Age-Related Changes in Nanoparticle Albumin Bound (Nab) Paclitaxel Pharmacokinetics and Pharmacodynamics
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: City of Hope Medical Center

 
IRB # 07157 
 
07/22/19 
Version: 13 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DIVISION OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  
Age-Related Changes in Nanoparticle Albumin Bound (nab) Paclitaxel Pharmacokinetics 
and Pharmacodynamics 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 07157  
 
 
        VERSION: 13 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S):   
Initial Submission 
Protocol Dated 9/30/07 
Version: 00 
Initial Approval 
Protocol Dated 11/27/07 
Version: 00 
COH Amendment 01 
Protocol Dated 3/28/08  
Version: 01 
COH Amendment 02 – Adding Pasadena 
Title Page Dated 05/27/08 
Version: 02 
COH Amendment 03 
Protocol Dated 06/09/08 
Version: 03 
COH Amendment 04 
Protocol Dated 10/22/08 
Version: 04 
COH Amendment 05 
Protocol Dated 11/7/08 
Version: 05 
COH Amendment 06 
Title Page Change 02/4/09 
Version: 06 
COH Amendment 07 
Protocol Dated 02/26/09 
Version: 07 
COH Amendment 08 
Protocol Dated 6/4/09 
Version :08 
COH Amendment 09 
Title Page Dated 9/17/09 
Version :09 
COH Amendment 10 
Title Page Dated 7/02/10 
Version :10 
COH Amendment 11 
Protocol Dated 3/7/11 
Version: 11 
COH Amendment 12 
Title Page Dated 10/02/13 
Version: 12 
COH Amendment 13 
TP and Protocol Dated 7/22/19 
Version: 13 
 
DISEASE SITE: 
Breast Cancer 
STAGE: 
 
 
 
 
 
All 
 
MODALITY(IES): 
 
 
 
 
All 
TYPE:  
 
 
 
 
 
All 
 
PRINCIPAL INVESTIGATOR: 
 
Mina Sedrak, MD, MS 
 
 
(Former PI: Arti Hurria, M.D.) 
 
PARTICIPATING CLINICIANS: 
 
 
Medical Oncology:  Joseph Chao, M.D., Warren Chow, 
M.D.; Marianna Koczywas, M.D., Joanne Mortimer, M.D., 
Stephen Koehler, M.D. 
  
 
Biostatistics: Can-Lan Sun, PhD, Heeyoung Kim 
 
Analytical Pharmacology: Timothy Synold, Ph.D. 
 
Radiology: Arnold Rotter, M.D. 
 
PARTICIPATING INSTITUTION: 
 
 
City of Hope National Medical Center 
 
 
 
 
 
 
 
City of Hope Medical Group, Pasadena 

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Age-Related Changes in Nanoparticle Albumin Bound (nab) Paclitaxel 
Pharmacokinetics and Pharmacodynamics 
 
 
Principal Investigator:  
Mina Sedrak, MD, MS 
 
 
 
 
 
Co-Investigators:  
 
Medical Oncology:  
Joanne Mortimer, MD 
Joseph Chao, MD 
Warren Chow, MD 
Marianna Koczywas, MD 
Stephen Koehler, MD 
 
Biostatistics:  
 
Can-Lan Sun, PhD 
 
 
 
 
Heeyoung Kim 
 
Pharmacology: 
 
Timothy Synold, PhD  
 
 
Radiology: 
 
 
Arnold Rotter, MD 
 
 
 
Protocol Revised: 11/07/08 
 
  Revised:  6/4/09 
 
   Revised:  3/7/11 
 
 Revised: 07/22/19 (face page only) 
 
 
 
 
 
 
In Memory of Dr. Arti Hurria 

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SYNOPSIS 
 
Study Objectives 
 
The primary objective of the study is to determine age-related changes in the 
pharmacokinetics and pharmacodynamics of weekly nab-paclitaxel. The secondary 
objectives are to determine response and time to progression, to explore predictors of the 
need for dose reduction, dose delays, or grade 3 or 4 toxicity, and to explore how the 
factors captured in a geriatric assessment (called “self-assessment measure for this 
protocol) are associated with changes in the pharmacokinetics and pharmacodynamics of 
cancer therapy 
 
Eligibility:  
 
Metastatic breast cancer, first or second line chemotherapy treatment for metastatic 
disease, age >18 years., KPS >70%, resolution of grade > 2 toxicity from prior therapy 
(other than alopecia), peripheral neuropathy < grade 1, hematologic inclusion (white 
blood cell count >3,000cells/mm3, 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 metatasis are present in the absent of liver metastases, bilirubin < 
1.5mg/dl, CrCl > 30ml/min) and negative pregnancy test in patients of childbearing 
potential, 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 
 
Pharmacokinetic sampling: 
Pharmacokinetic sampling will be obtained cycle 1, week 1 at the following time points: 
0,0.25,0.5,1,1.5,2,4,6,8,24, and 48 hours. 
 
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 3.0. 
 
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       Nab-Paclitaxel ................................................................................................................8 
2.4       Rationale and Goals of this Study: Pharmacokinetics of Nab-Paclitaxel ....................13 
2.5       Evaluating Factors Other than Chronological Age Which May Affect 
Treatment Tolerance ....................................................................................................14 
 
3. PATIENT SELECTION ..........................................................................................................15 
 
3.1       Inclusion Criteria..........................................................................................................15 
 
3.2  
Exclusion Criteria ........................................................................................................16 
 
3.3  
Inclusion of Women and Minorities ............................................................................16 
 
4. RECRITMENT AND REGISTRATION PROCEDURES .....................................................16 
 
4.1  
Subject Identification and Recruitment .......................................................................16 
4.2       Registration Process .....................................................................................................17 
4.3       Procedures for On-Study and Treatment Deviations ...................................................17 
 
 
5. TREATMENT PLAN ..............................................................................................................17 
 
5.1  
Guidelines for Nab-Paclitaxel Administration ............................................................17 
5.2       Pharmacokinetic Sampling ..........................................................................................18 
5.3       Duration of Therapy .....................................................................................................18 
 
6. DOSE DELAYS/DOSE MODIFICATIONS ..........................................................................19 
 
6.1       Dose Modifications schema .........................................................................................19 
 
6.2       Dose Modifications for hematological toxicity ...........................................................19 
 
6.3  
Dose Modifications for non-hematological toxicity ....................................................19 
 
 
7.  PHARMACEUTICAL INFORMATION .................................................................................21 
7.1 
Availability ..................................................................................................................21 
7.2 
Storage and Stability ....................................................................................................21 
7.3 
Study Medication Administration ................................................................................22 

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8.      QUESTIONNAIRES ............................................................................................................23 
8.1      Data to be Gathered by the Research Interviewer ........................................................24 
8.2      Data to be Gathered by the Study Participant ...............................................................24 
8.3      Data to be Collected in Follow-Up ...............................................................................24 
8.4      Description of Questionnaire Measures ........................................................................25 
 
9.      STUDY CALENDAR ..........................................................................................................28 
 
10.    MEASUREMENT OF EFFECT ...........................................................................................29 
10.1    Eligibility ......................................................................................................................29 
10.2    Method of Measurement ...............................................................................................30 
10.3    Baseline Measurement of “Target” and “Non-Target Lesions” ...................................30 
10.4.   Response Criteria ..........................................................................................................31 
10.5.   Reporting of Results .....................................................................................................33 
 
11.  REGULATORY AND REPORTING REQUIREMENTS ....................................................33 
11.1    Identification, Recording, and Handling Adverse Events ............................................34 
11.2    Definitions and Types of Adverse Events ....................................................................34 
11.3    Documentation of Adverse Events Observed During the Study Procedure .................36 
11.4.   Adverse Events Emerging Subsequent to Study Cessation ..........................................37 
11.5.   Safety Reporting Requirements and Timeline ..............................................................37 
11.6.   Data Safety and Monitoring ..........................................................................................38 
11.7.   Human Subjects Issues .................................................................................................40 
 
12. STATISTICAL CONSIDERATIONS .....................................................................................40 
12.1    Primary Objective .........................................................................................................41 
12.2    Statistical Power Calculation ........................................................................................41 
12.3    Secondary Objectives ....................................................................................................42 
 
13.   REFERENCES ......................................................................................................................43 
 
 
INFORMED CONSENT  
APPENDICES 
 
 
APPENDIX I 
 
APPENDIX II 
 
APPENDIX III 
 
 
  
 

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1.0. OBJECTIVES 
 
1.1. Primary objective: 
 
1.1.1 To determine age-related changes in the pharmacokinetics of 
weekly nab-paclitaxel 
 
1.1.2 To determine age-related changes in the pharmacodynamics 
(toxicity) of nab-paclitaxel 
 
1.2. Secondary objectives: 
 
1.2.1. To determine response and time to progression 
 
1.2.2. To explore predictors of pK parameters 
 
1.2.3. To explore predictors of the need for dose reduction, dose delays, 
or grade 3 or 4 toxicity  
 
 
 
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 
 
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 

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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 
blood cell and absolute neutrophil count in comparison to younger patients. Possible 

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explanations for this finding include the increased exposure to paclitaxel or decreased 
bone marrow reserve in older patients.19 
 
2.2.2. Docetaxel 
 
In a population pharmacokinetic analysis of 640 patients who received docetaxel, the 
impact of age on docetaxel clearance was modest, estimated at a 7% decrease in 
clearance for a patient 71 years of age. Docetaxel clearance decreased in patients with 
abnormal liver function. A 27% decrease in clearance was noted among patients with 
elevated transaminases (SGOT or SGPT > 1.5 times upper limit of normal) and alkaline 
phosphatase (> 2.5 times upper limits of normal). A decrease in docetaxel clearance was 
a strong predictor of grade 4 neutropenia and febrile neutropenia (a 50% decrease in 
clearance was associated with a 4.3-fold increased risk of grade 4 neutropenia and a 3-
fold increased risk of febrile neutropenia). Based on this, the authors recommended no 
specific dose adjustments in older patients; however, dose adjustment in patients with 
liver impairment was recommended.20 
 
The pharmacokinetics and toxicity of docetaxel at 75 mg/m2 every 3 weeks was evaluated 
in a cohort of 20 patients age 65 and older (median 71 years; range 65 to 80), and 20 
patients less than age 65 (median 53 years; range 29 to 64). There was no significant 
difference in docetaxel pharmacokinetics between these 2 groups. In particular, there was 
no association between age and docetaxel clearance or age and the AUC of docetaxel. 
Older patients were more likely to experience grade 4 neutropenia (63% > age 65 vs 30% 
< age 65) and febrile neutropenia (16% > age 65 vs 0% < age 65). There was no 
significant difference in AUC values between patients with grade 4 neutropenia and 
patients with less than grade 4 neutropenia. Among the 10 patients with an AUC in the 
upper quartile, 3 out of 6 patients > age 65 experienced febrile neutropenia compared 
with zero out of 4 patients < age 65. The frequency of nonhematologic toxicity was 
similar between the older and younger patients.21 
 
The pharmacokinetics of weekly docetaxel was evaluated in 2 studies that also included 
the Erythromycin Breath Test, a surrogate measure of cytochrome 3A4 activity, which is 
the main enzyme responsible for docetaxel metabolism. In a study by Salviero and 
colleagues, the pharmacokinetics of docetaxel 40 mg/m2 was evaluated in a cohort of 54 
patients with advanced cancer (median age 63; range 40 to 83). There was no significant 
association between age and clearance. However, there was a significant correlation 
between Erythromycin Breath Tests results, liver function enzymes, and docetaxel 
clearance.22 Hurria and colleagues studied the pharmacokinetics and toxicity of weekly 
docetaxel 35 mg/m2 for 3 weeks followed by a 1-week break in a cohort of 20 patients 
age 65 and older (median age 75; range 66 to 84). In this cohort, 19 patients were 
evaluable for pharmacokinetic analysis. There were no significant age-related 
pharmacokinetic differences in this cohort of older patients. There was a statistically 
significant association between decreased cytochrome 3A4 activity (as measured by the 
Erythromycin Breath Test) and decreased docetaxel clearance and increased AUC; 
however, there was no significant association between either the Erythromycin Breath 

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Test results or docetaxel pharmacokinetic parameters and the frequency of grade > 3 
toxicity.23 
 
The pharmacokinetics and pharmacodynamics of weekly docetaxel (for 3 out of 4 weeks) 
in combination with cisplatin (25 mg/m2 every 4 weeks) was evaluated in 27 patients age 
75 and older and 25 patients under age 75.  Patients under age 75 received a docetaxel 
dose of 35 mg/m2 and patients age 75 and older received 20 mg/m2. There was no 
significant difference in the clearance or volume of distribution of docetaxel in older and 
younger patients. In comparison with younger patients, older patients had a smaller AUC 
of docetaxel; however, both groups experienced similar rates of neutropenia, suggesting 
that older patients were more sensitive to docetaxel exposure than younger patients.24 
 
2.3. 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.  
 
2.3.1. 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  
 
2.3.2. Clinical Studies with Nab-paclitaxel  
 
2.3.2.1. 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.  

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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 
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 

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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.  
 
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 
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.  
 
2.3.2.2. 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 

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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 
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  
 
2.3.2.3. 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.  
 
2.3.2.4. Potential Risks of Abraxane  
 
Toxicities  
Myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, hypotension, 
abnormal ECG changes, cough, dyspnea, edema, sensory neuropathy, bilirubin/liver 
enzyme elevations, 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 #1 below: 
 

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Table 1: Frequencya of Important Treatment Emergent Adverse Events in 
the Randomized Study on an Every-3-Weeks Schedule 
  
Percent of Patients  
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  
24  
20  
Febrile Neutropenia  
2  
1  
Bleeding  
2  
2  
Hypersensitivity Reactione  
All  
4  
12  
Severef 
0  
2  
Cardiovascular  
Vital Sign Changesg 
Bradycardia  
<1  
<1  
Hypotension  
5  
5  
Severe Cardiovascular Eventsf 
3  
4  
Abnormal ECG  
All patients  
60  
52  
Patients with Normal Baseline  35  
30  
Respiratory  
Cough  
7  
6  
Dyspnea  
12  
9  
Sensory Neuropathy  
Any Symptoms  
71  
56  
Severe Symptomsf 
10  
2  
Myalgia / Arthralgia  
Any Symptoms  
44  
49  
Severe Symptomsf 
8  
4  

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Table 1 (continued): Frequencya of Important Treatment Emergent Adverse 
Events in the Randomized Study on an Every-3-Weeks Schedule  
Percent of Patients  
Nab-Paclitaxel  
260/30minb  
(n=229)  
Paclitaxel  
Injection  
175/3hc,d  
(n=225)  
Asthenia  
Any Symptoms  
47  
39  
Severe Symptomsf  
8  
3  
Fluid Retention/Edema  
Any Symptoms  
10  
8  
Severe Symptomsf  
0  
<1  
Gastrointestinal  
Nausea  
Any symptoms  
30  
22  
Severe symptomsf  
3  
<1  
Vomiting  
Any symptoms  
18  
10  
Severe Symptomsf  
4  
1  
Diarrhea  
Any Symptoms  
27  
15  
Severe Symptomsf  
<1  
1  
Mucositis  
Any Symptoms  
7  
6  
Severe Symptomsf 
<1  
0  
Alopecia  
90  
94  
Hepatic (Patients with Normal Baseline)  
Bilirubin Elevations  
7  
7  
Alkaline Phosphatase Elevations  36  
31  
AST (SGOT) Elevations  
39  
32  
Injection Site Reaction  
<1  
1  
 
a Based on worst grade  
b Abraxane 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.  
 

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2.4. Rationale and Goals of this Study: Pharmacokinetics of Nab-Paclitaxel 
 
The goal of this study is to determine the age-related changes in the pharmacokinetics of 
nab-paclitaxel. The rationale for exploring weekly dosing is based on the hypothesis that 
more frequent dosing minimizes tumor regrowth and decreases the emergence of drug 
resistance. This hypothesis is supported by clinical data from CALGB 9840.35 In this 
randomized study, patients with metastatic breast cancer treated with weekly paclitaxel 
had a superior response and time to progression in comparison to patients treated with 
every three week paclitaxel. In addition, there is a lower risk of grade 3 or 4 neutropenia 
with weekly dosing, an important consideration for older patients who have decreased 
bone marrow reserve. In a phase I trial of weekly nab-paclitaxel, the MTD for heavily 
treated patients was 100mg/m2 and the MTD for lightly pre-treated patients was 
150mg/m2.31 Gradishar et al. evaluated the efficacy and toxicity of weekly verses every 
3-week nab-paclitaxel. Patients receiving the weekly nab-paclitaxel dose had a 
statistically significant higher response rate than patients receiving the every three week 
dosing. Two different weekly schedules were evaluated: 100mg/m2 verses 150mg/m2 
delivered 3 weeks in a row followed by a 1 week break. The 100mg/m2 dose was 
associated with a lower risk of peripheral neuropathy, neutropenia, fatigue, and 
arthralgias.36 Based on all of this data, the 100mg/m2 3 week on, 1 week off dosing 
schedule will be used in this study. The specific aims of this study are to: 1) to determine 
age-related changes in the pharmacokinetics of weekly nab-paclitaxel; 2) to determine 
age-related changes in the pharmacodynamics (toxicity) of nab-paclitaxel 
 
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 

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(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 all ages in order to identify factors other than chronological 
age which can predict toxicity to cancer therapy. Therefore, we will replace the term 
“Comprehensive Geriatric Assessment” with the term “Self-Assessment Measure” 
 
 
3.0. 
PATIENT SELECTION 
 
 
3.1. 
 
Inclusion Criteria  
 
 
3.1.1 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 >18 years.   
 Because no dosing or adverse event data are currently available on the 
use of nab-paclitaxel in patients <18 years of age, children are 
excluded from this study.  
To be assured of getting adequate variability in age, we will define 4 
age strata <50, 50-60, 60-70, and >70 years of age and require at least 
10 patients in the <50 age group, at least 5 patients in the > 70 age 
group, the two groups we expect to be the most difficult to accrue. 
 
3.1.5 KPS >70% 
 
3.1.6 Resolution of grade > 2 toxicity from prior therapy (other than 
alopecia) 
 
3.1.7 Peripheral neuropathy < grade 1 
 
3.1.8 Hematologic inclusion: 
 
 white blood cell count  
 
>3,000cells/mm3 
 absolute neutrophil count 
 
>1,500/mm3 
 platelets  
 
 
 
 
 
>100,000cells/mm3 
 Hb   
 
 
 
 
 
 
> 9.0g/dl 
 
 
 
 

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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 
absent of liver metastases) 
- 
bilirubin  
 
 
< 1.5mg/dl 
 
- 
creatinine clearance  
> 30ml/min 
(calculated or 24 hour) 
 
3.1.10 Negative pregnancy test in patients of childearing potential. Patients 
with reproductive potential must use an effective method to avoid 
pregnancy for the duration of the trial 
 
3.1.11 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 Women who are lactating 
 
3.2.6 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 
 

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4.1. Subject Identification and Recruitment:  
 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team.  Potential subjects will be contacted by their 
treating physician and will be referred to the investigator/research staff of the study. 
 
The principal investigator 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 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 may also review 
portions of their medical records at COH 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.   
 
In most cases, 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.  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.  
 
To be assured of getting adequate variability in age, we will define 4 age strata <50, 50-
60, 60-70, and >70 years of age and require at least 10 patients in the <50 age group, at 
least 5 patients in the > 70 age group, the two groups we expect to be the most difficult to 
accrue. 
 
4.2. Registration Processes 
 
  
All eligible patients will be registered at the City of Hope. Once the signed informed 
consent has been obtained, all pretreatment evaluations have been performed, patients 
will be entered on study. To register a patient, the research nurse or CRA must complete 

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the Eligibility Checklist. The research nurse or CRA will register the patient onto the 
study and assign a patient accession number. 
 
 
4.3. Procedures for On-Study and Treatment Deviations   
 
Any waivers or deviations from the study protocol need to be approved by the IRB 
 
 
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.  
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 2.3.2.4.  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.Pharmacokinetic Sampling 
 
Peripheral blood samples (each in a 7 ml sodium or lithium heparin containing 
Vacutainer tube) will be collected from a site distal to the site of drug infusion during 
cycle 1, week 1 at the following time points: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 24, and 48 

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hours. A separate pharmacokinetic flow sheet will be used to record the actual times of 
blood draws and pertinent dosing information (Appendix III). Blood samples will be kept 
on ice and processed within 1 hour of drawing.  Processing will consist of separation of 
plasma from whole blood by centrifugation at 1500 x rpm for 10 minutes at 4C.  Plasma 
will be transferred to appropriately labeled polypropylene tubes and stored at < -70C 
until analysis in the City of Hope Analytical Pharmacology Core laboratory;   
 
Dr. Timothy Synold 
 
Kaplan Clinical Research Bldg. Rm 1012 
 
City of Hope National Medical Center 
 
1500 E. Duarte Rd. 
 
Duarte, CA  91010 
 
Phone (626) 359-8111 
 
Fax – (626) 301-8898 
 
 
 
Email – tsynold@coh.org 
 
5.3. 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 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 the white 
blood cell count returns to >3,000cells/mm3, absolute neutrophil count >1,500/mm3, 
platelets >100,000cells/mm3, and Hb > 9.0g/dl. For patients receiving weekly nab-
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patients must have an white blood cell count returns to >3,000cells/mm3, absolute 
neutrophil count >1,500/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.  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:  
 
Use of G-CSF and Dose Reductions for Hematologic Toxicity  
Adverse Event  
Occurrence  Action to be Taken  

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ANC < 500 cells/mm3 (nadir 
count) with neutropenic fever > 
38°  
OR  
Delay of next cycle due to 
persistent leukopenia (WBC 
<3,000cells/mm3) or 
neutropenia (ANC < 1500 
cells/mm3)  
OR  
For patients on weekly 
treatment whose next treatment 
within the cycle (Day 8 or Day 
15) is omitted persistent 
leukopenia (WBC 
<3,000cells/mm3) or 
neutropenia (ANC < 1500 
cells/mm3) 
OR  
Neutropenia < 500 cells/mm3 
for > 1 week  
Any 
Occurrence  
At the first occurrence of a 
hematological toxicity (as outlined in 
the Adverse Event column), 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.  
If G-CSF is given concurrently with 
weekly nab-paclitaxel, administration 
may begin the day after nab-paclitaxel 
is given and should stop at least 48 
hours prior to when nab-paclitaxel is 
given the following week.  
Thrombocytopenia Grade 3 or 
Grade 4*  
1st 
Occurrence  
Dose reduction to next lower level  
Recurrence  
Dose reduction to next lower level  
 
*See NCI Toxicity Criteria 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). 
 
6.4.2. Sensory Neuropathy  
 
Nab-paclitaxel should be withheld in patients who experience ≥ Grade 2 sensory 
neuropathy. Treatment may be resumed at the next lower dose level (see Table 2) 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 

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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, 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 Table 2).  Patients who present 
with grade 2 toxicities may have their treatment held 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 Abraxis BioScience, LLC, 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 Abraxis BioScience, LLC.  Allow at least 5 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 Abraxis BioScience, LLC at 908-393-
8304. 

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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.  
 
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.  
 

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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.  
 
• 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.  
 

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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  
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 (aka “Self-Assessment Measure”) 
 
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: Hospital Anxiety and Depression Scale 
5) Social functioning and support:  
a) MOS Social Activity Limitation: 
b) Medical Outcomes Study (MOS) Social Support Subscale 

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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 in follow-up  
The following information will be collected at each clinic visit via the toxicity tool (see 
Appendix III): 
1) Grade 3 or 4 toxicity 
2) Hospitalization 
3) Dose delay or reduction 
4) Discontinuation of chemotherapy course because of toxicity 
 
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 

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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 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 

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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 
 
Hospital Anxiety and Depression Scale (HADS) 
The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-administered 
measure that has been well tested in cancer populations.56 It has two 7-item subscales that 
assess depression and anxiety. The scale is considered particularly appropriate for use 
with medically ill patients because of the absence of somatic items which often confound 
the determination of psychiatric problems in a medically ill population. Reported anxiety 
and depression cutoff scores on the HADS have varied from 8 to 11.57, 58 The total cutoff 
score for psychological distress has ranged from 13, reflecting adjustment disorder, to 19, 
reflecting major depressive disorders.59 Ibbotson and colleagues found that an overall 
cutoff score of 15 or greater resulted in 80% sensitivity, 76% specificity, and a positive 
predictive value of 41% for psychological distress.60 
 
8.4.5. Social Functioning 
 
Medical Outcomes Study (MOS) Social Activity Limitations Measure 
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 

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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 
 
 
 
9.0. STUDY CALENDAR 
 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
 
Parameter 
Pre-
study 
PK 
Sampling 
with First 
Dose*** 
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, differential, 
platelet count 
X 
 
X 
X 
 
X 
 
 
 
CMP* 
X 
 
X 
 
X 
 
 
 
CEA, CA15-3 
X 
 
X 
 
 
 
 
 
CT Chest, Abdomen, 
Pelvis 
X 
 
 
 
 
 
X 
 
Bone scan 
X 
 
 
 
 
 
X 
 
Pharmacokinetic 
Sampling*** 
 
X 
 
 
 
 
 
 
Self-Assessment 
Questionnaire** 
X 
 
 
 
 
X 
 
X 

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*CMP = comprehensive biochemical screening profile (which includes electrolytes, 
BUN, creatinine, AST, ALT, total bilirubin, total protein, albumin, alkaline phosphatase, 
and glucose) 
**+/- 2 weeks 
*** Pharmacokinetic sampling will be obtained cycle 1, week 1 at the following time 
points: 0,0.25,0.5,1,1.5,2,4,6,8,24, and 48 hours. 
 
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 
 
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.  
 
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 with longest diameter  20 mm using conventional techniques or 
10 mm with spiral CT scan. 
 
Non-measurable lesions - all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT 
scan), i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic 
lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
 
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 

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the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment.  
 
 
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 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). 
 

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10.3. Baseline documentation of “Target” and “Non-Target” lesions 
 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions 
in total, representative of all involved organs should be identified as target lesions 
and  recorded and measured at baseline.  
 
 
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either 
by imaging techniques or clinically).  
 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor. 
 
 
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.  
 
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). 

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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 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
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.  
 

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 
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 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. 
 

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 
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) 
 
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. Special Considerations for Laboratory Results 
 

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Any CTCAE grade 3 or 4, or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory values not solely considered a result of disease progression will 
be considered an AE.  
 
11.2.4. Treatment Non-Response as an Adverse Event  
 
"Lack of efficacy" or treatment non-response for an unproven therapy will not generally 
considered an adverse event.  If there is deterioration in the underlying condition for 
which the study regimen is designed to treat, there may be uncertainty as to whether this 
is an AE.  In such a case, the investigating physician must judge the treatment as a 
possible contributor to the deterioration. Unless local governing regulations require 
otherwise, such deterioration will be considered to be an issue of treatment efficacy and 
not an AE.  This situation constitutes an exception to the general rule that AEs are 
initially identified regardless of perceived causality attribution.  Adverse events that are 
unequivocally due to progression of disease should be recorded as “progressive disease” 
rather than as AEs.  However, the development of an additional (even if similar) disease 
will be regarded as an AE. For example, if a patient taking an experimental drug to treat 
underlying breast cancer develops a second primary cancer of non-metastatic origin, this 
would be considered a unique AE. 
 
11.2.5. Types of Adverse Events 
 
In the clinical study setting, adverse events are most often subcategorized as either 
SERIOUS or NON-SERIOUS. This distinction is critical, as SERIOUS AEs require 
additional documentation that is both time-sensitive and detailed.  
 
11.2.5.1 Serious Adverse Events (SAE) 
 
Definition 
A serious adverse event as defined by ICH is any adverse experience that at any 
dose meets any of the following conditions: 
 
 results in death 
 is life-threatening (The patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have 
caused death if it were more severe) 
 requires inpatient hospitalization or prolongation of existing 
hospitalization 
 results in persistent or significant disability/incapacity, or 
 is a congenital anomaly/birth defect 
Note: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations; for example, important 
medical events may not be immediately life-threatening or result in death or 

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hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
Hospitalization that do not meet this criteria are: 
 
 reasons described in the protocol, e.g., drug administration, protocol-
required testing 
 social reason in the absence of an AE 
 surgery or procedure planned prior to entry into the trial 
 
11.2.5.2. "Serious" Versus "Severe" Adverse Events 
 
There will be an acknowledged distinction between serious and severe AE’s.  
Assessment of seriousness will be made solely by the serious criteria listed above.  
Severity of AEs will be graded according to the NCI Common Terminology 
Criteria for Adverse Events v3.0. Therefore, serious events will not be 
automatically considered severe.  For example, a stroke that results in only a 
limited degree of disability may be considered a mild (not severe) stroke, but it 
would still meet serious criteria and thus, be captured as an SAE.  Similarly, 
severe events may not always be serious.  An example would be an episode of 
severe, transient nausea which persists for several hours. This would be classified 
as a "severe" episode of nausea, but if it did not require treatment, intervention, or 
somehow meet other serious criteria, it would not be considered an SAE. 
 
11.2.5.3. Nonserious Adverse Events 
 
Any adverse event that is not an SAE is, by default, a non-serious AE.  
 
 
11.3. Documentation of Adverse Events Observed during the Study Period 
 
All AEs (serious and nonserious) will be documented.  Any experience or condition that 
is identified from the signing of the informed consent through the 30-day follow-up 
period must be captured as an adverse event (AE).  Information collected will include a 
description of the event, date of onset and resolution, assessment of serious (SAE) 
criteria, any action taken (e.g., changes to study treatment), final outcome, and the 
investigator’s assessment of causality (i.e., the relationship to the study treatment[s]).  
 
11.3.1. AE Term Selection 
To facilitate proper analysis of any observed adverse events within the study, 
consistent and medically accurate standards of AE term selection will be applied.  
Whenever possible, an AE term will be the formal diagnosis or disease term 

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experienced by the patient.  If the final diagnosis remains differential or is 
pending, then the presenting signs, symptoms and/or abnormal laboratory results 
will be captured as AEs until a diagnostic term can be applied.  
 
11.3.2. Causality 
For each adverse event an investigator will assess the possibility that a study drug 
or regimen may have caused or contributed to an adverse event as described in the 
previous section entitled "Definition and Types of Adverse Events."   
 
11.3.3 Deaths 
ANY deaths occurring within the trial period or within 30 days after discontinuing 
protocol treatment will be captured without exception, regardless of perceived 
causal relationship to study drug.  A single AE term will be selected, the event 
will be considered an SAE, and "death" will serve as the positive criteria applied 
to the seriousness assessment.  If the cause of death is unknown, then "death" will 
be captured as the sole AE term. Whenever possible the underlying cause, not the 
specific mechanism, of death will be selected as the SAE term, unless the 
investigator feels the specific mechanism of death is clinically relevant or offers 
significance that might otherwise be lost if not captured.  
 
11,3.4. Follow up Procedures for Adverse Events Observed During the Study 
Period  
 
All adverse events (serious and non-serious) that are unresolved or unimproved 
since initial presentation will be followed until resolution or improvement of the 
AE. With respect to AEs that are abnormal laboratory or investigational results, 
an unresolved or persistent CTCAE grade 3 or 4 laboratory abnormality at study 
completion or withdrawal will be followed until the laboratory abnormality has 
either returned to a comparable baseline value, or is judged to have a severity of 
grade 2 or better.   
 
If, in the investigator's medical judgment, any AE noted in the study is not likely 
to resolve or improve, the investigator will document that opinion in the patient's 
medical record.  Should the patient become lost to follow-up or further 
information is otherwise unattainable, the investigator will note this in the 
patient's medical record. 
 
 
11.4. Adverse Events Emerging Subsequent to Study Cessation 
 
For 30 days subsequent to study completion or withdrawal, new onset adverse events will 
be captured.  Follow up of these events will follow the same procedure as described 
above for AEs observed during the study period. 
 
11.5. Safety Reporting Requirements and Timelines 
 

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The Sponsor-Investigator will utilize the FDA voluntary 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/). 
 
All serious adverse events regardless of severity or relationship must be reported to 
Abraxis BioScience and Abraxis Oncology within 24 hours of the investigational staff’s 
knowledge (using the Abraxis Bioscience SAE form).   
 
 
Abraxis BioScience, LLC.  
Drug Safety and Surveillance Department 
4505 Emperor Blvd, Suite 400 
Durham, NC 27703 
Ph: 919-433-8515 (8am-5pm EST, normal business days and hours) 
Ph: 919-606-1832 (24hr hotline)  
Fax: 919-433-8402  
E-mail: SAE-REPORTING@abraxisbio.com 
 
 
AbraxisBioScience, LLC. 
200 Somerset Corporate Blvd - Suite 8000 
Bridgewater, NJ 08807  
Office:  908-393-8248 
Fax:  908-393-8304 
Cell:  267-337-2720 
Email: AbraxisMedAffairs@abraxisbio.com 
 
 
In addition, the Sponsor-Investigator will adhere to the safety reporting requirements and 
timelines described in the Research Funding Agreement with Abraxis BioScience.  
   
The sponsor-investigator will provide full and timely cooperation with any requests from 
Abraxis, governing IRB, institution, or regulatory agency with any requests regarding 
reports of individual reports of adverse events. 
 
11.6.    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.infosci.coh.org/ocrqa/forms/guidance.doc 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. 
 

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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 3 & 4 toxicities.  
Reporting of data and safety to the DSMB will occur at intervals of 6 months using the 
PMT report. 
 
C) 
Adverse Events 
 
Reporting:  Adverse events must be reported to the COH DSMB and IRB and GCRC 
according to definitions and guidelines at 
http://www.infosci.coh.org/ocrqa/forms/guidance.doc and http://iris.coh.org, which are 
defined below.  AEs will be monitored by the PMT.  Less than serious adverse events 
will be reported only at the time of protocol continuation reports. 
 
Adverse Event - An adverse event (AE) 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. 
 
Serious Adverse Event - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be recorded on the City of Hope National 
Medical Center Adverse Events (COH AER) form (http://iris.coh.org). 
 
A serious adverse event (SAE) is defined as any expected or unexpected adverse event 
(AE, generally equivalent to CTCAE grades 3, 4 or 5) that is related or unrelated to 
the intervention that results in any of the following outcomes: 
 
Death 
 
A life-threatening event 
 
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 
 
Causes cancer 
 
Is an overdose 
 
Certain medical events that may not result in death, be life-threatening, or require 
hospitalization, may also be considered a serious adverse event when appropriate medical 
or surgical intervention is necessary to prevent one of the outcomes listed above. 
 
Unexpected Adverse Event - Any event in which the severity or specificity is not 
consistent with the risk information described in the protocol, and the event is not 
anticipated from the subject's disease history or status. 

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Expected Adverse Event - Any event in which the severity or specificity is consistent 
with the risk information described in the protocol or is anticipated based on the subject's 
medical history. 
 
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 Investigator after considering the clinical information, the 
medical history of the subject, and past experience with the research agent/intervention.  
This is recorded using the Adverse Event Report (COH AER) form (http://iris.coh.org) in 
one of five categories scored as the following: 5=related, 4=probably related, 3=possibly 
related, 2=unlikely related, and 1=unrelated.  The attribution is subject to change as 
follow-up information becomes available and it can be changed by the DSMB or by the 
IRB in the process of review. 
 
11.7. Human Subjects Issues 
 
11.7.1. 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.  
 
11.7.2. Alternatives 
 
Participation in this study is voluntary. Participants may choose to participate or decline. 
There are no adverse consequences to not participating. 
 
11.7.3. Confidentiality 
 
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.  
 
11.7.4. Financial Compensation and Obligation to be Incurred by the Research 
Subject 
 

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There will be no financial compensation for participating in this study. 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 Primary objectives 
 
12.1.1. To determine age-related changes in the pharmacokinetics of weekly nab-     
paclitaxel 
 
12.1.2. To determine age-related changes in the pharmacodynamics (toxicity) of 
nab-paclitaxel 
 
 
12.1.1 Statistical Rationale 
 
Linear regression analysis will be used to examine the strength of the relationship 
between the explanatory variable age and the pharmacokinetic response variables such as 
log transformation of clearance  (log(Cl)) and log transformation of area under the curve 
(log(AUC)).    
 
Generalized linear models assuming a binomial distribution and implementing a logit link 
will be used to examine the strength of the relationship between age and the PD variables 
(i.e., dose reductions, dose delays and grade 3 & 4 toxicities) 
 
Descriptive statistics including means, medians and modes as measures of location and 
standard deviation and quartiles as measures of the dispersion will be provided for the PK 
parameters, such as log(Cl) and log(AUC). Counts and percentages will be provided for 
dose reductions, dose delays and grade 3 & 4 toxicities.  
 
12.2. Statistical Power Calculation 
 
The calculation of sample size for this study focuses on r, the coefficient of correlation, 
and its square, the coefficient of determination, R2, from a linear regression analysis 
examining the strength of the relationship between the explanatory variable age and the 
response variable log(Cl).   Note below the formula for r. 
 
r= ß * σage / σlog(Cl) 
 
As this formula shows, r, the correlation coefficient, is based on three components: the 
linear regression coefficient, β, and the variation in the predictor age as measured by the 
standard deviation(σage), and the variation in the response variable log(Cl) as measured by 
the standard deviation(σlog(Cl)). This means that r and thus R2 increase with increasing 
slope or increasing variation in the predictor value age, or by minimizing variation of the 
response variable log(Cl).   
 

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To be assured of getting adequate variability in age, we will define 4 age strata <50, 50-
60, 60-70, and >70 years of age and require at least 10 patients in the <50 age group, at 
least 5 patients in the > 70 age group, the two groups we expect to be the most difficult to 
accrue. 
 
Table 1 provides information on the variability of log(Cl) Nab-Paclitaxel. 
Table1. 
Drug of interest 
 σlog(Cl) 
Nab-Paclitaxel  (100, 150 mg/m2) 
.32, .6231 
 
We have selected a sample size of 40 subjects which would provide at least 80% power 
with an alpha level of 0.05 (R2 can only increase – this study is powered to be 
comparable to a two-tailed r) to find a relationship between age and log(Cl) if age 
predicts at least 17% of the variation in log(Cl). 
  
12.3. Secondary objectives: 
 
12.3.1.  To determine response and time to progression:  Counts and percentages will be 
provided for categories of response criteria examining both target and non-target lesions 
based on the definitions provided in section 10.4.  Median time to progression and 
associated confidence limits will be calculated using a Kaplan Meier method. 
 
12.3.2. To explore predictors of pK parameters.   After the initial examination of 
univariate relationship between the pK parameters  (log(Cl), log(AUC))  and age, we will 
refine our linear model(s) by  examining the effects of including variables associated with 
disease stage, cancer diagnosis,  nutritional status, physical functioning level and the 
geriatric assessment measures. We will limit our study to a select set of models based on 
the current knowledge base. Models will be compared using a small sample Akaike 
information criteria (AIC). 
 
12.3.2. To explore predictors of the need for dose reduction, dose delays, or grade 3 or 4 
toxicity.   We will use the same general approach to modeling the PD response variables 
as the pK parameters but we will implement a generalized linear model with a binomial 
distribution and logit link. 
 
In the case that we have multiple drugs in a class we can extend our model to recognize 
the hierarchical structure of the data using generalized estimating equations.62 Combining 
the data on multiple drugs will boost the sample size thus providing a more full range in 
the variables of interest for modeling the pharmacokinetics and pharmacodynamics.  

 
44
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