
 
1.1. Primary objective: 
 
1.1.1 To evaluate the tolerability (grade 2-5 toxicity, neuropathy grade 2 
or higher, need for dose reductions, or delays) of weekly nab-
paclitaxel in older adults with locally advanced or metastatic breast 
cancer 
 
1.2. Secondary objectives: 
 
1.2.1. To evaluate the efficacy (response and time to progression) of 
weekly nab-paclitaxel in older adults with locally advanced or 
metastatic breast cancer using a stratification factor based on 
patient age (at least 5 patients age 75 years or older and no more 
than 15 patients age 65-70 years) 
 
1.2.2. To explore predictors of the need for dose reduction, dose delays, 
or grade 2-5 toxicity and neuropathy grade 2 or higher based on a 
cancer-specific geriatric assessment 
 
 
 
2.0. BACKGROUND 
 
2.1. Pharmacology and Aging 
 
Aging brings about a progressive decrease in physiologic reserve that affects each 
individual at a unique pace.1, 2 The age-related physiological decline in organ systems 
typically begins in the 3rd decade of life and is not evident at times of rest but becomes 
most apparent when the body is stressed.3 Either cancer or cancer treatment can be 
considered a physiological stressor, and the age-related decrease in physiologic reserve 
may affect tolerance to cancer treatment.  
 
A number of age-related changes in drug absorption, distribution, metabolism, and 
excretion with aging may contribute to differences in treatment tolerance between older 
and younger patients. The absorption of drugs can be affected by decreased 
gastrointestinal motility, decreased splanchnic blood flow, decreased secretion of 
digestive enzymes, and mucosal atrophy.4, 5 With the increased use of oral therapy, drug 
compliance is an important issue.6 As a person ages, body composition changes, with an 
increase in body fat and decrease in lean body mass and total body water. The increase in 
body fat leads to a rise in the volume of distribution for lipid soluble drugs and a 
diminution in the volume of distribution for hydrophilic drugs. In the cancer population, 
malnutrition and hypoalbuminemia may result in an increased concentration of drugs that 
are albumin-bound.7 
 

  
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Hepatic mass and blood flow decrease with age.1, 8 The impact of the decline in hepatic 
mass and blood flow on hepatic enzyme function is controversial.9-11 In a study of 226 
patients, the cytochrome P450 content in liver biopsy samples decreased by 
approximately 30% in patients over the age of 70.12 Phase 1 metabolism occurs primarily 
via the cytochrome P450 microsomal system and exhibits genetic variability. 13, 14 
 
Over a lifespan, renal mass decreases by approximately 25% to 30%, and renal blood 
flow decreases by 1% per year after age 50.7 The decline in glomerular filtration rate with 
age is estimated at 0.75 ml/minute/year after age 40; however, approximately one third of 
patients have no change in creatinine clearance with age.15 This reduced renal function, 
however, does not usually result in increased serum creatinine levels because of the 
simultaneous loss of muscle mass.16 Therefore, serum creatinine is not an adequate 
indicator of renal function in the older patient. 
 
2.2. Age-Related Changes in the Pharmacokinetics of Taxane Chemotherapy 
 
2.2.1. Paclitaxel 
  
The pharmacokinetics of paclitaxel given at 175 mg/m2 over 3 hours every 3 weeks was 
studied by Lichtman and colleagues on behalf of the Cancer and Leukemia Group B. The 
153 patients who entered the study were divided into 3 cohorts based on age: cohort 1 age 
55-64 (n=51), cohort 2 age 65-74 (n=56), cohort 3 age >75 (n=46), Pharmacokinetic data 
for the first cycle of chemotherapy were available in 122 of the 153 patients. The mean 
area under the curve (AUC) of paclitaxel increased (P = .01), and the mean paclitaxel 
clearance decreased (P = .007) across cohorts of increasing age. Older patients 
experienced an increased incidence of grade >3 neutropenia and lower absolute 
neutrophil count nadir than younger patients; however, this did not translate into an 
increased incidence of hospitalization, fever >38◦C, or receipt of intravenous antibiotics. 
17 
 
The results of pharmacokinetic studies of weekly paclitaxel in older patients have 
conflicted. Fidias and colleagues reported on the efficacy and toxicity of weekly 
paclitaxel (90 mg/m2 over 1 hour) in 35 patients over the age of 70 (median age 76; range 
70 to 85). Among these patients, 13 consented to pharmacokinetic sampling, and 8 
patients had pharmacokinetic sampling performed with the first and 6th cycle.  The 
authors compared the pharmacokinetic parameters from this cohort to values that had 
been reported in younger patients and concluded that the pharmacokinetics did not differ 
by age and the values did not change with repeated weekly dosing.18 Smorenburg and 
colleagues reported on the pharmacokinetics of weekly paclitaxel in 8 patients age 70 and 
older (median age 77; range 70 to 84) and 15 patients less than age 70 (median 54 years, 
range 22 to 69). The younger group received paclitaxel 100 mg/m2 over 1 hour, and the 
older group received 80 mg/m2 over 1 hour. The authors found that the clearance of 
unbound (P = .002) and bound paclitaxel (P = .04) was significantly lower in older 
patients, and that clearance was inversely related to age. There was an approximate 50% 
decrease in the clearance of unbound paclitaxel in older versus younger patients. Despite 
receiving a lower dose of paclitaxel, older patients experienced similar decreases in white 

  
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blood cell and absolute neutrophil count in comparison to younger patients. Possible 
explanations for this finding include the increased exposure to paclitaxel or decreased 
bone marrow reserve in older patients.19 
 
2.2.2. Nab-Paclitaxel 
Nab-paclitaxel is a novel biologically interactive albumin-bound paclitaxel combining a 
protein with a chemotherapeutic agent in the particle form. This composition provides a 
novel approach of increasing intra-tumoral concentration of the drug by a receptor-
mediated transport process allowing transcytosis across the endothelial cell wall, thereby 
breaching the blood/tumor interface. This albumin-specific receptor mediated process 
involves the binding of a specific receptor (gp60) on the endothelial cell wall, resulting in 
activation of a protein caveolin-1, which initiates an opening in the endothelial wall with 
formation of a little caves or caveolae, with transport of the albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor interstitium.25 A 
protein specifically secreted by the tumor (SPARC) binds and entraps the albumin, 
allowing release of the hydrophobic drug to the tumor cell membrane.26 Nab-paclitaxel is 
the first biologically interactive nanoparticle leveraging this gp-60/caveolin-
1/caveolae/SPARC pathway to increase intra-tumoral concentration of the drug and 
reducing toxic drug in normal tissue.  
 
2.2.2.1 Preclinical Studies with Nab-paclitaxel  
 
Preclinical studies comparing nab-paclitaxel to paclitaxel demonstrated lower toxicities, 
with a MTD approximately 50% higher for nab-paclitaxel compared to paclitaxel. At 
equal doses there was less myelosuppression and improved efficacy in a xenograft tumor 
model of human mammary adenocarcinoma. At equitoxic doses of paclitaxel, nab-
paclitaxel was found to be markedly more efficacious than paclitaxel.27  
 
2.2.2.2. Clinical Studies with Nab-paclitaxel  
 
2.2.2.2.1. Every 3 Weeks Schedule  
 
In a phase I study, the maximum tolerated dose (MTD) of nab-paclitaxel was determined 
to be 300 mg/m2 by 30 minute infusion every 3 weeks, without premedication or G-CSF 
support.28 No severe hypersensitivity reactions occurred with nab-paclitaxel despite the 
absence of premedication. Dose-limiting toxicities included sensory neuropathy, 
stomatitis, and superficial keratopathy, which occurred at a dose of 375 mg/m2.  
 
Two multicenter phase II studies have evaluated 2 dose levels of nab-paclitaxel (300 
mg/m2, n=63, and 175 mg/m2, n=43) in patients with metastatic breast cancer.29 The 
overall response rates in these 2 phase II trials were 40% (95% CI 25-54%) for the 175 
mg/m2 dose, and 48% (95% CI 35-60%) for the 300 mg/m2 dose. Of 39 patients 
receiving 300 mg/m2 as first-line therapy for metastatic breast cancer, 64% (95% CI 49-
79%) responded. This was contrasted with a 45% response rate in similar patients at the 

  
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lower dose level. Grade 4 neutropenia was noted in 24% of patients at the higher dose 
level, occurred primarily during the first cycle and resolved rapidly.  
 
A Phase III trial in patients with metastatic breast cancer compared nab-paclitaxel 260 
mg/m2 to paclitaxel 175 mg/m2 given every 3 weeks.30 Efficacy analyses were based on 
the ITT population. The ORR was significantly greater for nab-paclitaxel than for 
paclitaxel for all patients (33% v 19%, respectively; P = 0.001), patients who received 
first-line therapy (42% v 27%, respectively; P = 0.029), patients who received second-
line or greater therapy (27% v 13%, respectively; P = 0.006), and patients who had 
received prior anthracycline therapy in either the adjuvant/metastatic setting (34% v 18%, 
respectively; P = 0.002) or the metastatic setting only (27% v 14%, respectively; P = 
0.010). Tumor response rate was also significantly higher for nab-paclitaxel than for 
paclitaxel in patients with visceral dominant lesions (34% v 19%, respectively; P = 
0.002) and in patients aged younger than 65 years (34% v 19%, respectively; P < 0.001). 
ORR also was greater for nab-paclitaxel compared with standard paclitaxel in patients 
with nonvisceral dominant lesions (34% v 19%, respectively) and in patients ≥ 65 years 
old (27% v 19%, respectively), but the results did not reach statistical significance 
because of the small number of patients in these subsets. 
 
Median TTP was significantly longer with nab-paclitaxel than with paclitaxel for all 
patients (23.0 v 16.9 weeks, respectively; hazard ratio [HR] = 0.75; P = 0.006). There 
was a trend for greater median survival for all patients treated with nab-paclitaxel than 
with paclitaxel (65.0 v 55.7 weeks, respectively; P = 0.374). Although no difference in 
survival was observed in first-line patients, the difference was statistically significant in 
patients who received nab-paclitaxel, compared with paclitaxel, as second-line or greater 
therapy (56.4 v 46.7 weeks, respectively; HR = 0.73; P = .024).30 The incidence of 
hypersensitivity reactions (any grade) was low for both arms (1% for nab-paclitaxel and 
2% for paclitaxel). No severe (grade 3 or 4) treatment-related hypersensitivity reactions 
occurred in any of the patients in the nab-paclitaxel group despite the absence of 
premedication. In contrast, grade 3 hypersensitivity reactions occurred in the paclitaxel 
group despite standard premedication (chest pain, two patients; allergic reaction, three 
patients). Per protocol, corticosteroids and antihistamines were not administered routinely 
to patients in the nab-paclitaxel group; however, premedication was administered for 
emesis, myalgia/arthralgia, or anorexia in 18 patients (8%) in the nab-paclitaxel group in 
2% of the treatment cycles, whereas 224 patients (> 99%) in the paclitaxel group received 
premedication in 95% of the cycles.  
 
Although the patients in the nab-paclitaxel group received an average paclitaxel dose-
intensity 49% greater than that received by patients in the paclitaxel group, the incidence 
of treatment-related grade 4 neutropenia was significantly lower in the nab-paclitaxel 
group than in the paclitaxel group (9% v 22%, respectively; P < 0.001), with a higher 
mean neutrophil nadir (1.67 v 1.31x109/L, respectively; P = 0.046), suggesting that 
polyethylated castor oil may have contributed to this toxicity in patients who received 
standard paclitaxel.  
 

  
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As expected with a higher dose of paclitaxel, treatment-related grade 3 sensory 
neuropathy occurred more frequently in the nab-paclitaxel arm than in the paclitaxel arm 
(10% v 2%, respectively; P < 0.001); however, these episodes improved with interruption 
of treatment to grade 2 or 1 in a median 22 days and were easily managed with treatment 
interruption and dose reduction. By day 28 after its first occurrence, the number of 
patients with persistent grade 3 sensory neuropathy was the same (n = 4) in both study 
arms. No episodes of motor neuropathy or grade 4 sensory neuropathy were reported in 
either group. The only clinical chemistry value that was notably different between the 
two treatment arms was higher serum glucose levels in the paclitaxel–treated patients, 
who also had a higher incidence of hyperglycemia reported as an AE compared with nab-
paclitaxel–treated patients (7% v 1% respectively; P =0.003). Subgroup analyses 
revealed that the safety profiles of nab-paclitaxel and paclitaxel in patients who received 
the drugs as first-line therapy were similar to those in the overall study population. 
 
In subgroup analyses by age, the reported AEs were similar in patients less than 65 years 
old and patients ≥ 65.  In the patients ≥ 65 years old, AEs were notably lower in the nab-
paclitaxel group than in the paclitaxel group: neutropenia (23% v 59%, respectively), 
leukopenia (10% v 31%, respectively), nausea (20% v 38%, respectively), hyperglycemia 
(0% v 19%, respectively), and flushing (0% v 16%, respectively). These data indicate no 
additional safety concerns for nab-paclitaxel in patients ≥ 65 years old compared with 
younger patients. Six patients (3%) in the nab-paclitaxel group and eight patients (4%) in 
the standard paclitaxel group died during the study, all as a result of disease progression. 
No treatment-related deaths occurred in the nab-paclitaxel group; one patient (< 1%) in 
the paclitaxel group died of multiorgan failure, which was considered by the investigator 
to be possibly related to treatment but may also have been a result of sepsis and/or 
progressive disease. Overall, however, the incidence of these adverse effects 
(neutropenia, leukopenia, nausea, hyperglycemia, flushing) were lower in the nab-
paclitaxel vs. standard paclitaxel groups in patients over age 65.   
 
2.2.2.2.2 Weekly for 3 Weeks, Every 4 Weeks Schedule 
  
Thirty-nine patients were enrolled into A Phase I study of nab-paclitaxel administered 
weekly for 3 weeks followed by a 1 week rest in patients with advanced solid tumors.31 
The MTDs for heavily and lightly pre-treated patients were 100 and 150 mg/m2 
respectively. Dose limiting toxicities included grade 4 neutropenia and grade 3 sensory 
neuropathy. Premedication was not required, and unexpected, non-taxane associated 
toxicities were not observed.  
 
In a Phase II trial in heavily pretreated patients with taxane-refractory metastatic breast 
cancer, objective antitumor responses occurred in 15% of women treated with nab-
paclitaxel 100 mg/m2 on this schedule.32 Nab-paclitaxel weekly regimen was well 
tolerated. 91% of patients were treated at the full dose of 100 mg/m2 of nab-paclitaxel 
without dose reductions. Based on the activity and low toxicity documented with the nab-
paclitaxel 100 mg/m2 weekly regimen, this study was expanded to evaluate the efficacy 
and safety/tolerability of a higher dose of nab-paclitaxel 125 mg/m2 weekly regimen in 

  
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75 additional patients. Results of this dose-finding study confirm the dose of nab-
paclitaxel 100 mg/m2 as the appropriate dose for further study in this patient population.33  
 
2.2.2.2.3 Weekly Schedule  
 
The NSABP studied the administration of nab-paclitaxel in a neoadjuvant setting to 
patients with locally advanced breast cancer at a dose of 100 mg/m2 weekly for 12 weeks, 
with no break.34 Four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) 
were administered sequentially based on patients’ HER2 status: HER2 negative patients 
received FEC-100 (F: 500 mg/m2, E: 100 mg/m2, C: 500 mg/m2 Q3 weeks) and HER2 
positive patients received weekly trastuzumab in addition to FEC-75 (F: 500 mg/m2, E: 
75 mg/m2, C: 500 mg/m2 Q3 weeks). Weekly trastuzumab was permitted during nab-
paclitaxel and FEC-75 treatment at the discretion of the investigator. The primary 
objective of the trial was to determine the pathologic complete response rate (pCR) in the 
breast. At the time of initial report at SABCS 2006, 65 patients had been entered on study 
and were evaluable for cCR and safety. Following 12 weeks of nab-paclitaxel, a clinical 
complete response rate (cCR) of 32% was noted. The therapy was well tolerated, with 
48/65 patients receiving 12 doses in 12 weeks and 13/65 receiving 12 doses in 13-14 
weeks. The incidence of peripheral (sensory) neuropathy was low (11% grade 2, 5% 
grade 3) as was neutropenia (3% grade 3 and no grade 4). The authors concluded that the 
administration of nab-paclitaxel 100 mg/m2 weekly x 12 was both effective and 
tolerable.  
 
2.2.2.2.4  Phase II Studies of Nab-Paclitaxel in Metastatic Breast Cancer 
 
Single Agent Therapy 
a. In a phase II trial performed by Ibrahim and colleagues29, 63 patients with 
metastatic breast cancer received 300 mg/m2 of nab-paclitaxel every three weeks.  
The average age of participants in the study was 48.2 years, with a range between 
28-69 years.  The distribution of patients ≥ age 65 is not specified.  The median 
time to disease progression was 26.6 weeks, and median overall survival was 63.6 
weeks.  Overall response rate was 48%.  The main toxicities included grade 3-4 
neutropenia (51%), grade 3-4 leukopenia (24%), grade 3 sensory neuropathy 
(11%), and grade 4 febrile neutropenia (5%).  The age-specific tolerability of 
toxicities in patients ≥ age 65 is not specified. 
 
b. In a phase II trial performed by Blum and colleagues68, 181 patients with 
metastatic breast cancer received 100 mg/m2 or 125 mg/m2 on days 1, 8, and 15 
on a 28-day cycle.  The median age of participants in the study was 53 years, 
range 34-76, at 100 mg/m2 and 53 years, range 33-74, at 125 mg/m2.  The 
percentage of participants ≥65 years was 19% at 100 mg/m2 and 25% at 125 
mg/m2.  Median progression-free survival time was 3 months at 100 mg/m2 and 
3.5 months at 125 mg/m2.  Median survival time was 9.2 months at 100 mg/m2 
and 9.1 months at 125 mg/m2.  Overall response rate was 14% for 100 mg/m2 and 
16% for 125 mg/m2.  The main toxicities at 100 mg/m2 were grade 3-4 
neutropenia (17%), grade 3-4 leukopenia (19%), and grade 3 sensory neuropathy 

  
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(8%).  The main toxicities at 125 mg/m2 were grade 3-4 neutropenia (32%), grade 
3-4 leukopenia (33%), and grade 3 sensory neuropathy (19%).  In patients 
receiving 100 mg/m2, there was a greater incidence of grade 3-4 neutropenia, 
fatigue, and diarrhea in patients ≥ age 65.  In patients receiving 125 mg/m2, there 
was a greater incidence of sensory neuropathy and diarrhea in patients ≥ age 65. 
c. In an open-label, randomized phase II trial performed by Gradishar and 
colleagues71, 302 patients with metastatic breast cancer received 300 mg/m2 nab-
paclitaxel every 3 weeks, 100 mg/m2 nab-paclitaxel weekly, 150 mg/m2 nab-
paclitaxel weekly, or 100 mg/m2 docetaxel every 3 weeks.  The mean age was 
54.0 years, with 17% patients ≥ 65 years.  By independent radiologist review, 
overall response rate was 49% for 150 mg/m2 nab-paclitaxel, 45% for 100 mg/m2 
nab-paclitaxel, 37% for 300 mg/m2 nab-paclitaxel, and 35% for docetaxel.  The 
100 mg/m2 and 150 mg/m2 nab-paclitaxel treatments exhibited a higher overall 
response rate than docetaxel, but this difference did not reach statistical 
significance.  Also by independent radiologist review, progression-free survival 
was 12.9 months for 150 mg/m2 nab-paclitaxel, 12.8 months for 100 mg/m2 nab-
paclitaxel, 11.0 months for 300 mg/m2 nab-paclitaxel, and 7.5 months for 
docetaxel.  The 150 mg/m2 nab-paclitaxel treatment demonstrated statistically and 
clinically significant longer progression-free survival over the docetaxel 
treatment, supported by both the independent radiologist and investigator 
evaluations.  The 100 mg/m2 nab-paclitaxel treatment also showed a significantly 
higher progression-free survival over the docetaxel treatment, but this was not 
confirmed by the investigator assessment.  The main toxicities included grade 3 
neutropenia (39% v. 20% v. 35% v. 19% for 300 mg/m2 nab-paclitaxel, 100 
mg/m2 nab-paclitaxel, 150 mg/m2 nab paclitaxel, and docetaxel, respectively), 
grade 4 neutropenia (5% v. 5% v. 9% v. 75% for 300 mg/m2 nab-paclitaxel, 100 
mg/m2 nab-paclitaxel, 150 mg/m2 nab paclitaxel, and docetaxel, respectively), 
and grade 3 sensory neuropathy (17% v. 8% v. 14% v. 12% for 300 mg/m2 nab-
paclitaxel, 100 mg/m2 nab-paclitaxel, 150 mg/m2 nab paclitaxel, and docetaxel, 
respectively).  The age-specific tolerability of toxicities in patients ≥ age 65 is not 
specified. 
 
Combination Therapy 
a. In a phase II trial performed by Lobo and colleagues66, 30 patients with metastatic 
breast cancer received 150 mg/m2 nab-paclitaxel and 1500 mg/m2 gemcitabine, 
and 10 mg/kg bevacizumab on days 1 and 15 of a 28-day cycle until disease 
progression.  The median age of participants in the study was 53.8 years, with 
range 34-69 years.  The distribution of patients ≥ age 65 is not specified.  Median 
progression-free survival was 10.4 months, and the overall response rate was 
75.9%.  Grade 3 or 4 toxicities potentially related to the study treatment were 
experienced in eight patients; these included port-a-cath infections (6.9%) and 
abscess, fever/sepsis, breast abscess, hematuria, leukopenia, peripheral 
neuropathy, seizure/syncope, shortness of breath, cardiac tamponade, 
thrombocytopenia, and UTI (3.4% each).  The age-specific tolerability of 
toxicities in patients ≥ age 65 is not specified. 
 

  
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b. In a retrospective analysis performed by Link and colleagues67, 33 patients with 
metastatic breast cancer received 80-125 mg/m2 nab-paclitaxel on days 1, 8, and 
15 on a 28-day cycle or 170-200 mg/m2 nab-paclitaxel every 14 days on a 28-day 
cycle.  In addition, 10 mg/kg every 14 days of bevacizumab was given to all 
patients.  The median age of participants in the study was 46 years, range 31-71 
years.  The distribution of patients ≥ age 65 is not specified.  Median time to 
progression for the responders was 128 days (4.2 months).  Overall response rate 
was 48.5%.  The main toxicities included grade 3 neuropathy (1 pt, 2.5%), grade 
3 anemia (2 pts, 5%), and grade 3 pain or bone pain (3 pts, 7.5%).  The age-
specific tolerability of toxicities in patients ≥ age 65 is not specified. 
 
Table 1.  Phase II clinical studies of nab-paclitaxel 
Author 
Regimen 
# of Patients 
Median 
Age 
Efficacy 
Profile 
(Overall 
Response 
Rate, %) 
Toxicity 
Ibrahim et al29 
Nab-paclitaxel 
300 mg/m2 
q3w 
63 
48.2 
48 
Neutropenia g3-4 (51%) 
Leukopenia g3-4 (24%) 
Sensory Neuropathy g3 (11%) 
Febrile Neutropenia g4 (5%) 
Lobo et al66 
Nab paclitaxel 
150 mg/m2 
q2w, 
Gemcitabine 
1500 mg/m2 
q2w, and 
Bevacizumab 
10 mg/kg q2w 
30 
53.8 
75.9 
Neutropenic fever g4 (1 pt) 
PortAcath infection g3 (2 pts) 
Leukopenia g3 (1 pt) 
Thrombocytopenia g3 (1 pt) 
Peripheral neuropathy g3 (1 pt) 
Abscess (1 pt) 
Link et al67 
Nab-paclitaxel 
(varied 
dosing) and 
Bevacizumab 
10mg/kg q2w 
33 
46 
48.5 
Neuropathy g3 (1 pt) 
Anemia g3 (3 pts) 
Pain/Bone Pain g3 (3 pts) 
Blum et al68 
Nab-paclitaxel 
100 mg/m2 
q3/4w 
 
Nab-paclitaxel 
125 mg/m2 
q3/4w 
181 
53 
14 
 
 
 
16 
Neutropenia g3-4 (17%) 
Leukopenia g3-4 (19%) 
Sensory Neuropathy g3 (9%) 
 
Neutropenia g3-4 (32%) 
Leukopenia g3-4 (33%) 
Sensory Neuropathy g3 (19%) 
Gradishar et 
al71 
Nab-paclitaxel 
300 mg/m2 
q3w 
 
Nab-paclitaxel 
100 mg/m2 w 
 
 
Nab-paclitaxel 
150 mg/m2 w 
 
 
76 
 
 
 
76 
 
 
 
74 
 
 
 
51.7 
 
 
 
55.4 
 
 
 
53.3 
 
 
 
46 
 
 
 
63 
 
 
 
74 
 
 
 
Neutropenia g3 (39%) 
Neutropenia g4 (5%) 
Sensory Neuropathy g3 (17%) 
 
Neutropenia g3 (20%) 
Neutropenia g4 (5%) 
Sensory Neuropathy g3 (8%) 
 
Neutropenia g3 (35%) 
Neutropenia g4 (9%) 
Sensory Neuropathy g3 (14%) 
 

  
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Docetaxel 100 
mg/m2 q3w 
74 
55.4 
39 
Neutropenia g3 (19%) 
Neutropenia g4 (75%) 
Sensory Neuropathy g3 (12%) 
 
2.2.2.2.5  Phase III Studies of Nab-Paclitaxel in Metastatic Breast Cancer 
 
In a phase III trial performed by Gradishar and colleagues30, 454 patients with metastatic 
breast cancer received 260 mg/m2 nab-paclitaxel or 175 mg/m2 standard paclitaxel every 
three weeks.  The average age of participants in the study was 53.2 years, range 26-83 
years.  13% of participants receiving nab-paclitaxel and 14% of participants receiving 
standard paclitaxel were ≥ 65 years old.  Median time to progression was 23.0 weeks 
with nab-paclitaxel and 16.9 weeks with standard paclitaxel.  Overall response rate was 
33% with nab-paclitaxel and 19% with standard paclitaxel.  Reported adverse events 
were similar in patients less than 65 years old and patients ≥ 65 years old in both groups.  
Among all patients, the incidence of grade 3 sensory neuropathy was 10% in the nab-
paclitaxel group v. 2% in the standard paclitaxel group, and incidence of grade 4 
neutropenia was 9% in the nab-paclitaxel group v. 22% in the standard paclitaxel group, 
despite the higher dose of nab-paclitaxel administered.  Among patients ≥ age 65, the 
main adverse events in the nab-paclitaxel versus standard paclitaxel groups included: 
neutropenia (23% v. 59%, respectively), leucopenia (10% v. 31%, respectively), nausea 
(20% v. 38%, respectively), hyperglycemia (0% v. 19%, respectively), and flushing (0% 
v. 16%, respectively). 
 
This phase III trial was used by Celgene Corporation to gain FDA approval for the drug.  
Based on this study, the ABRAXANE package insert states, “Geriatric use: Of the 229 
patients in the randomized study who received ABRAXANE, 11% were at least 65 years 
of age and <2% were 75 years or older.  No toxicities occurred notably more frequently 
among elderly patients who received ABRAXANE.” 
 
Table 2.  Phase III studies of nab-paclitaxel 
Author 
Regimen 
# of Patients 
Median 
Age 
Efficacy 
Profile 
(Overall 
Response 
Rate, %) 
Toxicity 
Gradishar et 
al30 
Nab-paclitaxel 
260 mg/m2 
q3w 
 
 
 
 
Standard 
paclitaxel 175 
mg/m2 q3w 
229 
 
 
 
 
 
 
225 
53.1 
 
 
 
 
 
 
53.3 
33 
 
 
 
 
 
 
19 
Sensory Neuropathy g3 (10%) 
Neutropenia g4 (9%) 
\ 
 
Sensory Neuropathy g3 (2%) 
Neutropenia g4 (22%) 
 
 
Examining these six major phase II studies and one major phase III study with nab-
paclitaxel, the number of patients ≥ age 65 is not specified in three of the six studies.  In 
the three studies where age breakdown was specified, the patients ≥ age 65 were a 

  
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minority, constituting 22% in the phase II study by Blum et al, 17% in the phase II study 
by Gradishar et al, and 14% in the phase III study by Gradishar et al.  With low 
representation of the geriatric population in the studies, there exists a knowledge gap of 
the toxicity and efficacy of nab-paclitaxel specifically in patients ≥ age 65.  This study 
addresses this issue in its objectives to evaluate tolerability, efficacy, and predictors of 
the need for dose reduction, dose delays, or grade 3-5 toxicity and sensory neuropathy 
grade 2 and higher for patients ≥ age 65 receiving nab-paclitaxel as treatment for locally 
advanced or metastatic breast cancer. 
 
2.2.2.2.6  Potential Risks of nab-Paclitaxel  
Toxicities  
Myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, hypotension, 
abnormal ECG changes, cough, dyspnea, edema, sensory neuropathy, bilirubin/liver 
enzyme elevations, pneumonitis, allergic reactions, alopecia, asthenia, arthralgia, and 
myalgia. During post marketing surveillance, rare cases of severe hypersensitivity 
reactions have occurred. The frequency of important treatment related adverse events are 
detailed in Table #3 below: 
 

  
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Table 3: Frequencya of Important Treatment Emergent Adverse Events in the 
Randomized Study on an Every-3-Weeks Schedule 
  
Percent of Patients  
Adverse Event 
Nab-
Paclitaxel  
260/30minb  
(n=229)  
Paclitaxel  
Injection  
175/3hc,d  
(n=225)  
Bone Marrow  
Neutropenia  
< 2.0 x 109/L  
< 0.5 x 109/L  
 
80 
9  
 
82  
22  
Thrombocytopenia  
< 100 x 109/L  
< 50 x 109/L  
 
2  
<1  
 
3  
<1  
Anemia  
< 11 g/dL  
< 8 g/dL  
 
33  
1  
 
25  
<1  
Infections  
Febrile Neutropenia  
Bleeding  
24  
20  
2  
1  
2  
2  
Hypersensitivity Reactione  
All  
Severef 
4  
12  
0  
2  
Cardiovascular  
Vital Sign Changesg 
Bradycardia  
Hypotension  
Severe Cardiovascular Eventsf 
<1  
<1  
5  
5  
3  
4  
Abnormal ECG  
All patients  
Patients with Normal Baseline  
60  
52  
35  
30  
Respiratory  
Cough  
Dyspnea  
7  
6  
12  
9  
Sensory Neuropathy  
Any Symptoms  
Severe Symptomsf 
71  
56  
10  
2  
Myalgia / Arthralgia  
Any Symptoms  
Severe Symptomsf 
44  
49  
8  
4  

 
 
  
 
 
 
18
Table 3 (continued): Frequencya of Important Treatment Emergent Adverse Events in the Randomized 
Study on an Every-3-Weeks Schedule 
Percent of Patients  
Adverse Event 
Nab-
Paclitaxel  
260/30minb  
(n=229)  
Paclitaxel  
Injection  
175/3hc,d  
(n=225)  
Asthenia  
Any Symptoms  
Severe Symptomsf  
47  
39  
8  
3  
Fluid Retention/Edema  
Any Symptoms  
Severe Symptomsf  
10  
8  
0  
<1  
Gastrointestinal  
Nausea  
Any symptoms  
Severe symptomsf  
30  
22  
3  
<1  
Vomiting  
Any symptoms  
18  
10  
Severe Symptomsf  
4  
1  
Diarrhea  
Any Symptoms  
Severe Symptomsf  
27  
15  
<1  
1  
Mucositis  
Any Symptoms  
Severe Symptomsf 
7  
6  
<1  
0  
Alopecia  
90  
94  
Hepatic (Patients with Normal Baseline)  
Bilirubin Elevations  
Alkaline Phosphatase Elevations  
AST (SGOT) Elevations  
Injection Site Reaction  
7  
7  
36  
31  
39  
32  
<1  
1  
 
a Based on worst grade  
b nab-Paclitaxel dose in mg/m2/duration in minutes  
c paclitaxel injection dose in mg/m2/duration in hours  
d paclitaxel injection pts received premedication  
e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) 
that began on a day of dosing.  
f Severe events are defined as at least grade 3 toxicity  
g During study drug dosing.  
 
 
 

 
 
  
 
 
 
19
2.3 COH IRB 07157: Age-related changes in the pharmacokinetics (pK), response, and toxicity of weekly 
nab-paclitaxel in patients with metastatic breast cancer 
 
The goals of this study were 1) to evaluate the age-related changes in the pharmacokinetics and 
pharmacodynamics of weekly nab-paclitaxel in patients with metastatic breast cancer; 2) to determine response 
rate; and 3) to explore the relationship of age with pK and pD parameters (i.e., dose reductions, dose delays and 
grade > 3 toxicities). Forty patients with MBC, receiving 1st or 2nd line chemotherapy, entered an IRB approved 
protocol to evaluate the age-related changes in the pK of weekly nab-paclitaxel administered at 100 mg/m2 IV 
for 3 weeks followed by a 1-week break. Patients were accrued from 4 age strata <50, 50-60, 60-70, and >70 
years of age. Blood samples were collected for pK analysis with the first dose of nab-paclitaxel. Response was 
assessed every 2 cycles. Toxicity was graded using the NCI Common Toxicity Criteria for Adverse Events (v 
3.0) and was adjudicated as attributable to nab-paclitaxel if it was possibly, probably, or definitely related. 
Linear regression analysis was used to examine the strength of the relationship between patient age and natural 
logarithm of 24 hour area under the curve (AUC). Two-sided two-sample t-tests were used to assess if there was 
a difference in mean age based on the presence of pD variables (i.e., dose reductions, dose delays and grade > 3 
toxicities). The significance level was set to 0.05. 
 
Of the 40 patients who entered the study, 39 (98%) were evaluable with a mean age of 60 (SD=13.4; min=30; 
max=81). Patients were accrued in the following age cohorts: <50 (n= 10; 26%), 50-60 (n= 5; 13%), 60-70 (n= 
15; 38%), and >70 (n= 9; 23%) years of age. The median number of courses completed was 4 (min=1, 
max=21). The response rate was: 0% (n=0) CR, 31% (n=12) PR, 38% (n=15) SD. Grade 3 toxicity was 
experienced by 26% (n=10). We observed 8% (n=3) grade 3 hematological toxicities [neutrophils (n=1; 3%), 
leukocytes (n=2; 5%)] and 18% (n=7) grade 3 non-hematological toxicities [nausea and hypophosphatemia 
(n=1; 3%), diarrhea and infection without neutropenia (n=1; 3%), fatigue (n=2; 5%), hyponatremia (n=1; 3%), 
and infections without neutropenia (n=2; 5%)]. There were no cases of grade 4 or 5 toxicity. Grade 2 sensory 
neuropathy was experienced by 8% (n=3; no cases in the 70+ age cohort). Dose reductions or course delays 
were experienced by 62% (n=24) and 21% (n=8), respectively. There was a borderline significant positive 
association between age and natural logarithm of total nab-paclitaxel 24 hour AUC (coef=.01; se=.006; 
p=0.055; n=36). There were no differences in the mean ages based on the presence of grade 3 or higher toxicity 
(p =0.75), need for dose reductions (p=0.48), or need for dose delays (p=0.61). 
 
In summary, this study demonstrated that here is a borderline statistically significant relationship between age 
and 24 hour AUC but no differences in mean age based on pD variables (i.e., dose reductions, dose delays and 
grade > 3 toxicities) were identified.  The treatment was well-tolerated across all age groups.  
 
2.4 Rationale and Goals of this Study 
 
The goal of this study is to build upon the prior study (which accrued patients of all ages) by specifically 
focusing on the older adults with breast cancer. Older adults have been under-represented on therapeutic clinical 
trials. This study will help to address this knowledge gap by evaluating the tolerability (grade 2-5 toxicity, 
sensory neuropathy grade 2 and higher, need for dose reductions, or delays) of weekly nab-paclitaxel in older 
adults with metastatic breast cancer. The rationale for exploring tolerability of weekly nab-paclitaxel is based 
on the observation that physiological changes with aging can affect drug disposition and tolerability to 
chemotherapy treatment.  Nab-paclitaxel is a particularly attractive drug for an older patient population.  The 
therapy is efficacious and in contrast with paclitaxel, no pre-medications are required with nab-paclitaxel.30  In 

 
 
  
 
 
 
20
addition, previous studies have shown a favorable toxicity profile.30  This study will help further our knowledge 
regarding the tolerability and efficacy of nab-paclitaxel in older patients. 
 
2.5 Evaluating Factors Other Than Chronological Age Which May Affect Treatment Tolerance: The 
Role of Geriatric Assessment  
 
Aging is a heterogeneous process. While certain declines in organ function are universal as the human body 
ages, the rate of this decline and the consequences of this decline on everyday function proceeds at a unique 
pace in each individual. Therefore, chronologic age tells us relatively little about the specific individual. A more 
detailed evaluation of an older adult patient is needed in order to capture factors other than chronological age 
that predict for morbidity and mortality. A comprehensive geriatric assessment may serve this purpose. The 
comprehensive geriatric assessment includes an evaluation of functional status, comorbid medical conditions, 
cognitive function, nutritional status, social support and psychological state, and a review of medications. 
Conclusions from several studies are emerging regarding the benefits of performing a comprehensive geriatric 
assessment for older patients with cancer: 
 
(1) Factors evaluated in a comprehensive geriatric assessment predicts survival; 37 
(2) Factors evaluated in a comprehensive geriatric assessment predicts toxicity to chemotherapy; 38 
(3) A comprehensive geriatric assessment uncovers problems not detected by routine history and physical in 
initial consultation and in follow-up care; 39-41 
(4) Patients undergoing a comprehensive geriatric assessment and intervention based on the results had 
improved pain control; 42 
(5) A comprehensive geriatric assessment and intervention improves an older patient’s mental health and 
well-being. 42 
 
Consensus guidelines recognize these benefits and recommend the inclusion of a geriatric assessment as part of 
the evaluation of an older patient. 43, 44 In this study we will capture this information in patients of age 65 or 
greater. 
 
 
3.0. 
PATIENT SELECTION 
 
3.1. 
 
Inclusion Criteria  
 
3.1.1 Locally advanced or metastatic breast cancer 
 
3.1.2 Any ER, PR, or Her2neu status as long as the patient will receive nab-paclitaxel alone 
 
3.1.3 First or second line chemotherapy treatment for metastatic disease 
 
3.1.4 Age >65 years.   
 
3.1.5 KPS >70% 
 
3.1.6 Resolution of grade > 2 toxicity from prior therapy (other than alopecia) 
 

 
 
  
 
 
 
21
3.1.7 Peripheral neuropathy < grade 1 
 
3.1.8 Hematologic inclusion: 
 
 absolute neutrophil count 
 
>1,500/mm3 
 platelets  
 
 
 
 
 
>100,000cells/mm3 
 Hb   
 
 
 
 
 
 
> 9.0g/dl 
 
 
 
 
3.1.9 Hepatic and renal inclusion: 
- 
AST and ALT  
 
< 2.5 x institutional upper limit of  
normal 
- 
alkaline phosphatase    
< 2.5 x upper limit of normal unless 
bone metatasis are present in the absence of liver 
metastases 
- 
bilirubin  
 
 
< 1.5mg/dl 
 
- 
creatinine clearance  
> 30ml/min 
(calculated or 24 hour) 
 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients may not be receiving any other investigational agents. 
 
3.2.2. Untreated CNS metastases or symptomatic CNS metastases requiring escalating doses of 
corticosteroids 
 
3.2.3 Known history of allergic reactions to paclitaxel 
 
3.2.4 Presence of any serious or uncontrolled infection 
 
3.2.5 Receipt of a taxane for adjuvant therapy or metastatic disease in the last 12 months 
 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial; however, we anticipate 
that the majority of patients will be female based on the demographics of breast cancer 
 
 
 
4.0. RECRUITMENT AND REGISTRATION PROCEDURES 

 
 
  
 
 
 
22
 
4.1. Subject Identification and Recruitment:  
 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator (at the participating site), or research team (at the participating site).  Potential subjects will be 
contacted by their treating physician and will be referred to the investigator/research staff of the study. 
 
The principal investigator (at the participating site) may also screen the medical records of patients with whom 
they do not have a treatment relationship for the limited purpose of identifying patients who would be eligible to 
enroll in the study and to record appropriate contact information in order to approach these patients regarding 
the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff (at the participating site) and the patient; 
the patient may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process.  The investigator/research staff (at the participating site) may also review portions of their 
medical records in order to further assess eligibility.  They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment.  If the patient turns out to be ineligible for the research study, the research staff will destroy all 
information collected on the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screening log purposes.   
 
The initial contact with the prospective subject will be conducted either by the treatment team, investigator or 
the research staff working in consultation with the treatment team at the participating site.  The recruitment 
process outlined presents no more than minimal risk to the privacy of the patients who are screened and 
minimal PHI will be maintained as part of a screening log.  For these reasons, we seek a (partial) limited waiver 
of authorization for the purposes of (1) reviewing medical records to identify potential research subjects and 
obtain information relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential subjects; and (4) 
maintaining information in a screening log of patients approached (if applicable). 
 
Eligible patients will be given the opportunity to participate in the study. The goals of the study will be 
described and the patient will be given a copy of the informed consent to review. The interested patient will sign 
the consent form and retain a copy.  
 
4.2. Registration Processes 
 
  
The following person(s) at City of Hope may obtain informed consent: Arti Hurria, M.D., George Somlo, M.D., 
FACP, Joanne Mortimer, M.D., Joseph Chao, M.D., Warren Chow, M.D., Yuan Yuan, M.D., and Stephen 
Koehler, M.D. 
 
Confirm in the electronic medical record that the patient has received the Notice of Privacy Practice. This must 
be obtained before the eligibility confirmation and obtaining of the research informed consent. 
 
 
 
4.2.1 Registration Process (City of Hope patients) 

 
 
  
 
 
 
23
 
 
Registrations for this protocol must be made through the CTO office at the City of Hope 
between the hours of 8:30 a.m. to 4:30 p.m., Monday through Friday (except holidays). 
 
Patients must be registered within 2 weeks prior to initiation of protocol therapy. 
 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact (626) 256-4673 ext. 62468 and ask for the CRA in 
charge of this study. 
 
Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to the study calendar. 
 
Patients must sign an informed consent prior to registration. 
 
Confirm that the patient meets all inclusion and exclusion eligibility criteria for the 
protocol. 
 
Complete the Eligibility Checklist.  
 
Verify that all required pre-study tests were performed. 
 
Fax the completed Eligibility Checklist and the signed, dated informed consent to CTO.  
The FAX number is (626) 301-8393.  
 
Call CRA at (626) 256-4673 x 62468 to confirm the FAX arrival. If the Coordinator is not 
in the office, have her paged. 
 
If the patient qualifies, the City of Hope Coordinator will assign the patient's study ID 
number.   
 
Once a patient has been registered, CRA will confirm registration of the patient.  
 
The outside institution patient registration process will be handled by the Department of Clinical Research 
Information Support (CRIS) Data Coordinating Center (DCC) at City of Hope.  Documentation of current IRB 
approval must be on file with the DCC prior to registration of patients on this study for participating institutions.  
  
The steps below are to be taken when registering a patient at a participating institution: 
 
4.2.2    Registration Process (Participating Institutions) 
The participating institution’s research staff must assure they have the most current and updated 
version of the protocol and informed consent prior to enrolling a patient.  If a question arises, 
please contact the Data Coordinating Center at 626-256-4673 extension 63968 or via pager at 626-
423-6486. 
The participating institution must assure that all pre-study laboratory tests, scans and x-rays have 
been completed prior to registration according to the study calendar. 
The participating institution must assure that the patient has signed an approved informed consent 
prior to registration, including Experimental Subject Bill of Rights (if applicable) and appropriate 
HIPAA authorization.   
The participating institution must confirm that the patient meets all inclusion and exclusion 
eligibility criteria for a protocol.  The eligibility checklist must be completed in its entirety.     
A patient failing to meet all protocol requirements may not be registered.  Patients must be 
registered within 2 weeks prior to initiation of protocol therapy. 
Once a patient is eligible, all the pre-study requirements have been fulfilled, and 
the informed consent obtained, the research nurse or the data manager (study 
coordinator) at the participating center will inform the Data Coordinating Center (626-

 
 
  
 
 
 
24
256-4673, ext 63968; pager 626-423-6486) and FAX (fax number 626-301-8422) a copy of 
the signed informed consent, patients’ Bill of Rights, signed HIPPA consent, 
completed eligibility checklist and corresponding source documentation confirming 
eligibility (including pathology reports, lab reports, x-ray reports, etc.). 
 
4.2.3 The Data Coordinating Center will: 
 
 
Review all materials received to ensure the patient is eligible. 
 
Ensure the consent form is valid and is signed correctly by all parties.  If additional 
information is needed or should there be any questions, the Data Coordinating Center will 
immediately contact the participating institution and registration will not occur until all 
issues are resolved.  No exceptions will be granted. 
 
The patient will be registered centrally at City of Hope. 
 
Confirmation of Registration will be emailed/faxed to the participating institution noting 
study number as well as assigning the dose (if applicable) within 24 hours via fax or 
email.   
 
The Data Coordinating Center will call the research nurse or data manager (study 
coordinator) at the participating site and verbally confirm registration. 
 
 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.  The Data Coordinating Center should be 
notified of cancellations as soon as possible. 
 
4.3. Procedures for On-Study and Treatment Deviations   
 
Any amendments to the study protocol need to be approved by the IRBs at both the study sponsor site as well as 
at all participating centers. All deviations or single subject exceptions to the study protocol must be reported to 
the primary IRB of the participating site, and to Dr. Arti Hurria, the study PI at the sponsoring institution. 
 
 
5.0. TREATMENT PLAN 
 
5.1.Guidelines for Nab-Paclitaxel Administration  
 
Nab-paclitaxel (ABI-007, nab-paclitaxel, albumin-bound paclitaxel) is a Cremophor EL-free, albumin-bound 
form of paclitaxel with a mean particle size of approximately 130 nanometers. Each 50-mL single-use vial 
contains 100 mg of paclitaxel, and approximately 900 mg of human albumin. Nab-paclitaxel is supplied as a 
white to off-white sterile lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection 
USP.  
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters during the 
administration of nab-paclitaxel. In any event, filters of pore-size less than 15 micrometers must not be 
used.  
 

 
 
  
 
 
 
25
5.1.1 Nab-paclitaxel Premedication  
 
Patients do not require premedication prior to nab-paclitaxel administration, as hypersensitivity reactions are 
rare. In the unlikely event of a mild hypersensitivity reaction, premedication may be administered using the 
premedication regimen the institution typically uses for solvent based paclitaxel. In the rare event of a severe 
hypersensitivity reaction, discontinue nab-paclitaxel.  
 
5.1.2. Treatment Plan 
 
Nab-paclitaxel 100mg/m2 will be administered on a 3 week on +/- 1 day from indicated dates, 1 week off 
schedule. Treatment will be administered on an outpatient basis.  Comprehensive adverse events and potential 
risks for nab-paclitaxel are described in Section 2.2.2.2.6.  Appropriate dose modifications for nab-paclitaxel 
are described in Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy.  
 
5.2. Duration of Therapy 
 
Protocol therapy will continue until one of the following criteria applies: 
 
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse events 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient’s condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
 
Restaging will be performed after every two cycles. All patients who enter the trial will undergo a 
comprehensive assessment consisting of an evaluation of the individual’s functional status, comorbid medical 
conditions, cognition, nutritional status, psychological state, and social support. The assessment will be repeated 
at the end of 2 cycles of therapy and upon completion of therapy. Data regarding grade 2, 3 or 4 toxicity, dose 
delays, and dose reductions will be recorded.  
 
All staff involved in the study will have adequate procedural training regarding the identification, 
documentation, and reporting adverse events as described in this protocol.  The principal investigator will be 
responsible for ensuring that adequate training is performed and documented for study staff members. 
 
 
6.0. DOSING DELAYS/DOSE MODIFICATIONS 
6.1. Administration of Study Drug to Patients with Abnormal Hematologic Function  
Nab-paclitaxel dosing should not be administered at the start of each cycle until absolute neutrophil count is >1,500/mm3, 
platelets are  >100,000cells/mm3, and Hb is > 9.0g/dl. If the ANC is below threshold, GCSF can be given per physician 
discretion and GCSF must be administered with subsequent cycles. Treatment will be held until ANC >1500/mm3. In the 
event that day 1 is held, the day 8 criteria for treatment must be: ANC >1,500/mm3, platelets >100,000cells/mm3, and Hb 
> 9.0g/dl. If days 1 and day 8 are held, the day 15 criteria for treatment must be: ANC >1,500/mm3, platelets 
>100,000cells/mm3, and Hb > 9.0g/dl.  
 

 
 
  
 
 
 
26
For patients receiving weekly nab-paclitaxel, for each subsequent dose of nab-paclitaxel within a cycle (Days 8 and 15), 
patients must have an absolute neutrophil count >1,000/mm3, platelets >100,000cells/mm3, and Hb > 9.0g/dl. If the counts 
are not adequate for treatment on Day 8 and/or 15, the dose will be omitted and the total cycle length remains the same. 
Upon a grade 2 ANC (<1500  to 1000/mm3) on day 8 or day 15 of treatment, treatment will be administered and GCSF 
support will be initiated. Treatment will be held for a grade 3 ANC (<1000 to 500/mm3) and GCSF support would be 
initiated and continued on all subsequent cycles, support following the day 15 dose may be held based on physician 
discretion. Patients who experience hemoglobin below 9.0 g/dl may receive a blood transfusion to stimulate counts.  
Normal treatment may be given if counts are then documented as adequate and the patient falls in the +/-1 day window 
but will remain on the original treatment schedule.  
6.2. Administration of Study Drug to Patients with Abnormal Hepatic Function  
Study drug should only be administered if hepatic function is within the parameters established in the eligibility 
criteria. Hepatic toxicity from taxanes may occur but it is uncommon. Therefore, hepatic dysfunction that 
occurs while the patient is on study should prompt an evaluation to determine the cause, including the 
possibility of progressive metastatic disease and hepatotoxicity from concurrent medications.  
6.3. Dose Modification  
Dose Level  
Nab-Paclitaxel Dose 
0  
 
100 
-1  
 
80  
-2  
 
60  
Patients who require dose modifications will be allowed to continue on study for 2 dose modifications (down to 
dose level -2). If the patient experiences any further toxicity necessitating a dose reduction beyond dose level -
2, they will be removed from the study protocol.   
 
6.4. Dose Reductions and Guidelines for Use of Growth Factors for Hematologic Toxicity  
 
The table below provides a guideline for implementing dose reductions and optional use of growth factor 
treatment for hematologic toxicity:  
 
 

 
 
  
 
 
 
27
 
Table 4:Use of G-CSF and Dose Holds for Hematologic Toxicity  
 
Day 1* 
 
If counts are… 
Action to be Taken 
ANC 
<1500 mm3       
Hold treatment and initiate GCSF for subsequent doses 
(GCSF can be initiated following the dose hold per MD 
discretion)       
Platelets 
< 100,000cells/mm3 
Hold treatment       
Hemoglobin 
< 9.0g/dl. 
Hold treatment. Patient may receive a blood transfusion. 
Treatment may be given if counts are then documented as 
adequate and the patient is +/- 1 day from the original 
treatment date.              
Day 8 and 15 
ANC 
<1000 mm3       
Hold treatment and initiate GCSF  
 
<1500 to 1000/mm3 
Treatment is given and GCSF support is initiated for this 
cycle and all subsequent cycles 
Platelets 
< 100,000cells/mm3 
Hold treatment       
Hemoglobin 
< 9.0g/dl. 
Hold treatment. Patient may receive a blood transfusion. 
Treatment may be given if counts are then documented as 
adequate and the patient is +/- 1 day from the original 
treatment date.              
* These criteria will be applied for day 8 if the day 1 dose is omitted and applies for day 15 if days 1 and 8 doses are 
omitted.  
Note: Once GCSF support is initiated, it must be continued on all subsequent doses. Support following day 15 may be 
held based on physician discretion.  
 
 
*See NCI Toxicity Criteria 4.0 Scale for definition of Grade 3 and Grade 4 events. 
** Treatments skipped due to toxicity will be omitted and total cycle length remains the same.     
 
6.4.1. G-CSF Administration  
 
For weekly study drug administration administer G-CSF 5 mcg/kg/day (rounded to the nearest vial size per 
investigator/institution’s standard of care).  The number of days of G-CSF is up to the discretion of the treating 
MD; however, the patient must start at least 24 hours after the dose of chemotherapy and be held at least 48 
hours prior to the next dose.  The dose of the G-CSF can be adjusted based on the investigator’s discretion. The 
delivery of G-CSF following week #3 of any cycle is per investigator discretion (since the patient will have a 2 
week break prior to the next dose). At the first occurrence of a hematological toxicity (as outlined above), the 
same dose is maintained and G-CSF is given as outlined below. In the event that a hematological toxicity re-
occurs in the face of G-CSF, dose reduction to the next lower level will be required for subsequent cycles once 
ANC is ≥ 1500 cells/mm3.  
 
 
 
6.4.2. Sensory Neuropathy  
 

 
 
  
 
 
 
28
Nab-paclitaxel should be withheld in patients who experience ≥ Grade 2 sensory neuropathy. Treatment may be 
resumed at the next lower dose level (see Section 6.3) in subsequent cycles after the sensory neuropathy 
improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 should be the adverse event duration used for 
adverse event reporting. In those patients who experience Grade 4 sensory neuropathy, study drug should be 
withheld, and treatment resumed at a reduction of 2 dose levels (Dose Level -2; see Table 2) in subsequent 
cycles after the sensory neuropathy improves to ≤ Grade 1. 
 
 
6.4.3. Hypersensitivity Reactions  
 
Hypersensitivity reactions rarely occur. If they do occur, minor symptoms such as flushing, skin reactions, 
dyspnea, lower back pain, hypotension, or tachycardia may require temporary interruption of the infusion. 
However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema or generalized urticaria require immediate discontinuation of study drug administration and 
aggressive symptomatic therapy. Patients who experience a severe hypersensitivity reactions to nab-paclitaxel 
should not be re-challenged.  
 
6.4.4. Other Toxicities  
 
If toxicities are ≥ grade 3, except for anemia, any pre-existing comorbidities, or toxicities deemed unrelated to 
cancer or cancer treatment (such as hypertension, hyperglycemia, decreased lymphocyte count, non-cancer 
related pain, fracture or orthopedic surgery), treatment should be withheld until resolution to ≤ grade 1 or 
baseline if baseline was greater than grade 1, then reinstituted, if medically appropriate, at the next lower dose 
level (see Section 6.3).  Patients who present with grade 1-2 toxicities may have their treatment held at the 
discretion of the treating physician. Patients may also have their dose reduced to the next lower level based on 
grade 1-2 toxicities at the discretion of the treating physician. Treatments skipped due to toxicity will be omitted 
and total cycle length remains the same.     
 
6.4.5. Concomitant Medications  
 
Supportive care, including but not limited to anti-emetic medications, may be administered at the discretion of 
the Investigator. Concurrent treatment with bisphosphonates is allowed. Erythropoietin and G-CSF may be 
administered at the discretion of the investigator, consistent with institutional guidelines.  
 
 
7.0. PHARMACEUTICAL INFORMATION 
 
7.1. Availability / Distribution 
 
Nab-paclitaxel will be supplied by Celgene Corporation, in single-use vials. Each single-use 50 mL vial will 
contain paclitaxel (100 mg) and approximately 900 mg human albumin (HA) as a stabilizer. Each vial will be 
labeled according to country-specific regulatory requirements for labeling of investigational products.  
 
Investigational sites will be supplied with nab-paclitaxel upon identification and screening of a potential trial 
subject.  No supplies will be shipped until regulatory approval has been obtained.  Upon identification of a 
potential subject, sites must fax a completed Drug Request Form to Celgene Corporation.  Allow at least 5 

 
 
  
 
 
 
29
working days for drug shipment.  There are no shipments on Fridays or holidays.  For re-supply of drug, 
complete and fax the Drug Request Form to Celgene Corporation at 908-673-2779. 
 
7.2. Storage and Stability  
 
Unreconstituted nab-paclitaxel should be stored at controlled room temperature (20° to 25°C or 68° to 77°F) in 
its carton. Retain in the original package to protect from bright light. Unopened vials of albumin-bound 
paclitaxel are stable until the date indicated on the package when stored at the above temperatures in the 
original package. Reconstituted albumin-bound paclitaxel should be used immediately, but may be refrigerated 
at 2°C to 8°C (38°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of 
reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any 
unused portion.  Also, the suspension for infusion (reconstituted as recommended) is stable in an IV bag at 
room temperature 20°C to 25°C (68-77°F) and ambient lighting conditions for up to 8 hours if necessary. 
 
7.3. Study Medication Administration  
 
Albumin-bound paclitaxel should be administered by IV over 30 minutes. NOTE: It is not a requirement to 
use filter needles in the preparation of, or in-line filters during the administration of nab-paclitaxel. In 
any event, filters of pore-size less than 15 micrometers must not be used.  
 
7.3.1. Reconstitution and use of Nab-paclitaxel  
 
1. Calculate the patient’s body surface area at the beginning of the study and if the weight changes by > 10%.  If 
the patient’s weight changes by >10%, a new body surface area will be calculated and used to determine Total 
Dose for subsequent chemotherapy administrations. 
 
2. Calculate the total dose (in mg) to be administered by:  
 
Total Dose (mg) = BSA x (study dose mg/m2)  
 
3. Calculate the total number of vials required by:  
 
Total Number of Vials = Total Dose (mg)  
100 (mg/vial)  
 
Round up the number of vials to be reconstituted to the next higher whole number when a fractional number of 
vials is obtained by the above formula (eg, if the total number of vials = 4.05 or 4.5, then 5 vials would be 
reconstituted).  
 
4. Using sterile technique, prepare the vials for reconstitution.  
 
5. Swab the rubber stoppers with alcohol.  
 
6. Reconstitute each nab-paclitaxel vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP or 
equivalent into each vial over a period of not less than 1 minute.  
 

 
 
  
 
 
 
30
• Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using 
the sterile syringe directing the solution flow onto the inside wall of the vial.  
 
• DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the lyophilized 
cake as this will result in foaming.  
 
• Once the injection is complete, allow the vial to sit for a minimum of 5 (five) minutes to ensure 
proper wetting of the lyophilized cake/powder.  
 
• Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any 
cake/powder occurs. Rapid agitation or shaking will result in foaming.  
 
• If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.  
 
• Each ml of reconstituted product will contain 5 mg of paclitaxel.  
 
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient:  
 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml)  
 
8. The reconstituted sample should be milky and homogeneous without visible particulates. If unsuspended 
powder is visible, the vial should be gently inverted again to ensure complete resuspension, prior to use.  
 
9. Once the exact volume of reconstituted nab-paclitaxel has been withdrawn from the vials, discard any excess 
solution left over in accordance with standard operating procedures.  
 
10. Further dilution is not necessary. Inject the calculated dosing volume of reconstituted nab-paclitaxel 
suspension into an empty sterile, standard PVC IV bag using an injection port. Inject perpendicularly into the 
center of the injection port to avoid dislodging plastic material into the IV bag.  
 
11. Administer the calculated dosing volume of reconstituted nab-paclitaxel suspension by IV infusion over 30 
minutes. The use of in-line filters is not necessary. If used, in-line filters with pore sizes of < 15μ should not be 
used.  
 
12. Use within 8 hours of reconstitution. If not used immediately, store reconstituted nab-paclitaxel in a 
refrigerator for no longer than 8 hours.  
 
 
8.0. QUESTIONNAIRES 
 
Appendix I and II describe the data which will be captured as a part of this study. Appendix I is data gathered 
by the research interviewer. Appendix II is the “Self-Assessment Measure” is completed by the patient. If the 
patient requires assistance, a member of the healthcare or research team will assist them. Appendix I and II will 
be completed at three time points (+/- 2 weeks):  
 
1) prior to initiation of cycle #1  

 
 
  
 
 
 
31
2) prior to the 3rd cycle  
3) end of the study  
 
8.1. Data to be gathered by the research interviewer (Appendix I): 
 
1) Medical Characteristics: 
a) Cancer diagnosis* 
b) Disease stage* 
c) Chemotherapy regimen* 
d) Labs: Hemoglobin, Creatinine, LFTs, albumin 
2) Functional Status:  
a) Physician rated KPS (to be obtained from the primary MD) 
b) Timed Up and Go 
3) Cognition: Blessed Orientation-Memory-Concentration* 
4) Nutrition 
a) Body Mass Index 
b) Percent Unintentional Weight Loss* 
 
*Time point #1 only 
 
8.2. Data to be completed by study participants: (Appendix II: Geriatric Assessment Measures) 
 
1) Demographics (Age, Marital status, Educational Status, Household composition, Employment status, Race, 
Ethnicity) 
2) Functional Status:  
a) Older American Resources and Services (OARS): Instrumental Activities of Daily Living (IADL) 
b) Medical Outcomes Study (MOS): Physical Functioning 
c) Karnofsky Performance Status (KPS): Patient Rated 
d) Number of falls in last 6 months 
3) Comorbidity: OARS Physical Health Sub-scale 
4) Psychological status: Mental Health Inventory - 17 
5) Social functioning and support:  
a) MOS Social Activity Limitation: 
b) Medical Outcomes Study (MOS) Social Support Subscale 
6) Nutritional Status:  
a) Amount of involuntarily weight loss over the past 6 months 
b) Baseline weight 
7) Questions Concerning the Geriatric Assessment 
 
8.3. Data to be collected at each clinic visit while on treatment: 
The following information will be collected at each clinic visit  
1) Grade 2, 3 or 4 toxicity 
2) Hospitalization 
3) Dose delay or reduction 
4) Discontinuation of chemotherapy course because of toxicity 
 

 
 
  
 
 
 
32
8.4. Description of Questionnaire Measures 
 
8.4.1. Functional Status 
 
a) Activities of Daily Living: [subscale of Medical Outcomes Study (MOS) Physical Health]  
The MOS Physical Health Scale contains measures of higher levels of physical functioning than those described 
in other activities of daily living scales. The variation in functioning among healthier patients in the study will 
be examined through asking about higher order functioning. The scale includes items on vigorous activities 
(running, lifting heavy items) as well as basic activities (bathing and dressing). Items are rated on a three-point 
Likert scale of independent performance of the activity.  The sum of the scores is divided by the total number of 
items responded to in that scale. The scale score is then transformed into a 0-100 score. Internal consistency of 
the physical function score is high at 0.92.45 
 
b) Instrumental Activities of Daily Living (IADL): [subscale of the Older American Resources and Services 
(OARS)] 
The OARS Multidimensional Functional Assessment Questionnaire (MFAQ) was developed to provide a 
profile of the level of functioning and need for services of older persons who live at home but may have some 
degree of impairment. The MFAQ has been tested on over 6,000 older community residents.46 The Instrumental 
Activities of Daily Living (IADL) subscale consists of 7 questions rated on a three-point Likert scale of degree 
to which the activity can be performed independently. Norms are available for the MFAQ based on 2,146 
elderly community residents.47 
 
c) Karnofsky Physician-Rated Performance Rating Scale (KPS) 
The Karnofsky Performance Status, has been widely used in the evaluation of cancer patients.48 It is a general 
measure of patient independence in carrying out normal activities. Patients are given a score on a numerical 
scale of 0-100 as a global indicator of functional status. Studies on inter-rater reliability between nurse and 
social worker KPS ratings indicate good correlation (r = 0.69, p<.001). KPS was most strongly correlated with 
variables related to physical functioning (difficulty with stairs: r = 0.63; difficulty with balance: r = 0.61).49 
 
d) Karnofsky Self-Reported Performance Rating Scale 
A patient self-report version of the Karnofsky Performance Scale was developed by several researchers to 
assess the patient’s perception of performance status.50 The Wingard version is chosen for this study because it 
is significantly related to survival. Items range from severely disabled, requiring continuous nursing care, to 
normal activities requiring no assistance.51 
 
e) Timed Up & Go 
The timed “up and go” is a test of physical mobility. The test, measured in seconds, is the time it takes for an 
individual to stand up from a standard arm-chair (approximate seat height of 46 cm), walk a distance of 3 
meters (10 feet), turn, walk back to the chair, and sit down again. Intra-rater and inter-rater reliability was 
extremely high (intra-class correlation 0.99). Performance on the timed “up and go” test significantly correlated 
with scores of other performance measures including Berg Balance Scale (r = -0.81), gait speed (r = -0.61), and 
Barthel Index of ADL (r = -0.78).52 
 
f) Number of Falls in Last 6 Months 
Older patients are at risk for falls and injury secondary to falls because of gait and balance impairments. In 
patients with cancer the risk is even greater for a number of reasons. First, bony metastases may place them at 

 
 
  
 
 
 
33
risk of a pathologic fracture with falls. Secondly, patients receiving chemotherapy may have a low platelet 
count which puts them at greater risk of hemorrhage. Lastly, commonly used chemotherapy drugs may have 
neurologic complications resulting in falls. For example, paclitaxel and cisplatin may cause neuropathy, 
fluorouracil and cytarabine may cause cerebellar toxicity. For these reasons, knowing a patient’s risk of falling 
before treatment could help providers make treatment decisions.53 
 
 
 
 
 
8.4.2. Comorbidity 
 
Physical Health Section [subscale of The Older American Resources and Services Questionnaire (OARS)]: 
The OARS Physical Health Section is a comorbidity scale which contains a list of concurrent illnesses and the 
degree to which they impair daily activities, rated on a three-point scale of “not at all” to “a great deal.” 
Medication use is recorded. Test-retest reliability was excellent (r = .66) over a five-week period. In terms of 
validity, the Physical Health subscale correlated significantly with health professional ratings (Kendall's tau co-
efficient =.75).46 
 
8.4.3. Cognition 
 
Blessed Orientation-Memory-Concentration Test 
The BOMC consists of 6 questions designed to screen for gross cognitive impairment. A score >11 signifies 
cognitive impairment. The test-retest reliability is high (Spearman Rank Correlation 0.96; p < 0.001).54 The 
BOMC has excellent validity as a screening instrument, correlates highly with clinicians' ratings of dementia 
severity (r=0.89), predicts results from a longer (26 item) mental status questionnaire, and discriminates 
between patients with mild, moderate, and severe cognitive deficits.55 
 
8.4.4. Psychological 
 
Mental Health Inventory - 17 
The Mental Health Inventory (MHI) (Revised General Well-Being Scale) is based upon the General Well-Being 
Scale, developed by Dupuy for the National Health Interview Survey, and was included in a battery of health 
measures in the Rand Health Insurance Study.64  The full length MHI consists of 38 items grouped into five 
subscales (anxiety, depression, general positive effect, emotional ties, and loss of behavior control) and three 
global scores (Psychological Distress – negative effect, Psychological Well-Being – positive effect, and the 
MHI total score).  The MHI-17, a 17 item version of the full 38 item MHI, will be used in this study to measure 
psychological health, in order to reduce respondent burden,  The MHI-17 will yield three global scores of 
Psychological Distress, Psychological Well-Being, and MHI total score, as in the original 38 item MHI.61 Each 
score is on a scale of 0-100: a higher Psychological Distress score indicates higher distress, a higher 
Psychological Well-Being score indicates greater well-being, and a higher MHI score indicates greater mental 
health.   The MHI has demonstrated an excellent external consistency (alpha coefficient = .96).61 
 
8.4.5. Social Functioning 
 
Medical Outcomes Study (MOS) Social Activity Limitations Measure 

 
 
  
 
 
 
34
The impact of cancer on patients’ social functioning will be assessed by the Social Activity Limitations scale 
from the Medical Outcome Study (MOS).61 As with all MOS measures, the Social Activity Limitations scale 
was developed from a national sample of medically ill patients being treated in outpatient facilities. The four-
item scale assesses the extent to which physical or emotional problems have interfered with social activities. All 
items are rated on a 5-point Likert scale, with response categories varying with each item. The mean of the total 
score is transformed to a scale of 0-100, with a higher number indicating greater support. Internal consistency 
was good (alpha coefficient = .77). The scale correlates significantly with a range of measures: role limitations 
due to physical (r= .52) and emotional (r = .49) health, psychological distress (r= .64) and pain (r = .55).  
 
8.4.6. Social Support 
 
Medical Outcomes Study (MOS) Social Support Survey: Emotional/Information and Tangible Subscales 
This is a 20-item measure of social support, with four subscales: emotional/informational, tangible, affectionate, 
and positive social interactions. The scale was developed as part of the Medical Outcome Study, tested on 2987 
patients, and designed to assess quality of life across medical conditions. In this study, we use the Tangible 
(access to material aid or behavioral assistance) and Emotional/Information (the expression of positive affect 
and empathetic understanding; the offering of advice, information, guidance, or feedback) subscales. All but 
one item is rated on a five-point Likert scale from “None of the Time” to “All of the Time.” Internal 
consistency of the subscales and total score are excellent (alpha coefficient > 0.91). Convergent validity was 
demonstrated by significant correlations of social support total score with measures of mental health (r =.45).61 
 
8.4.7. Nutrition  
 
a) % Unintentional Weight Loss 
Patients will be asked to quantify the amount of unintentional weight loss in the past 6 months and to record 
their baseline body weight 6 months ago. 
 
The following is the calculation for % unintentional weight loss:  
   
unintentional weight lost in last six months 
% unintentional weight loss  =  100 x  
 
 
baseline body weight 
 
b) Body Mass Index 
Weight and height will be measured in order to calculate body mass index, by the following formula: 
 
   
 
Weight in kg 
BMI   = 
 
 
 
 
 
 
 
 
Height in m2 
 
 
 
 
 
 
 
 

 
 
  
 
 
 
35
 
 
 
 
 
 
 
 
9.0. STUDY CALENDAR 
 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
*CMP = comprehensive biochemical screening profile (which includes electrolytes, BUN, creatinine, AST, 
ALT, total bilirubin, total protein, albumin, alkaline phosphatase, and glucose) 
**CEA, CA15-3 baseline tumor marker evaluations are to be conducted within 2 weeks of administration of 
protocol therapy  
***+/- 2 weeks 
† For baseline evaluations, if a PET-CT was done within the 4 week window prior to start of therapy, the study team will 
review with the study radiologist to see if the CT portion is sufficient to measure baseline target lesions. With the study 
radiologist’s confirmation, the PET-CT will then be utilized for the baseline radiologic evaluation.  
 
Baseline evaluations are to be conducted within 2 weeks prior to administration of protocol therapy.  Scans and 
x-rays must be done within 4 weeks prior to the start of therapy.  Tests indicated for the following weeks may 
be performed within ± two days of the indicated dates. Cycles consist of three weeks of therapy +/- 1 day from 
indicated dates followed by a one week break. 
 
 
10.0 MEASUREMENT OF EFFECT 
 
 
 
Parameter 
Pre-
study 
Prior to 
the 1st 
dose of 
each cycle 
Prior to 
the 2st 
dose of 
each cycle 
Prior to 
the 3rd 
dose of 
each cycle 
Prior to 
the 3rd 
cycle 
After 
every 
2 
cycles  
Study 
Termi-
nation 
MD Visit 
X 
X 
 
X 
 
 
 
Physical examination 
X 
X 
 
X 
 
 
 
Vital signs 
X 
X 
 
X 
 
 
 
CBC, ANC, platelet 
count 
X 
X 
X 
 
X 
 
 
 
CMP* 
X 
X 
 
X 
 
 
 
CEA, CA15-3** 
 
X 
 
 
 
 
 
CT Chest, Abdomen, 
Pelvis 
X† 
 
 
 
 
X 
 
Comprehensive 
Geriatric 
Assessment*** 
X 
 
 
 
X 
 
X 

 
 
  
 
 
 
36
In this protocol, assessment of response and TTP will be a secondary objective. We will use RECIST criteria to 
assess response; however, due to limited resources, confirmatory scans will not be performed. RECIST criteria 
are described below. 
 
10.1 Eligibility 
 
 
Only patients with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  
 
Key criteria for assessing tumor burden is taken verbatim from RECIST.  For full reference, see the 
Revised RECIST guideline by Eisenhauer et al. 
 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
Measurable lesions - lesions that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam 
 20 mm by chest X-ray 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.  
Lesions considered truly non-measurable include: blastic bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, and also abdominal masses/abdominal organomegaly that are identified by physical 
exam but are not measurable by reproducible imaging techniques. 
 
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. A PET-CT may be used for the baseline evaluation 
if done within the specified window and the study radiologist confirms that the CT portion of the PET-
CT is adequate for baseline tumor measurements.  
 
 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up.  
 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes). For the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
10.2. Methods of Measurement  
 
 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected 
for response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 

 
 
  
 
 
 
37
algorithm.  This applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
 
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should not be 
used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by clinical examination. 
 
 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a high level of 
expertise that may only be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in specialized centers. However, 
such techniques can be useful in confirming complete pathological response when biopsies are obtained. 
 
 
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response when all lesions 
have disappeared. 
 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor types 
such as germ cell tumors). 
 
 
 
10.3. Baseline documentation of “Target” and “Non-Target” lesions 
 
 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded at baseline (this means in instances where patients have 
only one or two organ sites involved a maximum of two and four lesions respectively will be recorded)..  
 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  
 
 
Pathological nodes which are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  ≥15mm by CT scan.  Only the short axis of these nodes will contribute to 
the baseline sum. 
 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used 

 
 
  
 
 
 
38
as reference to further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form. 
 
10.4. Response Criteria 
Evaluation of target lesions 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference the 
baseline sum LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level 
* Incomplete Response/         
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker 
level above the normal limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be confirmed later on by the review panel (or study chair). 
10.4.1. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment will depend on the achievement of both measurement 
and confirmation criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 

 
 
  
 
 
 
39
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
10.4.2. Confirmation 
 
 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met. 
Longer intervals as determined by the study protocol may also be appropriate.  
 
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol  
 
10.4.3. Duration of overall response 
 
 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever status is recorded first) until the first date that recurrence or PD is objectively documented, 
taking as reference for PD the smallest measurements recorded since the treatment started. 
 
10.4.4. Duration of stable disease 
 
 
SD is measured from the start of the treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started.  
 
 
The clinical relevance of the duration of SD varies for different tumor types and grades. Therefore, it is 
highly recommended that the protocol specify the minimal time interval required between two 

 
 
  
 
 
 
40
measurements for determination of SD. This time interval should take into account the expected clinical 
benefit that such a status may bring to the population under study.  
 
10.4.5. Response review 
 
 
For trials where the response rate is the primary endpoint it is strongly recommended that all responses 
be reviewed by an expert(s) independent of the study at the study’s completion.  Simultaneous review of 
the patients’ files and radiological images is the best approach.  
 
10.5. Reporting of results 
 
 
All patients included in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
 
 
All of the patients who met the eligibility criteria should be included in the main analysis of the response 
rate.  Patients in response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in exclusion 
from the analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
 
 
All conclusions should be based on all eligible patients. 
 
 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses may not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.   
 
 
The 95% confidence intervals should be provided. 
 
 
11.0 REGULATORY AND REPORTING REQUIREMENTS 
 
11.1 Identification, Recording, and Handling Adverse Events 
 
All staff involved in the study will have adequate procedural training regarding the identification, 
documentation, and reporting adverse events as described in this protocol.  The principal investigator will be 
responsible for ensuring that adequate training is performed and documented for study staff members. 
 
11.2 Definitions and Types of Adverse Events 
 
11.2.1 Adverse Event (AE) 
 

 
 
  
 
 
 
41
An adverse event is defined as the development of an untoward medical occurrence, undesirable medical 
condition, recurrence or deterioration of a pre-existing medical condition subsequent to exposure of a 
pharmaceutical product or treatment.  An adverse event is additionally defined as occurring at any dose, 
independent of perceived causal relationship to the product.  Adverse events may or may not be formal medical 
diagnoses, and can also include signs, symptoms or abnormal laboratory findings.  Common examples include 
nausea, chest pain, tachycardia, enlarged liver, or electrocardiogram abnormalities.  
 
11.2.2 Causality  
 
The definition of an adverse event is independent to a perceived causal relationship to the drug.  Causality is a 
separate assessment that is performed for AEs.  Causality assessment to a study drug or regimen will be a 
medical judgment based made in consideration of the following factors: temporal relationship of the AE to 
study drug exposure, known mechanism of action or side effect profile of study treatment, other recent or 
concomitant drug exposures, normal clinical course of the disease under investigation, and any other underlying 
or concurrent medical conditions.  
 
11.2.3. Adverse Events Grading and Data Collection 
 
Adverse events will be graded according to the CTCAE v4.0.  Any CTCAEgrade 2-5 will be considered an AE 
an collected on the CRFs.  
 
11.3.    Additional Criteria for COH Data and Safety Monitoring 
 
A) 
Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures for Data and Safety 
Monitoring for In-House Trials at City of Hope”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx 
because it is a Phase II/ Pharmacokinetics clinical trial where the risks are at least balanced by the potential 
benefit to subjects and the importance of the knowledge that may result. 
 
B) 
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, CRA, protocol nurse, 
and statistician is responsible for monitoring the data and safety of this study, including implementation of any 
stopping rules for safety and efficacy.  
 
Data and safety will be reported to the COH DSMB.  Protocol specific data collection will include the following 
items: dose reductions, dose delays and grade 2, 3 & 4 toxicities.  Reporting of data and safety to the DSMB 
will occur at intervals of 6 months using the PMT report. 
 
C) 
Definitions Adverse event (AE) - An adverse event is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or not it is considered to 
be related to the protocol intervention.  
 
Attribution - For reporting purposes, attribution is the assessment of the likelihood that an AE is 
caused by the research agent or protocol intervention.  The attribution is assigned by the Principal 

 
 
  
 
 
 
42
Investigator after considering the clinical information, the medical history of the subject, and past 
experience with the research agent/intervention.  The attribution is subject to change as follow-up 
information becomes available, and it can be changed by the DSMC or by the IRB during the process 
of review. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor 
of the research participant experiencing the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected adverse 
event that results in any of the following outcomes: 
 Death 
 Is life-threatening event (places the subject at immediate risk of death from the event as it 
occurred); 
 Requires in-patient hospitalization (not required as part of the treatment) or prolongation of 
existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect 
 Secondary Malignancy, or 
 Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasisas of convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all three of the 
following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research procedures 
described in the protocol-related documents such as the IRB approved research protocol, informed 
consent document or Investigator Brochure (IB); and b) the characteristics of the subject 
population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not listed in 
the investigator’s brochure and/or package insert; is not listed at the specificity or severity that has 
been observed; is not consistent with the risk information described in the protocol and/or consent; is 
not an expected natural progression of any underlying disease, disorder, condition, or predisposed risk 
factor of the research participant experiencing the adverse event. 
 
D. Reporting of Unanticipated Problems and Adverse Events 
 

 
 
  
 
 
 
43
Unanticipated Problems: Unanticipated problems must be reported to the COH DSMC and IRB 
within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs during the 
study conduct will be reported to the DSMC and IRB by submitting electronically in iRIS 
(http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the physician, 
nurse, or reported by the patient, will be reported according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 5 below.  Those SAEs that require 
expedited reporting will be submitted electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not meet the 
criteria of serious adverse event or are not unanticipated problems will be reported only at the time of 
protocol continuation reports (see Table 5 below). 
 
 
 
Table 5:  City of Hope Adverse Event Reporting Timelines for the IRB and DSMC 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 

 
 
  
 
 
 
44
Required Reporting Timeframe to DSMC  
Attribution 
UNEXPECTED 
EXPECTED 
 
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar  days 
No reporting required* 
Unlikely, Unrelated 
No reporting required* 
No reporting required* 
 
Grades 3 and 4 AND meeting the definition of 
“serious” 
Possibly, Probably, 
Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
5 calendar days 
5 calendar days 
 
Grade 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
*Such events are not required to be reported to the DSMC.  These events should be included with the 
SAE/AE summary provided in the IRB Annual Continuation reports. 
 
 
 
 
11.4. Safety Reporting Requirements and Timelines – City of Hope Process 
 
The Sponsor-Investigator will utilize the FDA MedWatch program for the reporting of adverse events and 
follow up information to those events.  Full information regarding these procedures is described on the FDA 
website. (http://www.fda.gov/medwatch/). 
 
The Sponsor-Investigator will also utilize the Celgene SAE Completion Form for the reporting of adverse 
events and follow up information to those events.  
 
All serious adverse events regardless of severity or relationship must be reported to Celgene Corporation within 
24 hours of the investigational staff’s knowledge.   
 
Celgene Corporation 
Drug Safety Department 
86 Morris Avenue 
Summit, NJ  07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 

 
 
  
 
 
 
45
 
and 
 
Industry Contact: 
Norma Powers 
Director, Medical Operations 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
Mobile: 267-337-2720 
Fax: 908-673-2779 
Email: npowers@celgene.com 
 
11.5 Safety Reporting Requirements and Timelines – Participating Sites 
The guideline is to provide a procedure for accurate and timely reporting of serious adverse events (SAEs) from 
the participating institution to the Principal Investigator (PI) at City of Hope (COH).  The participating 
institution, participating PI and/or study coordinators are responsible for reporting all serious adverse events 
immediately (within 24 hours after learning of the event) to their local IRB, the PI at City of Hope, and the Data 
Coordinating Center at COH. 
The participating investigator must report each serious adverse event, regardless of attribution, to the Principal 
Investigator within 24 hours of learning of the occurrence. In the event that the participating investigator does 
not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event.    
Report to City of Hope all serious adverse events by telephone (to Dr. Hurria and the DCC) and send via fax a 
copy of the following forms: 
 Participating sites internal serious adverse event form. 
 FDA MedWatch Form 3500A 
  Notification of Toxicity Form (Appendix IV) 
SAE Notification Contact Numbers: 
 
 
 
Dr. Arti Hurria 
 
Phone: 626-471-9200  
Fax: 626-301-8233  
 
Data Coordinating Center 
Phone:  626-256-4673x63968 Fax:  626-301-8422 

 
 
  
 
 
 
46
The participating institution will notify their local IRB as per their local established guidelines, and include a 
copy of the completed FDA MedWatch Form 3500A. 
The Data Coordinating Center at City of Hope will send a copy of the participating institutions serious adverse 
event (reported via FDA MedWatch Form) to the following internal departments: 
 City of Hope IRB 
 Celgene Corporation.   
Any supporting documentation to the reports (i.e., laboratory, pathology, progress notes, discharge summary, 
autopsy, etc.) explaining the adverse event should also be submitted to the Data Coordinating Center at City of 
Hope.  The Data Coordinating Center will then submit to our COH IRB as well as submit to Celgene in a timely 
manner. 
 
 
Drug Return and Destruction 
 
If the investigational site does not have a policy, procedure or SOP detailing the process to follow for study 
drug destruction, the study drug must then be returned to Celgene using the Drug Return Form provided in the 
package containing the study drug.  The following information must be recorded on the site’s pharmacy drug 
accountability log: quantity of vials to be returned, expiration date and lot number.  A copy of the Drug Return 
Form and the study drug should be returned to Celgene Clinical Supplies Dept. using the mailing address on the 
packaging slip that came with the original study drug order.  A copy of the Drug Return Form should be 
retained at the clinical site.  In the event of study completion or termination, a copy of all pharmacy records 
(drug dispensing log, drug accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations. 
 
If the investigational site has a policy, procedure or SOP detailing the process to follow for study drug 
destruction, the pharmacist or designee can choose to destroy the study drug on site.  The following information 
must be recorded on the site’s pharmacy drug accountability log: quantity of vials destroyed, expiration date 
and lot number.  The pharmacist must document that the study drug was destroyed in accordance with their 
institution’s drug destruction policy or SOP.  A drug destruction memo and the site’s drug destruction 
SOP/policy should be sent to Celgene Medical Operations Dept.  A copy of the drug destruction memo should 
be retained at the clinical site.  In the event of study completion or termination, a copy of all pharmacy records 
(drug dispensing log, drug accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations. 
 
In addition, the Sponsor-Investigator will adhere to the safety reporting requirements and timelines described in 
the Clinical Trial Agreement with Celgene Corporation.  
   
The Sponsor-Investigator will provide full and timely cooperation with any requests from Celgene, governing 
IRB, institution, or regulatory agency with any requests regarding reports of individual reports of adverse 
events. 
 
 
11.6. Human Subjects Issues 

 
 
  
 
 
 
47
 
11.6.1. Informed Consent Process 
 
Ethical standards for human subjects will be strictly followed. The purpose of the study will be thoroughly 
explained to potential subjects. It will be emphasized that participation is totally voluntary. Patients may choose 
to withdraw at any time without adverse consequence to medical care. Patients will be informed of the research 
nature of this project and that while their participation may enable improvements in patient care, there is no 
guarantee of personal benefit. Procedures for assuring confidentiality will be discussed. Informed consent will 
be contingent upon patient’s full awareness and affirmation of these ethical standards. Once all questions have 
been addressed, informed consent will be obtained. A consent document will be signed and maintained in their 
medical record.  
 
11.6.2. Alternatives 
 
Participation in this study is voluntary. Participants may choose to participate or decline. There are no adverse 
consequences to not participating. 
 
11.6.3. Confidentiality and Storage of Records 
 
The original data collection forms will be submitted into Medidata Electronic Data Collection (EDC).  Data will 
be stored in encrypted, password protected, secure computers that meet all HIPAA requirements.  When results 
of this study are reported in medical journals or at meetings, identification of those taking part will not be 
disclosed.  Medical records of subjects will be securely maintained in the strictest confidence, according to 
current legal requirements.  They will be made available for review, as required by the FDA, HHS, or other 
authorized users such as the NCI, under the guidelines established by the Federal Privacy Act and rules for the 
protection of human subjects 
 
The study protocol will strictly adhere to all HIPAA and COH IRB regulations. Confidentiality of the subjects 
will be maintained. No data will be linked to a particular name or personal identifiers. The individual results 
will not be disclosed. The de-identified dataset will be provided to the investigators for analysis. The composite 
results will be analyzed and summarized for presentation and publication.  
 
11.6.4. Financial Compensation and Obligation to be Incurred by the Research Subject 
 
There will be no financial compensation for participating in this study. 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
The study will be an open label, single arm, phase IIA toxicity study to describe the toxicity profile of nab-
paclitaxel in patients age 65 and older with locally advanced or metastatic breast cancer who are receiving first 
or second line treatment. We plan to study 40 subjects, using a stratification factor based on patient age (at least 
5 patients age 75 years or older and no more than 15 patients age 65-70 years) 
 
There will be one interim analysis after 20 subjects have completed one cycle of drug. 
 

 
 
  
 
 
 
48
12.1 Primary Objective 
 
12.1.1. To evaluate the tolerability (grade 2-5 toxicity, neuropathy grade 2 or higher, dose reductions, 
delays, or interruptions) of weekly nab-paclitaxel in older adults with locally advanced or metastatic 
breast cancer 
 
12.2 Secondary Objectives: 
 
12.2.1. To evaluate the efficacy (response and time to progression) of weekly nab-paclitaxel in older 
adults with locally advanced or metastatic breast cancer. 
 
12.2.2.  To explore predictors of the need for dose reduction, dose delays, or grade 2-5 toxicity and 
neuropathy grade 2 or higher based on a cancer-specific geriatric assessment. 
 
 
Sample Size Justification: Given a sample size of 40 subjects the widest half-width of the 95% confidence 
limits for the rate of grade 2 or higher neuropathy and grade 2 or higher other toxicities will be less than or 
equal to 0.16. For example if we saw a toxicity rate of 0.2 (8 subjects/40) the 95% lower and upper confidence 
limits would be .09 and .36, respectively.   
 
Interim Analysis:  After approximately 20 subjects have completed one full cycle, the study team will review 
the data and assess if the dose being studied is too high, that is requiring too many patients, in the opinion of the 
team, to experience a dose reduction.  If so, a reduction of the dose will be considered, otherwise the study will 
continue to completion at the planned dose. 
 
Analysis: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for 
1) grade 2 or higher neuropathy and grade 2 or higher other toxicities, and 2) dose reductions, delays, and 
interruptions, 3) objective response rate (CR+PR) and 4) clinical benefit rate (CR+PR+SD) as determined by 
RECIST. Progression free survival will be estimated using the product limit method of Kaplan and Meier. 
 
Tables will be created to summarize the toxicities and side effects by course, organ and severity for all 
patients.  We will describe all toxicities on a patient by patient basis.  Numbers of cycles received and dose 
reductions will be tabulated. Descriptive statistics will be provided for study patient demographics, including 
tumor characteristics. General linear models and graphical methods will be used to explore factors as identified 
by a cancer-specific geriatric assessment that may be predictive of toxicity/dose reduction or dose delays. 

 
 
  
 
 
 
49
13.0. REFERENCES 
 
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Di Costanzo F, Gasperoni S, Rotella V, Di Costanzo F.  Targeted delivery of albumin bound 
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Gradisher WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P.  
Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as 
first-line therapy for metastatic breast cancer.  J Clin Oncol 2009; 27(22): 3611-9. 

 
 
  
 
 
 
53
  
 
 
APPENDIX I and II: 
Geriatric Assessment Survey 
 
Please contact the Principal Investigator (Dr. Arti Hurria) or listed Protocol Personnel to obtain a copy of the 
Geriatric Assessment Survey. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
  
 
 
 
5 4  
A P P E N DI X III:  Eli gi bilit y C hec klist  
 
Effic ac y a n d T oler a bilit y of N a n o p article Al b u mi n B o u n d ( n a b) P aclit a xel i n P atie nts 6 5 
a n d Ol der wit h Met ast atic Bre ast C a ncer 
 
Eli gi bilit y C hec klist * 
 
Q uesti o n  
Yes  
N o  
 
 
D oes t his patie nt ha ve  l o call y a d va n ce d or met astatic 
breast c a ncer?  
 
 
 
 
 
1)  Will t he patie nt be recei vi n g na b -p aclita x el as a si n gle 
a ge nt?  
 
 
 
 
 
 
2)  Is t his first or sec o n d li ne c he m ot hera p y treat me nt f or 
metastatic disease?  
3)   
 
 
 
 
4)   
5)  Is t he p atie nt a ge > 6 5 years?   
 
 
 
 
6)   
7)  Is t he p atie nt’s K P S > 7 0 %?  
 
K P S %:  
 
 
 
Has t he patie nt ha d r es ol uti o n of gra de >  2 t o xicit y fr o m 
pri or t hera p y ( ot her t ha n al o pecia)?  
 
 
 
 
 
 
D oes t he patie nt ha v e peri p heral ne ur o p at h y <  gra de 1?  
 
 
 
 
 
 
D oes t he patie nt ha v e t he a bilit y t o u n dersta n d a n d t he 
willi n g ness t o si g n a writte n i nf or me d c o nse nt d o c u me nt?  
 
 
 
 
 
 

 
 
  
 
 
 
5 5  
Eli gi bilit y C hec klist * 
 
Q uesti o n  
Yes  
N o  
 
Is t he a bs ol ute ne utr o p hil c o u nt > 1, 5 0 0/ m m 3?  
 
 
 
 
 
A N C:  
Date:  
Is t he pl atelet c o u nt > 1 0 0, 0 0 0cells/ m m 3? 
 
 
 
 
Plt c o u nt:  
Date:  
 
Is t he H b >  9. 0 g/ dl?  
 
 
 
 
H b:  
 
Date:  
 
Is t he A S T a n d A L T <  2. 5 x i nstit uti o nal u p per li mit of 
n or mal?  
 
 
 
 
A L T:  
 
A S T:  
Date:  
Is t he al kali ne p h os p hatase <  2. 5 x u p per li mit of n or mal 
( u nless b o ne metatas es are prese nt i n t he a bse nt of li ver 
metastases)?  
 
 
 
 
Al k p h os:  
Date:  
Is t he bilir u bi n <  1. 5 m g/ dl?  
 
 
 
 
Bilir u bi n:  
 
Date:  
 
 

 
 
  
 
 
 
5 6  
Q uesti o n  
Yes  
N o  
 
 
Is t he creati ni ne cle ara n ce >  3 0 ml/ mi n?   
( 2 4 h o ur c ollecti o n or C o c kcr oft-Ga ult E q uati o n *)  
 
Please attac h a s heet wit h y o ur calc ulati o ns.  
 
 
 
Creati ni ne 
Cleara nce:  
 
 
Date:  
 
 
 
Will t he patie nt be recei vi n g a n y ot her i n vesti gati o nal 
a ge nts?  
 
 
 
 
 
 
 
 
D oes t he patie nt ha v e u ntreate d C N S metastas es or 
s y m pt o matic C N S metastases re q uiri n g escalati n g d oses 
of c ortic oster oi ds?  
 
 
 
 
 
 
 
 
D oes t he patie nt ha v e a k n o w n hist or y of aller gic reacti o n 
t o paclita x el? 
 
 
 
 
 
 
 
D oes t he patie nt ha v e t he prese nce of a n y s eri o us or 
u nc o ntr olle d i nfecti o n?  
 
 
 
 
 
 
 
 
 
Di d t he patie nt recei ve a ta x a ne f or a dj u va nt t hera p y or 
metastatic disease i n t he l ast 1 2 m o nt hs?  
 
 
 
 
 
 
 
 
* S h a de d b oxes m ust b e c h ecke d/ m arke d f or p atie nt t o be eli gi ble  
* C oc kcr oft- Ga ult e q uati o n:  
Creati ne cleara nce ( ml/ mi n) = ([ { 1 4 0 – a ge i n years } x b o d y wei g ht i n k g]/ { 7 2 x Cr i n m g/ dl }) x 0. 8 5 (fe male ge n der)  
Si g n at ures: 
 
C o nse nti n g M D: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _     
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
Pr ot oc ol R N: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ 

 
 
  
 
 
 
57
APPENDIX  IV 
Data Coordinating Center 
Department of Clinical Research Information Support 
City of Hope 
 
NOTIFICATION OF TOXICITY 
THIS FORM ALONG WITH A COPY OF LOCAL IRB REPORT and MEDWATCH 3500A FORM MUST 
BE FAX'D (626-301-8422) TO THE DATA COORDINATING CENTER WITHIN 24 HOURS OF 
KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT 
 
COH IRB #11139 
INSTITUTIONAL IRB # ___________ 
Efficacy and Tolerability of Nanoparticle Albumin Bound Paclitaxel (Abraxane) in Patients 65 
and Older with Locally Advanced or Metastatic Breast Cancer 
 
Participating/Treating Institution:  _________________________________________________________ 
Reporter:  ______________________________________ Phone #:________________________________ 
Email:   ________________________________ 
 
PATIENT INFORMATION 
Patient Name________________________________________ 
Pt Study ID:  _____________________ 
 
SERIOUS ADVERSE EVENT INFORMATION 
 
Serious Adverse Event:  _______________________________ 
 
Start Date of SAE: ____/____/____  
 
REPORTING INFORMATION 
Has the event been reported to the following? 
Via Phone/Fax to Dr. Arti Hurria? 
 
 
__ No    __ Yes  
  Date: __ __ / __ __  / __ __ 
 
Phone:  626-471-9200/Fax:  626-301-8233 
Institutional IRB?  
 
 
 
 
__ No    __ Yes  
  Date: __ __ / __ __  / __ __ 
Report sent to Data Coordinating Center (COH)? 
__ No    __ Yes  
  Date: __ __ / __ __  / __ __ 
Fax:  626-301-8422 
 
 
 
 
 
 
 

 
 
  
 
 
 
58
APPENDIX V:  Multicenter Guidelines 
 
 
 
Responsibility of the Protocol Chair  
 
The Protocol Chair will be the single liaison with sponsoring organization.  The Protocol Chair is responsible for 
the coordination, development, submission, and approval of the protocol as well as its subsequent amendments.  
The protocol must not be rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The Protocol Chair is 
responsible for assuring that all participating institutions are using the correct version of the protocol. 
 
The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for 
monitoring its progress.  All reporting requirements to the FDA and Celgene are the responsibility of the Protocol 
Chair.  
 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients. 
 
The Protocol Chair will be responsible for the review of and timely submission of data for study analysis. 
 
Responsibilities of the Coordinating Center 
 
Each participating institution will have an appropriate assurance on file with the Office for Human Research 
Protection (OHRP), NIH.  The Coordinating Center is responsible for assuring that each participating institution 
has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
 
The Coordinating Center is responsible for central patient registration.  The Coordinating Center is responsible for 
assuring that IRB approval has been obtained at each participating site prior to the first patient registration from 
that site. 
 
The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair. 
 
The Coordinating Center will maintain documentation of AE reports.  There are two options for AE reporting: (1) 
participating institutions may report directly to the FDA and Celgenewith a copy to the Coordinating Center, or 
(2) participating institutions report to the Coordinating Center who in turn report to Celgene and the FDA.  The 
Coordinating Center will submit AE reports to the Protocol Chair for timely review. 
 
Audits may be accomplished in one of two ways:  (1) source documents and research records for selected patients 
are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be 
audited on-site at participating sites.  If the study sponsor chooses to have an audit at the Coordinating Center, 
then the Coordinating Center is responsible for having all source documents, research records, all IRB approval 
documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, 
etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
 
The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and the name, telephone 
number and e-mail address of the responsible investigator at each participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be stated in the protocol. 
 Data collection forms should be of a common format.  Sample forms should be submitted with the protocol.  
The frequency and timing of data submission forms to the Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions through the Coordinating Center.