Clinical trial NCT02698891
Conditions: Early Stage Breast Cancer
Keywords: Early Stage Breast Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-04-07; Completion date: 2021-11-01
Enrollment: 127 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is testing the safety and feasibility of delivering the 4 cycles of 'dose-dense' paclitaxel without the use of Neulasta (Pegfilgrastim) as a Granulocyte Colony-stimulating Factor (G-CSF) support. The research study is for participants who have early stage breast cancer and have been recommended to receive a standard chemotherapy regimen, doxorubicin/cyclophosphamide (AC) plus Paclitaxel (T), in what is called a "dose-dense" fashion to prevent recurrences.

Detailed description:
Low white cell blood counts increase the risk of infections; thus, in order to give each cycle of chemotherapy, white blood cell count must have recovered adequately in between cycles. Traditionally, this regimen has been given with the use of a medicine called Neulasta (Pegfilgrastim) to speed the recovery of the white blood cell count in order to maximize the chances that the next cycle of chemotherapy can be given on time.

The names of the study interventions involved in this study are:

\-- Neulasta (Pegfilgrastim)

Arms: arm 1: After the screening procedures confirm participation in the research study:

175 mg/m\^2 Paclitaxel via IV, once every 2 weeks x 4 cycles. (1 cycle = 2 weeks)

\-- Neulasta™ (Pegfilgrastim) 6 mg SQ x1 is administered on day 2 of each treatment cycle, approximately 24 hours after the chemotherapy treatment, if:

* The patient experiences a prior episode of fever and neutropenia.
* If the patient has an active infection this decision will be at provider discretion.
* If Neulasta™(Pegfilgrastim) is administered in any Paclitaxel cycle for a given patient, it will be then administered for all future cycles.
Interventions: intervention 1: Paclitaxel intervention 2: Neulasta
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
Title:   
 
 
 
Feasibility and safety of avoiding granulocyte colony-stimulating factor  
prophylaxis during the Paclitaxel portion of dose dense Doxorubicin-
Cyclophosphamide and Paclitaxel regimen 
 
NCT Number:   
02698891 
 
IRB Approval Date:  March 3, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: 
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Protocol Version Date:   February 14, 2022 
 
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Protocol version date:    February 14, 2022 
DF/HCC Protocol#: 15-516 
 
TITLE: Feasibility and safety of avoiding granulocyte colony-stimulating factor  
prophylaxis during the Paclitaxel portion of dose dense Doxorubicin-Cyclophosphamide 
and Paclitaxel regimen  
 
Coordinating Center: 
 
 
Dana –Farber Cancer Institute   
 
 
 
 
 
 
 
 
 
 
*Principal Investigator (PI): 
 Nancy Lin, MD 
 
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-2335, Fax: 617-632-1930 
 
Email: Nancy_Lin@dfci.harvard.edu 
 
Other Investigators: 
 Ines Vaz Luis, MD, MSc  
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-3800 
 
Email: InesV_Luis@dfci.harvard.edu 
 
 
 
Sara Tolaney, MD, MPH 
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-3800 
 
Email: Sara_Tolaney@ dfci.harvard.edu 
 
 
Antonio Di Meglio, MD  
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-3800 
 
Email: Antonio_DiMeglio@dfci.harvard.edu 
 
 
Adrienne Gropper Waks, MD 
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-3800 
 
Email: awaks@partners.org 
 
 
 
 
 
Belen Fraile, MD, MPH 


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Dana-Farber Cancer Institute  
 
450 Brookline Avenue,  
 
Boston, MA 02215 
 
Phone: 617-632-4587 
 
Email: Belen_Fraile@ dfci.harvard.edu 
 
 
Michael Hassett, MD, MPH 
450 Brookline Avenue, 
Boston, MA 02215 
 
Phone: 617-632-3800 
 
Email: Michael_Hassett@dfci.harvard.edu 
 
Eric P Winer, MD 
 
450 Brookline Avenue, Boston, MA 02215 
 
Dana-Farber Cancer Institute  
 
Phone: 617-632-3800 
 
Email: Eric_Winer@dfci.harvard.edu 
 
 
 
Statisticians: 
 
 
Tianyu Li, MS 
450 Brookline Avenue, Boston, MA 02215 
Dana-Farber Cancer Institute  
Phone: 617-632-7997, Fax: 617-632-5444 
Email: tyli@ds.dfci.harvard.edu 
 
Hao Guo, MS 
450 Brookline Avenue, Boston, MA 02215 
Dana-Farber Cancer Institute  
Phone: 617.632.3626  
Email: Hao_Guo@dfci.harvard.edu 
 
 
 
Agent(s): Paclitaxel [Commercial], Neulasta™ (pegfilgrastim)[Commercial] 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ENROLLMENT AND REGISTRATION 
Stage I-III Breast Cancer 
Planned treatment with dose dense (neo) Adjuvant Doxorubicin Cyclophosphamide (AC)-
Paclitaxel  
 
TREATMENT 
 
4 Cycles of Paclitaxel  
*1 Cycle= 2 weeks 
 
Simplification of Paclitaxel pre-medication aimed to reduce the risk of hypersensitivity reactions 
(HRS) 
Granulocyte-colony stimulating factor (Neulasta™- Pegfilgrastim) support as 
defined by protocol.  
Pre-specified safety rules will be verified every cycle. 
OFF STUDY 
4 weeks post treatment with Taxol 


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TABLE OF CONTENTS 
 
SCHEMA ................................................................................................................................... 4 
1. 
OBJECTIVES ................................................................................................................. 7 
1.1 
Study design ........................................................................................................ 7 
1.2 
Primary  Objectives .............................................. Error! Bookmark not defined. 
1.3 
Secondary Objectives ........................................................................................... 7 
2. 
BACKGROUND ............................................................................................................. 8 
2.1 
Adjuvant chemotherapy for breast cancer ............................................................. 8 
2.2 
G-CSF support in dose dense regimens ................................................................ 8 
2.3 
Rationale ............................................................................................................ 11 
2.4 
Secondary studies background ........................................................................... 11 
3. 
PARTICIPANT SELECTION ....................................................................................... 12 
3.1 
Inclusion Criteria ............................................................................................... 12 
3.2 
Exclusion Criteria .............................................................................................. 13 
3.3 
Inclusion of Women and Minorities ................................................................... 14 
4. 
REGISTRATION PROCEDURES ................................................................................ 14 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ................................. 14 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions................................ 15 
5. 
TREATMENT PLAN .................................................................................................... 15 
5.1 
Treatment regimen: Chemotherapy administration, Pegfilgrastim and 
Supportive Measures .......................................................................................... 15 
5.2 
Pre-Treatment Criteria ....................................................................................... 17 
5.3 
Duration and sequencing of therapy ................................................................... 18 
5.4 
Duration of Follow up ........................................................................................ 18 
5.5 
Criteria for Taking a Participant Off Study ......................................................... 18 
5.6 
General Concomitant Medication and Supportive Care Guidelines ..................... 19 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................. 20 
6.1 
Chemotherapy .................................................................................................... 20 
6.2 
Pegfilgrastim ...................................................................................................... 22 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 23 
7.1 
Expected Toxicities ............................................................................................ 23 
7.2 
Adverse Event Characteristics ............................................................................ 24 
7.3 
Expedited Adverse Event Reporting ................................................................... 24 
7.4 
Expedited Reporting to Hospital Risk Management ........................................... 25 
7.5 
Routine Adverse Event Reporting ...................................................................... 25 


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8. 
PHARMACEUTIC INFORMATON ............................................................................. 25 
8.1 
Chemotherapy .................................................................................................... 25 
8.2 
Neulasta™ (pegfilgastrim) ................................................................................. 25 
9. 
STUDY CALENDAR ................................................................................................... 27 
9.1 
Study tests, procedures and treatment schedule .................................................. 27 
10. 
MEASUREMENT OF EFFECT .................................................................................... 30 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ......................................... 30 
11.1 
Data Reporting ................................................................................................... 30 
11.2 
Data Safety Monitoring ...................................................................................... 30 
12. 
REGULATORY CONSIDERATIONS.......................................................................... 31 
12.1 
Protocol Review and Amendments ..................................................................... 31 
12.2 
Informed Consent............................................................................................... 31 
12.3 
Ethics and Good Clinical Practice (GCP) ............. Error! Bookmark not defined. 
12.4 
Study Documentation ......................................................................................... 31 
12.5 
Records Retention .............................................................................................. 31 
13. 
STATISTICAL CONSIDERATIONS ........................................................................... 32 
13.1 
Study design/ endpoints ..................................................................................... 32 
13.2 
Sample Size/Accrual Rate .................................................................................. 32 
13.3 
Data analysis and Primary Objective .................................................................. 33 
13.4 
Statistical considerations for Secondary objectives ............................................. 33 
14. 
PUBLICATION PLAN ................................................................................................. 35 
14.1 
Publication of Results ........................................................................................ 35 
14.2 
Disclosure and Confidentiality ........................................................................... 35 
15. 
REFERENCES .............................................................................................................. 36 
16. 
APPENDICES ............................................................................................................... 38 
16.1 
APPENDIX A:  NATIONAL CANCER INSTITUTE COMMON 
TOXICITY CRITERIA...................................................................................... 38 
16.2 
APPENDIX B:   PERFORMANCE STATUS CRITERIA ................................. 39 
 
 
 


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1. OBJECTIVES 
 
1.1 
Study design 
 
This is an open label phase II, non-randomized study at Dana-Farber/Harvard Cancer Center 
(DF/HCC),  to evaluate the safety and feasibility of omitting granulocyte-colony stimulating factor 
(G-CSF), using pre-specified safety rules, during the Paclitaxel portion of dose- dense Doxorubicin 
and Cyclophosphamide (AC) and Paclitaxel (T) for patients with Stage I-III breast cancer. The 
planned sample size is 125 patients, Patients that have been deemed appropriate for adjuvant or 
neoadjuvant dose dense AC-T chemotherapy by their treating physician will be enrolled in the 
study at the beginning of Paclitaxel. We will examine the feasibility and safety of this strategy, 
and its impact on treatment schedule and costs. A Simon optimal two-stage design will be used to 
monitor the number of patients who are able to complete 4 cycles of Paclitaxel within 7 weeks 
from day 1 (D1) of cycle 1 of Paclitaxel to D1 of cycle 4 of Paclitaxel. The accrual will be halted 
if an excessive number of patients are not able to complete treatment within 7 weeks.  
 
1.2 
Primary Objectives 
 
1.2.1 To evaluate the rate of Paclitaxel treatment completion omitting Neulasta™ 
(Pegfilgrastim) using pre-specified safety rules within 7 weeks (from D1 of cycle 1 of 
Paclitaxel to D1 of cycle 4 of Paclitaxel).   
 
1.3 
Secondary Objectives 
 
1.3.1 Omission of Neulasta™ (Pegfilgrastim) during Paclitaxel portion of dose dense ACT  
 
• 
To characterize the utilization of Neulasta™ (Pegfilgrastim) using pre-specified safety rules 
in patients receiving dose dense Paclitaxel. 
 
• 
To evaluate safety of omitting Neulasta™ (Pegfilgrastim) support using pre-specified safety 
rules in patients receiving dose dense Paclitaxel (according to the Cancer therapy evaluation 
program (CTEP) active version of the National cancer institute (NCI) common terminology 
criteria for adverse events (CTCAE), version 4, Appendix A) 
a. To estimate the rate of hematological toxicity, including the incidence of grade 
3-5 neutropenia and febrile neutropenia among the 4 cycles of Paclitaxel 
b. To estimate the rate of other toxicities grade 3-4 among the 4 cycles of Paclitaxel 
 
• 
To evaluate the schedule impact of omitting Neulasta™ (Pegfilgrastim)  support using pre-
specified safety rules in patients receiving dose dense Paclitaxel: 
a. To estimate the percentage of patients who receive all planned cycles of 
chemotherapy 
b. To characterize reasons for treatment delays (defined as schedule/preference, 
absolute neutrophil count (ANC) < 1,000/mm3, hypersensitivity, neurotoxicity, 
transaminitis, other). 
 
 


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1.3.2 Simplification of the pre-medication used for the Paclitaxel portion of dose dense ACT 
 
• 
To estimate the safety of simplifying the pre-medication regimen used for the Paclitaxel 
portion of the regimen (withholding premedication after 2 cycles without evidence of 
allergic reactions). 
a. To evaluate the rate of hypersensitivity reactions on cycles 3-4 of Paclitaxel, 
when steroid is avoided. 
 
Exploratory Objectives: 
 
• 
To estimate the impact on costs of omitting Neulasta™ (Pegfilgrastim) support using pre-
specified safety rules in patients receiving dose-dense Paclitaxel 
a. To calculate the costs of omitting Neulasta™ (Pegfilgrastim)  using the 
planned treatment algorithm 
 
 
2. BACKGROUND 
 
2.1 
Adjuvant chemotherapy for breast cancer 
 
Multiple randomized clinical trials, supported by meta-analyses, have demonstrated that adjuvant 
chemotherapy significantly reduces the risk of recurrence in women with early breast cancer. The 
Early Breast Cancer Trialists' Collaborative Group estimated a relative risk reduction of 20-30% 
and overall survival (OS) improvement for women with early breast cancer.1 In addition, this same 
group also suggested that adding taxanes to anthracylines is associated with disease-free and 
overall survival gains.1  
 
2.1.1 Dose dense chemotherapy for breast cancer  
 
Over a decade ago a large cooperative group trial [CALGB 9741] which compared sequential 
Doxorubicin (A), Paclitaxel (T), and Cyclophosphamide (C) versus combination AC followed by 
Paclitaxel, all given on either an every 3 week or every 2 week schedule as postoperative treatment 
of node-positive breast cancer demonstrated improvements in survival outcomes [Disease-free 
survival (DFS) and OS] for breast cancer patients treated with “dose dense” schedules in the 
adjuvant setting. At 4 years, dose dense was associated with a risk ratio of 0.74; P = .010 for DFS 
and of 0.69; P = .013 for OS when compared with non- “dose dense regimens”.2 More recently, 
these findings were corroborated by a meta-analysis of 10 randomized controlled trials comparing 
standard vs. “dose dense” chemotherapy regimens, in which, patients who received dose dense 
chemotherapy had better survival outcomes,3 and by another large cooperative group study 
comparing a novel continuous schedule of AC vs. six cycles of AC once every two-weeks followed 
either by weekly Paclitaxel or by six cycles of Paclitaxel once every two weeks which, showed the 
highest OS in the arm using once-every-2-weeks treatment for both AC and Paclitaxel.4  
 
2.2 
G-CSF support in dose dense regimens 
 


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2.2.1 Use of Neulasta™support in dose dense regimens 
 
Historically, neutrophil recovery was the limiting factor in crafting chemotherapy schedules. The 
emergence of Neulasta™allowed the design and subsequent sucess of dose dense regimens. In the 
studies that tested dose dense ACT, no difference in the number of treatment delays and grade 3 
and 4 adverse events, particularly in the hematologic adverse events was found between the dose 
dense with Neulasta™support and conventional treatment arms.2 In a  prospective study that used 
Neulasta™ in D2 of every cycle of dose dense ACT, there were less than 2% of treatment delays 
due to hematologic toxicity; 88.6% of patients who started Paclitaxel completed the 4 cycles, with 
a mean cycle duration of 14 days and >85% of patients received planned chemotherapy dose on 
time.5  
 
2.2.2 Omitting Neulasta™in Paclitaxel portion of dose dense ACT 
 
Although G-CSFs are well-tolerated, they are not completely devoid of adverse reactions, the most 
common one being medullar bone pain, reported in ~ 25% of subjects. In addition, other adverse 
reactions such as leukocytosis, transient thrombocytopenia, increased risk of secondary 
myelodisplastic syndromes and acute myeloid leukemia, rare case of splenic ruptures, adult 
respiratory distress syndrome (ARDS), allergic type reactions, and severe sickle cell crisis have 
been reported in patients receiving G-CSF.6,7  Moreover, the use of Neulasta™ adds considerable 
expenses and represents the major driver of the variation in costs among treatments used for early 
breast cancer. A recent analysis described a 20-fold increase in costs for dose dense ACT regimen, 
primarily due to the need of growth factor.8 
 
Recently, it has been questioned whether the support of G-CSF is needed during all the cycles of 
a dose dense chemotherapy schedule. AC and Paclitaxel have different toxicity profiles, and it is 
well known that Paclitaxel is associated with a less myelosuppressive profile, in the CALGB 40101 
trial, the incidence of any grade 3 or higher hematologic toxicity was considerably higher in the 
AC arms compared with the Paclitaxel arms.9 In a prospective experience from the Dana-Farber 
Cancer Center, the absolute neutrophil count during the AC portion of dose dense ACT was 
5,000/L and during the Paclitaxel portion was 10,000/L.5 
 
To our knowledge, only one prospective trial has been conducted without G-CSF support in dose 
dense Paclitaxel. The primary endpoint of the trial was feasibility and tolerability of Paclitaxel 
every 2 weeks without G-CSF support defined as the absence of neutropenic fever and neutropenia 
on the day of planned treatment. Patients were considered eligible for the study if they had an 
absolute neutrophil count of 1,500/mm3. The granulocyte count was repeated on the day of each 
planned treatment and if the count was less than 1,000/ mm3 the patient would be considered an 
“attempt to treat failure” and would drop out study. No pre-specified safety rules were applied. 
Fifty-four patients were initially enrolled in the trial, which was terminated when the sixth patient 
could not be treated on time because of neutropenia. At the time of study termination, 15 patients 
were evaluable, only 9 of whom completed the entire course of chemotherapy without treatment 
delays.10  
 
In contrast to this negative experience, two recent retrospective experiences suggest that there may 
be a role of omitting G-CSF in selected patients. 


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In the retrospective study from SUNY Upstate Medical University, Syracuse, of 115 patients, 109 
received no G-CSF support during the Paclitaxel portion. 88 patients completed all the 4 planned 
cycles of Paclitaxel and only 5 patients had dose delays, with only a small minority developing 
neutropenic complications.11 In a retrospective experience of our institution, of 155 patients treated 
with dose dense ACT 13.6% did not receive any G-CSF support during the Paclitaxel portion of 
the regimen. Among those, who did not receive G-CSF, there were no treatment delays nor 
neutropenia, and 90.4% completed the 4 cycles of Paclitaxel treatment on time (Table 1). The 
median absolute neutrophil count among these patients ranged 2,820-3,612/mm3, minimum ranged 
from 1,480-1,670/mm3 and maximum ranged from 5,960-19,260/mm3. 12  
 
Table 1. Chemotherapy Cycles Administered. 
 
Patients who did not receive  
any G-CSF 
Patients who received G-CSF in at least  one cycle  
Treatment 
completion  
Delays   Duration of cycle 
length (weeks) 
Use of G-
CSF 
Treatment 
completion  
Delays   Duration 
of 
cycle 
length (weeks) 
Cycle  
 N (%) 
 N (%) 
Median Range  N (%) 
  N (%) 
 N (%) 
Median Range  
5 
21 (100%)  
 NA 
2 
2-2 
130 (97%) 
134 (100%) 
NA 
2 
2-5 
6 
19 (90%) 
0 (%) 
2 
2-2 
102 (77%) 
131 (98%) 
6 (5%) 
2 
2-4 
7 
 19 (90%) 
0 (%) 
2 
2-2 
100 (78%) 
127 (95%) 
2 (2%) 
2 
2-3 
8 
19 (90%) 
0 (%) 
NA 
NA 
74 (58%) 
127 (95%) 
1 (1%) 
NA 
NA 
 
In addition, in this study there was important variation in the use of G-CSF among providers 
(Figure 1), which by itself reveals the uncertainty on the need to use G-CSF in the Paclitaxel 
portion of dose dense ACT.12  
 
 
 
 
 
 
 
Figure 1. Use of G-CSF by providers/patient 
 


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The G-CSF could be more cost-effectively and cautiously applied to patients with identified risk 
factors and to those who are more likely not to manage to complete all the scheduled cycles of 
Paclitaxel without myeloid growth factor support.  
 
2.2.3 Risk of myelosuppression  
 
In a prospective cohort study, Lyman et al. validated a model to identify patients at greater risk for 
severe neutropenia or febrile neutropenia as the result of cancer chemotherapy in the community 
setting. Several factors were significantly associated with cycle 1 severe or febrile neutropenia in 
the final model and included: a history of previous chemotherapy, patients on other 
immunosuppressive medications, patients with elevated aspartate aminotransferase (AST), 
alkaline phosphatase or bilirubin, or reduced white blood count or reduced estimated glomerular 
filtration rate. Neutropenic events occurred in cycle 1 in 34% of patients classified as high risk 
compared with only 4% of those classified as low risk ( using these variables as classifiers).13   
We plan to use this information to identify patients for whom we can safely omit G-CSF during 
cycles of dose dense Paclitaxel. 
 
2.3 
Rationale 
 
Dose-dense chemotherapy has been proven to offer a survival advantage in the adjuvant treatment 
of breast cancer. Growth factor support is thought to be required in order to allow bone marrow 
recovery and facilitate the administration of chemotherapy in an every two week schedule.  
Nevertheless, G-CSF is not devoid of adverse effects, and adds significant costs to treatment. The 
different drugs employed in a dose-dense ACT regimen have different toxicity profiles, with 
Paclitaxel being the less myelotoxic drug than the AC combination.  The uncertainty regarding the 
safety of omitting Neulasta™ (Pegfilgrastin) in the Paclitaxel portion of dose dense ACT leads to 
significant variability in its use. In this study, we aim to define if, by using pre-specified safety 
rules, a subset of patients can undergo the Paclitaxel portion of dose-dense ACT without growth 
factor support, and complete all cycles of planned treatment timely fashion. 
2.4 
Secondary studies background 
 
 
Providers 
G-CSF use/patient 


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2.4.1 Pre-medication for dose dense Paclitaxel  
 
In early trials, hypersensitivity reactions to Paclitaxel occurred in up to 30 percent of patients 
receiving Paclitaxel, and some, were life-threatening and regimen-limiting. After the introduction 
of premedication with antihistamines and glucocorticoids and after prolonging infusion time the 
rate of severe reactions was reduced to 2 to 4 percent.14,15 
 
For Paclitaxel, conventional practice is to administer 12-20 mg of dexamethasone orally prior to 
drug administration, with H1- and H2- receptor antagonists administered IV 30 minutes prior to 
drug infusion  and with this approach the rate of severe infusion reactions is around 1-2%.16 
 
The vast majority of the reactions occur in the first 2 cycles.  In a study of 450 patients pre-treated 
with this regimen, 44 (approximately 9% of the patient population) experienced a total of 71 
episodes of clinically relevant Paclitaxel-associated hypersensitivity reactions.  48% of the total 
reactions occurred during the initial course of Paclitaxel, with 23%, 13%, 8%, and 4% reactions 
developing during cycles 2, 3, 4, and 5, respectively. Seventy-seven percent of the 44 patients who 
developed a Paclitaxel-associated hypersensitivity reaction experienced their first episode during 
their initial treatment with the agent, whereas 18% had their first reaction during cycle 2. Only 5% 
experienced an initial reaction to Paclitaxel after the second course of treatment with the drug.17 
 
Given this experience, for patients who did not have reactions within the first two cycles, our group 
began using a simplified schema to reduce glucocorticoid exposure. In this schema we omit the 
steroids received at 12 hours prior treatment. In this sub-study we aim to validate the safety of this 
approach. 
 
3.  PARTICIPANT SELECTION 
 
Participants must meet the following criteria on screening examination to be eligible for the 
study. All laboratory tests required for eligibility must be completed within 14 days prior to 
study entry. Other non-laboratory tests must be performed within 3 months of study entry. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed Stage I-III breast cancer (as 
defined by the revised, AJCC 7th edition criteria) and be at sufficient risk for tumor 
recurrence.  Staging studies to exclude metastatic disease are not required in 
asymptomatic patients. However, patients with findings considered suspicious for 
metastatic disease on any staging studies that are obtained need to be evaluated to 
exclude stage IV breast cancer. 
 
3.1.2 Patients must be deemed by their treating oncologist as candidates for (neo) adjuvant 
chemotherapy with dose dense ACT.  
 
3.1.3 Age ≥ 18 years and < 65 at the time of informed consent.   
 


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3.1.4 ECOG performance status (PS) ≤ 1 (Appendix B). 
 
3.1.5 Any grade 3 or clinically significant grade 2 treatment-related non-hematological toxicity 
must be resolved to grade 1 before retreatment with chemotherapy (with exception of 
alopecia) 
 
3.1.6 Laboratory Evaluations: 
• Adequate blood marrow function defined as:  
o Absolute neutrophil count (ANC) ≥1500 L, 
o Hemoglobin  ≥9.0 g/dl 
o Platelets  ≥100,000/mm3 
• Adequate hepatic function defined as:  
o Total bilirubin ≤ 1.2 institutional upper limit of normal (ULN) 
o AST(SGOT), ALT(SGPT), alkaline phosphatase ≤ 1.5 X ULN  
• Adequate renal function defined as: 
o Serum creatinine ≤ 1.5 X ULN  
• Premenopausal women (including women who have had a tubal ligation and for 
women less than 12 months after the onset of menopause) must have a negative 
serum pregnancy test. 
 
 
3.1.7 Patients with risk factors for Hepatitis B or C should be tested (anti-HCV antibody, 
HBsAg or anti-HBc).  If infection is suspected, HBV DNA and HCV RNA should be 
requested as appropriate.  
 
Note: Patients with positive Hepatitis B or C serologies without known active disease 
must meet the eligibility requirements for ALT, AST, total bilirubin, and alkaline 
phosphatase and must have a normal INR on at least two consecutive occasions, 
separated by at least 1 week, within the 30 day screening period. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have received previous cytotoxic chemotherapy including an AC-T regimen 
or previous therapeutic radiation therapy for any reason in the last 5 years. Because of 
possible limitations in bone marrow reserve, patients with such prior treatments are not 
appropriate candidates for this trial. Patients who have had prior hormonal therapy (for 
instance, tamoxifen for prevention of breast cancer) are eligible. Patients who have 
participated in a window study (treatment with an investigational agent prior to surgery 
for ≤2 weeks) are eligible but must have discontinued the investigational agent at least 14 
days before enrollment. 
 


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3.2.2 Participants who are receiving any other investigational agents 
 
3.2.3 Have had at least one prior episode of fever and neutropenia (ANC< 500/mm3 or 
expected to fall below < 500/mm3) during AC. 
 
3.2.4 Patients taking lithium. 
 
3.2.5 Patients receiving chronic treatment with oral steroids or another immunosuppressive 
agent (excluding steroids as part of the chemotherapy pre-medication or emetic 
medication).  
 
3.2.6 Known HIV-positive individuals or with any immunodeficiency status. 
 
3.2.7 Patients with history of hematologic disease, including myelodisplasia or bone marrow 
malignancies. 
 
3.2.8 History of allergic reaction attributed to compounds of similar chemical or biologic 
composition to Paclitaxel, which cannot be managed by premedication. 
 
3.2.9  Currently pregnant or breast-feeding. 
 
3.2.10 Uncontrolled intercurrent illness including, not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements 
or other significant diseases or disorders that, in the investigator’s opinion, would exclude 
the subject from participating in the study.  
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the 
initiation of protocol therapy. Any participant not registered to the protocol before protocol 
therapy begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
 


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Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the QACT Registrar of registration cancellations as soon as 
possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
• Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295.  
 
• The QACT Registrar will (a) review the eligibility checklist, (b) register the participant 
on the protocol. 
 
• An email confirmation of the registration will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment regimen: Chemotherapy administration, Neulasta™ (Pegfilgrastim) and 
Supportive Measures 
 
Treatment will be administered on an outpatient basis. Pre-treatment criteria are described in 


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Section 5.2. Reported adverse events and potential risks are described in Section 7. Appropriate 
treatment and dose modifications for adjuvant chemotherapy are described in Section 6. 
 
Patients may receive treatment as adjuvant therapy after breast surgery, or as part of a 
neoadjuvant treatment program (see Section 5.3.2). 
 
5.1.1 Paclitaxel 
 
Following completion of 4 cycles of dose dense AC, patients will start protocol therapy and 
receive dose dense Paclitaxel, consisting of: 
 
Paclitaxel 175 mg/m2 IV as an approximately 3 hour infusion once every 2 weeks x 4 cycles 
(total of 4 doses). The day of treatment is day 1. The chemotherapy dose is determined by actual 
body weight on the day of treatment for cycle 1. If there is a ≥5% weight modification the dose 
will be modified accordingly.  
 
Paclitaxel therapy will begin two weeks after the last dose of AC chemotherapy.  
 
Prior to receiving the first and second dose of Paclitaxel, patients should be pre-medicated 
with the following to reduce the risk of hypersensitivity reactions:  
 
- Dexamethasone 12 mg PO taken approximately 2-6 hours prior to infusion;  
- Diphenydramine 25 or 50 mg PO/IV approximately 30-60 minutes prior to infusion; 
- Any histamine H2 blocker (ranitidine 150 mg PO or 50 mg IV; famotidine 20mg; or 
equivalent) approximately 30-60 minutes prior to infusion.  
 
If after completion of the first 2 cycles no hypersensitivity reaction has occurred, the 
Dexametasone will be withdrawn, otherwise the regimen will be maintained.   
 
Suggested management of Paclitaxel hypersensitivity reactions is as follows. Investigators 
may use clinical judgment for diverge from guidelines below as clinically indicated.  
 
Mild symptoms: localized cutaneous reactions such as mild pruritus, flushing, or rash: 
- Consider decreasing the rate of infusion until recovery from symptoms, stay at bedside and 
monitor patient. Assess vital signs. If symptoms resolve or do not progress, complete 
Paclitaxel infusion at the initial planned rate. 
 
Moderate symptoms: any symptom that is not listed above (mild symptoms) or below (severe 
symptoms) such as generalized pruritus, flushing, rash, or dyspnea, hypotension with systolic BP 
80 mmHg: 
- Interrupt Paclitaxel infusion 
- Assess vital signs, including oxygen saturation 
- Give dyphenydramide 50 mg IV with or without dexamethasone 10 mg IV 
- Monitor patient until resolution of symptoms 
- Resume Paclitaxel infusion after recovery of symptoms; depending o the physician’s 
assessment of the patient, the Paclitaxel can be resumed at a slower infusion rate, and then 


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increased incrementally to the planned rate of infusion 
- Depending on the intensity of the observed reaction, additional oral or intravenous 
premedication should also be given prior to the next cycle of treatment, and the rate of 
infusion should be decreased initially and the increased back to the recommended rate. 
 
Severe symptoms: any reaction such as bronchospasm, generalized urticaria, hypotension with 
systolic BP < 80 mmHg, angioedema: 
- Discontinue Paclitaxel infusion 
- Assess vital signs, including oxygen saturation 
- Alert treating physician 
- Give diphenydramine 50 mg IV with or without dexamethasone 10 mg IV with or 
without epinephrine 0.1 cc 1:1000 solution SC 
- Consider supplemental oxygen therapy and intravenous fluid therapy 
- Monitor patient until symptoms resolve 
- Re-treat as per recommendations under moderate symptoms 
 
Anaphylaxis (toxicity grade 4): 
- Treat patient as for severe symptoms 
- Patient taken off study 
 
Patients may use analgesics to control symptoms of mylagias/arthralgias related to Paclitaxel 
use. 
 
5.1.2 Neulasta™ (Pegfilgrastim) 
If required by the protocol algorithm (section 5.2.2), Neulasta™ (pegfilgastrim) with be used for 
growth factor support. 
 
Neulasta™ (pegfilgastrim) will be administered as follows: 
- Neulasta™ (pegfilgastrim) 6 mg SQ x1 is administered on day 2 of each treatment cycle, 
approximately 24 hours after the chemotherapy treatment. 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 Chemotherapy pre-treatment criteria 
 
In order to initiate each cycle of chemotherapy (Paclitaxel) the following is needed: 
- ANC≥ 1000/mm3 
- Platelets ≥100.000/mm3 
 
If these criteria are not met, treatment must be delayed until counts return to ANC≥ 1000/mm3 
and Platelets ≥100.000/mm3.  It is recommended that these values be checked 3 days after the 
scheduled day. Refer to Section 6.0 for dose modification guidelines.  
 
5.2.2 Use of Neulasta™ (Pegfilgrastim) during treatment with Paclitaxel chemotherapy 
 
Neulasta™ (Pegfilgastrim) will be administered during treatment with Paclitaxel, if: The 


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patient experiences a prior episode of fever and neutropenia.  
 
Neulasta™ (Pegfilgastrim) will be administered at the discretion of the treating investigator during 
treatment with Paclitaxel, if: 
- If the patient has an active infection this decision will be at provider discretion. 
- Treatment delays of > 1 week  
 
 
If Neulasta™(Pegfilgrastim) is administered in any Paclitaxel cycle for a given patient, it will be 
then administered for all future cycles. Administration of Neulasta™(Pegfilgrastim)  will be as 
outlined in section 5.1.2. 
 
 
5.3 
Duration and sequencing of therapy 
 
5.3.1 Duration of treatment 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to a 
maximum of 4 cycles of Paclitaxel, or until one the following criteria applies: 
 
1. Disease progression; 
2. Intercurrent illness that prevents further administration of treatment; 
3. Unacceptable adverse event(s) per provider discretion; 
4. Patient decides to withdraw from the study;  
5. General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.3.2 Sequencing of treatment 
 
This protocol is generally intended as a trial of adjuvant therapy, with the administration of 
therapy following definitive breast surgery. However, patients may receive neoadjuvant 
chemotherapy treatment at the same doses and schedules as outlined above. In such instances, 
patients may receive 4 cycles of dose dense Paclitaxel as preoperative therapy. 
 
 
 
5.4 
Duration of Follow up 
 
Participants will be followed for 4 weeks after the last cycle of Paclitaxel or until stabilization of 
adverse events. It is recommended that a 4-8 week post-taxol visit take place with a provider, 
subsequent visits can occur with clinical staff by phone.  If the 4-week post-taxol visit creates 
significant burden for the patient, it is acceptable to do this visit by phone.  
 
5.5 
Criteria for Taking a Participant Off Study 
 
Participants will come off study once they have completed the duration of follow-up required or 
if they choose to end their participation. The reason for study removal and the date the 
participant was removed must be documented in the study-specific case report form (CRF). 


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In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Dr. Lin by phone 617-632-2335 OR by pager: 
42012. 
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
5.6.1 Antibiotics 
 
The use of prophylactic antibiotics such as cyprofloxacin (or equivalent) is prohibited in the 
study.  
 
5.6.2 Anticoagulants 
 
The use of systemic anticoagulation is not a contraindication to participation in the trial. Patients 
requiring such therapy should be appropriately monitored to ensure that they are not excessively 
anticoagulated. 
 
5.6.3 Red blood  cell (RBC) Transfusion  
 
The optimal Hgb for initiation of RBC transfusion is not well characterized. In general, ASCO 
guidelines and DF/HCC clinical guidelines suggest that Hgb be less than 10 g/dl before 
consideration of transfusion. Thus, RBC transfusion is left to the discretion of the treating 
clinician, but should not be initiated in patients with Hgb ≥ 10 g/dl. 
 
5.6.4 Other supportive care 
 
The intent of this protocol is to evaluate the safety and feasibility of omitting Pegfilgrastim 
support in the Paclitaxel portion of dose dense ACT. Any and all appropriate supportive 
measures not related to neutrophil recovery/function should be given as warranted to patients, 
using standard clinical judgment. 
 
5.6.5 Concurrent Therapy 
 
Patients may receive other appropriate medical treatments while undergoing dose dense adjuvant 
treatment, with the following exceptions: 
 
• Patients may not receive concurrent radiation therapy 
 
• Consistent with current clinical practice, patients should receive adjuvant hormonal 
therapy at the conclusion of chemotherapy treatment, and not while on study. 
However, use of adjuvant hormonal treatment is permitted if deemed medical 
necessary. Patients may for example be on ovarian suppression prior concurrently 
with chemotherapy. 
 


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• Patients may not receive other concurrent experimental therapy or be participating in 
other clinical trials that are designed as anti-neoplastic therapy. Patients may 
participate in supportive care studies, including use of biphosphonates, that do not 
affect utilization of growth factors or chemotherapy treatments 
 
5.6.6 Iron and nutritional supplements 
 
Patients who, during the course of the treatment, have evidence of iron or metabolite deficiency 
(e.g. folate or B12 deficiency) should receive appropriate repletion therapy. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
ACT dose-dense is a standard regimen used for early breast cancer.  
 
Dose delays and modifications will be made using the following recommendations and per 
treating physician discretion. Toxicity assessments will be done using the CTEP Active Version 
of the NCI CTCAE which is identified and located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be implemented per treating physician discretion. 
 
Grade 3-4 AEs experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit.  
 
6.1 
Chemotherapy 
 
6.1.1 Hematological toxicity 
 
Chemotherapy treatment with AC or Paclitaxel should be held if the ANC < 1000 l or PLT < 
100,000 l on the scheduled day of treatment. Chemotherapy should be administered as soon as 
reasonably possible once the ANC or PLT have recovered to allow treatment. If grade 3 or 4 
thrombocytopenia, treatment should be resumed, with a recommended 20% dose reduction in taxol 
dose. If grade 3 or 4 neutropenia without fever occurred for ≤ 7 days in the absence of growth 
factors, taxol dose should be maintained. In this situation, the use of prophylactic Pegfilgrastim is 
not manadatory per protocol, but it can be administered at the discretion of the treating investigator. 
If grade 3 or 4 neutropenia occurred in the presence of growth factor support, taxol dose should be 
reduced by 20%. If treatment delay of more than one week is required, taxol dose should be 
maintained and growth factor should be instituted when the cycle resumes (i.e. day 2 of the 
following cycle and subsequent cycles). If a delay ≥ 21 days is required it is recommended that the 
patient discontinue AC or Paclitaxel, but this decision will be per physician discretion 
 
6.1.2 Febrile neutropenia 
 
A 20% dose reduction in taxol dose was recommended in patients following episodes of febrile 


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neutropenia while receiving dose dense adjuvant chemotherapy in CALGB 9471. For patients not 
treated with prophilatic Pegfilgrastim, Pegfilgrastim should be instituted. 
 
6.1.3 Gastrointestinal toxicity 
 
Patients who develop gastrointestinal toxicity (mucositis, dysphagia, nausea, vomiting, diarrhea, 
constipation) in excess of grade 3 should have chemotherapy held until symptoms have resolved 
to grade 0 or 1. Chemotherapy dose is not reduced for grade 2 or 3 gastrointestinal toxicity. Patients 
with grade 4 gastrointestinal toxicity should have chemotherapy dose(s) reduced by 20% at the 
time of treatment. 
 
6.1.4 Hepatic toxicity 
 
Patients should have bilirubin ≤ 1.2 ULN at the time of each chemotherapy treatment. Contact the 
principal investigators if treatment delay in excess of one week is required. 
 
6.1.5 Neurotoxicity 
 
Paclitaxel will be discontinued for neurotoxicity of grade 3 or greater. For clinically significant 
grade 2 neurotoxicity, chemotherapy should be held until symptoms resolve to grade 1 or below. 
If symptoms resolve to grade 1 or below within 1 week, Taxol dose reduction is not required, but 
a 20% dose reduction may be considered at the discretion of the treating provider. If symptoms 
resolve after more than 1 week but less than 21 days, Taxol should be administered at a 20% dose 
reduction. If a delay ≥ 21 days is required it is recommended that the patient discontinue Taxol, 
but this decision will be per physician discretion 
 
 
6.1.6 Myalgias/arthralgias 
 
Chemotherapy dose or schedule is not affected. It is suggested that patients receive appropriate 
symptom control with analgesics and/or corticosteroids as required. 
 
6.1.7 Extravasation/phlebitis 
 
Skin damage or phlebitis from chemotherapy may occur. Extravasation should be treated urgently 
according to nursing and institutional practice. Chemical irritation on phlebitis are not reasons for 
discontinuing therapy, however, and chemotherapy can continue to be administered through 
appropriate intravenous access sites. 
 
6.1.8 Genitourinary Toxicity 
 
At the discretion of the treating physician, patients may receive mesna if they experience gross 
hematuria or symptomatic cystitis related to chemotherapy 
 
6.1.9 Other toxicity 
 


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Other grade 3 or clinically significant grade 2 treatment-related non-hematological toxicity should 
resolve to grade 1 before retreatment with chemotherapy and reduce Taxol by 20%. (with 
exception of alopecia).  
 
6.2 
Neulasta™ (Pegfilgrastim)  
 
There is no dose or schedule modification to Neulasta™ (Pegfilgrastim). Patients with bone pain 
related to administration of Neulasta™ (Pegfilgrastim) should be treated with appropriate 
analgesics. 
 
 


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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Chemotherapy 
 
While widely studied and used, Paclitaxel chemotherapy carries many potential side effects, some 
of which may be life-threatening of even fatal. Toxic side effects include bone marrow suppression 
(neutropenia, anemia, and thrombocytopenia, with risks of infection, sepsis, bleeding, fatigue, and 
the requirement for transfusion of blood products): hair loss: nausea: vomiting< diarrhea, 
mucositis, anorexia, liver function tests abnormalities, myalgias, arthralgias, flu-like symptoms, 
seizures, pharyngitis, and skin reactions. Local infiltration of Paclitaxel may cause erythema and 
discomfort that usually resolves in one week. 
 
Paclitaxel administration can be associated with acute anaphylactic reactions, including flushing, 
fever, urticaria, dyspnea, hypotension, and anaphylactic shock. Paclitaxel administration may 
cause transient bradycardia, chest pain, and myocardial infarction. See section 5.2.2 for  
Paclitaxel can cause peripheral neuropathy, which can be painful. Paclitaxel chemotherapy can 
cause ovarian failure, with cessation of menses and other symptoms of menopause such and hot 
flashes, weight gain, and vaginal dryness. 
 
In the recent CALGB 40101, the rate of selected grade 3 and 4 adverse events during the protocol 
therapy by treatment were as follows for 4 cycles of Paclitaxel (which was administered every 2)9: 
 
Table 3. Selected grade 3 and 4 adverse events during 4 cycles of Paclitaxel 
Adverse events 
% of events for 4 cycles of Paclitaxel 
 
Grade 3 
Grade 4 
Hemoglobin 
<1 
0 
Neutropenia 
2 
1 
Febrile neutropenia 
<1 
0 
Thrombocytopenia  
<1 
0 
Neuropathy 
5 
<1 
Diarrhea 
1 
0 
Vomiting  
<1 
<1 
Fatigue  
1 
<1 
Arthralgia 
2 
0 
 
 
Toxicity analyses with dose dense sequential ACT have noted that grade 4 neutropenia was less 
common in patients receiving dose dense ACT with G-CSF support than with standard 
chemotherapy scheduling where G-CSF was not routinely employed, though more lymphopenia 


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and anemia were noted. There was no apparent difference in the risk of secondary cancers, 
including leukemia, with dose dense therapy compared to standard dose scheduling, nor of 
cardiotoxicity. The risk of leukemia in CALGB 9741 was approximately 0.2% through 3 years of 
follow-up. One percent of patients receiving dose dense ACT had grade 3 or 4 cardiotoxicity, 
compared to 2.3% receiving the standard treatment schedule. There was a small increase in 
neurotoxicity with dose dense therapy; among such patients, 4.5% had grade 3 or 4 neurotoxicity 
compared to 3.9% with standard dose scheduling. 
 
7.1.2 Neulasta™ (Pegfilgastrim) 
 
The most common adverse event attributed to Neulasta™ (pegfilgrastim) in clinical trials was 
medullar bone pain, reported in 26% of subjects, which was comparable to the incidence in 
Filgrastim-treated patients and it is generally reversible with non-narcotic agents. This bone pain 
was generally reported to be mild-to-moderate severity. Approximately 12% of all subjects utilized 
non-narcotic analgesics and less than 6% utilized narcotic analgesics. No patients withdrew from 
the study due to bone pain. Reversible elevations in LDH, alkaline phosphatase and uric acid have 
been observed in clinical trials. Neulasta™ (Pegfilgrastim) has also been associated with 
leukocytosis and transient thrombocytopenia.  
 
7.2 
Adverse Event Characteristics 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
(Refer to appendix A) 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 


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7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
7.3.2 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All grade 3-4 Adverse Events must be reported in routine study data submissions to the Overall 
PI on the toxicity case report forms.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTIC INFORMATON 
 
8.1 
Chemotherapy 
 
Paclitaxel (Taxol) is a commercially available chemotherapeutic agent. The drug should be stored, 
reconstituted, prepared for administration, and administered according to manufacturer’s 
guidelines in the package insert, and in accordance with standard institutional practices. 
 
8.2 
Neulasta™ (Pegfilgastrim) 
 
8.2.1 Availability 
 
Neulasta™ (pegfilgastrim) is commercially available from Amgen.  
 
8.2.2 Packaging and formulation 
 
Neulasta™ (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G-CSF 
(filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble 175 amino acid 
protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained 
from the bacterial fermentation of a strain of E coli transformed with a genetically engineered 
plasmid containing the human G-CSF gene. To produce Neulasta™ (pegfilgrastim), a 20 kD 
monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl 
residue of filgrastim. The average molecular weight of Neulasta™ (pegfilgrastim) is 
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Neulasta™ (pegfilgrastim) is supplied in 0.6 mL prefilled syringes for subcutaneous injection. 
Each syringe contains 6 mg pegfilgrastim (based on protein weight) in a sterile, clear, colorless, 
preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), 
sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP. 
 
8.2.3 Storage conditions and stability 
 
Neulasta™  is supplied in a prefilled single use syringe containing 6 mg pegfilgrastim, supplied 
with a 27-gauge, 1/2-inch needle with an UltraSafe® Needle Guard. The needle cover of the 
prefilled syringe contains dry natural rubber (a derivative of latex). Neulasta™  is provided in a 
dispensing pack containing one syringe (NDC 55513-190-01). 
 
Neulasta™  must be stored refrigerated between 2° to 8°C (36° to 46°F) in the carton to protect 
from light, and might not be shaken. Syringes stored at room temperature for more than 48 hours 
must be discarded. Avoid freezing; if frozen, Neulasta ™ should be allowed to thaw in the 
refrigerator before administration. Syringes frozen more than once should be discarded. 
 
8.2.4 Preparation and administration 
 
No preparation is required for administration of Neulasta™ (pegfilgrastim). Each subject will 
receive a fixed dose of 6 mg of pegfilgrastim. The entire contents of the 0.6 mL prefilled syringe 
should be administered irrespective of the subject’s actual weight. 
 
8.2.5 Overdosage 
 
The maximum amount of Neulasta™  (pegfilgrastim) that can be safely administered in single or 
multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been 
administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious 
adverse effects. These patients experienced a mean maximum absolute neutrophil count (ANC) of 
55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum 
ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 
109/L. The duration of leukocytosis ranged from 6 to 13 days. The effectiveness of leukapheresis 
in the management of symptomatic individuals with Neulasta™ -induced leukocytosis has not 
been studied. 
 
8.2.6 Toxicity/Warnings 
 
Neulasta™ (pegfilgrastim) is contraindicated in patients with known hypersensitivity to E coli-
derived proteins, pegfilgrastim, filgrastim, or any other component of the product. In addition, 
the following events have also been reported: Splenic rupture, including fatal cases, can occur 
following the administration of Neulasta™. Evaluate for an enlarged spleen or splenic rupture in 
patients who report left upper abdominal or shoulder pain after receiving Neulasta™. 
- Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can 
occur in patients receiving Neulasta™. Evaluate patients who develop fever and lung 
infiltrates or respiratory distress after receiving Neulasta™, for ARDS. Discontinue 
Neulasta™  in patients with ARDS. 


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- Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in 
patients receiving Neulasta™. The majority of reported events occurred upon initial 
exposure. Allergic reactions, including anaphylaxis, can recur within days after the 
discontinuation of initial anti-allergic treatment. Permanently discontinue Neulast™ a in 
patients with serious allergic reactions. Do not administer Neulasta™ to patients with a 
history of serious allergic reactions to pegfilgrastim or filgrastim. 
 
- Use in Patients with Sickle Cell Disorders Severe sickle cell crises can occur in patients 
with sickle cell disorders receiving Neulasta™. Severe and sometimes fatal sickle cell 
crises can occur in patients with sickle cell disorders receiving filgrastim, the parent 
compound of pegfilgrastim. 
 
- Potential for tumor growth stimulatory effects on malignant cells. The G-CSF receptor 
through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The 
possibility that pegfilgrastim acts as a growth factor for any tumor type, including 
myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not 
approved, cannot be excluded. 
 
8.2.7 Pregnancy and Lactation 
 
There are no adequate and well-controlled studies in pregnant women¸ neither it is known whether 
pegfilgrastim is secreted in human milk. Therefore, pregnant or nursing mothers may not take part 
in this study. 
 
8.2.8 Drug interactions 
 
No formal drug interaction studies between Neulasta™  and other drugs have been performed. 
Increased hematopoietic activity of the bone marrow in response to growth factor therapy may 
result in transiently positive bone-imaging changes. Consider these findings when interpreting 
bone-imaging results. 
 
Drugs such as lithium may potentiate the release of neutrophils; patients receiving lithium are 
ineligible for the study. 
 
8.2.9 Preparation and administration 
 
No preparation is required for administration of (Neulasta™). Each subject will receive a fixed 
dose of 6 mg of Neulasta™. The entire contents of the 0.6 mL prefilled syringe should be 
administered irrespective of the subject’s actual weight. 
 
 
9.  STUDY CALENDAR 
 
9.1 
Study tests, procedures and treatment schedule  
 


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Table 2 presents the Schedule of Visits and Procedures. During the treatment period, visits 
should occur within +/- 3 days of the scheduled day.  If a subject fails to appear for a scheduled 
study visit, the investigator will make every attempt to contact the subject and determine the 
reason(s) for the missed visit as completely and accurately as possible.  Subjects will only be 
judged as lost to follow-up if they cannot be reached after three documented attempts (1 week 
apart) by the site to contact them.  For the post-treatment visits, visits should occur within +/- 2 
months of the scheduled day. 
 
 
 
Table 4. Study calendar  
a: Laboratory tests required for eligibility must be completed within 14 days prior to study entry. Informed consent to be 
completed within 30 days prior to registration. Patients are able to undergo screening during treatment with AC and should be 
registered to the trial within 14 days of begining treatment with paclitaxel.    
b: Sodium, potassium, chloride, bicarbonate, BUN, creatinine, total protein, albumin, total bilirubin, SGOT(AST), 
SGPT(ALT), Alkaline Phosphatase. At baseline, patients with high risk factors for Hepatitis B or C should be tested (anti-
HCV antibody, HBsAg and anti-HBc-positive). In case of suggestion of infection a HBV DNA or HCV RNA-positive should 
be requested as appropriate. Patients with positive Hepatitis B or C serologies should have an ALT, AST, total bilirubin, 
alkaline phosphatase, INR, sample collected on at least two consecutive occasions, separated by at least 1 week, within the 30 
day screening period. INR testing is not required for any other patients. 
c: Patients with risk high factors for Hepatitis B or C should be tested (anti-HCV antibody, HBsAg or anti-HBc-positive). In 
case of suggestion of infection a HBV DNA and HCV RNA-positive should be requested as appropriate. Note: Patients with 
positive Hepatitis B or C serologies without known active disease must meet the eligibility requirements for ALT, AST, total 
 
 
TREATMENT PERIOD  
Tests, procedures and treatments 
Pre- 
Study 
a 
Cycle 1 
Day 1  
(week 1) 
Cycle 2 
Day 1  
(week 3) 
Cycle 3 
Day 1  
(week 5) 
Cycle 4 
Day 1  
(week 7) 
Off –Study 
Visit h 
 (4-8 weeks post Taxol) 
Informed consent 
X 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
Xg 
ECOG PS  
X 
 
 
 
 
 
Vital signs, weight, height 
(height at baseline only)  
X 
X 
X 
X 
X 
 
 
CBC w/diff, platelets 
X 
X 
X 
X 
X 
 
Serum chemistry b 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Hepatitis B/Cc 
X 
 
 
 
 
 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
Pregnancy test d 
X 
 
 
 
 
 
PT/INRe 
X 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
 
CHEMOTHERAPY 
 
 
 
 
 
 
Paclitaxel f 
 
X 
X 
X 
X 
 
Neulasta™ (pegfilgrastim) g 
 
 
 
 
 
 


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bilirubin,  alkaline phosphatase  and INR on at least two consecutive occasions, separated by at least 1 week, within the 30 day 
screening period. 
d: Serum pregnancy test (women of childbearing potential). 
e: For patients deemed to be at risk for Hepatitis B and C. 
f: In order to initiate each cycle of chemotherapy (Paclitaxel) the following is needed: ANC≥ 1000/mm3; Platelets 
≥100.000/mm3.If these criteria are not met, treatment must be delayed until counts return to ANC≥ 1000/mm3 and Platelets 
≥100.000/mm3.  It is recommended that these values be checked 3 days after the scheduled day. Refer to Section 6.0 for dose 
modification guidelines.  
g: During Paclitaxel growth factor will be administered if: the patient experiences a prior episode of fever and neutropenia, the 
patient has an active infection, it is at provider discretion the use of Neulasta™. If Neulasta™  is administered in any Paclitaxel 
cycle for a given patient, it will be then administered for all future cycles. 
h:  If the 4-week post-taxol visit creates significant burden for the patient, it is acceptable to do this visit by phone.  
Patients with ongoing grade 3-4 AE will be followed until stabilization or resolution of AE. 
 
 
 
 
 


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10. MEASUREMENT OF EFFECT  
 
Effect will be measured as defined in Section 13. 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting 
 
11.1.1 Method 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
11.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the QACT according to the schedule set by the QACT. 
 
11.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; any 
response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
 


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12. REGULATORY CONSIDERATIONS 
 
12.1 
Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. 
The DF/HCC Overall PI (or Protocol Chair) will disseminate protocol amendment information 
to all participating investigators. All decisions of the IRB concerning the conduct of the study 
must be made in writing. 
 
12.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation 
in this study. The formal consent of a participant, using the IRB approved consent form, must 
be obtained before the participant is involved in any study-related procedure. The consent 
form must be signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be given a copy 
of the signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file.  
 
12.3 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record 
all observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. 
 
12.4 
Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  
 
 
 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study design/ endpoints 
 
This is a DF/HCC single-arm phase II study designated to evaluate the rate of Paclitaxel 
treatment completion omitting Neulasta™ (pegfilgrastim) using pre-specified safety rules within 
7weeks (from D1of cycle 1 of Paclitaxel to D1 of cycle 4 of Paclitaxel). If there is strong 
evidence of lack of feasibility/safety, accrual will terminate early. A Simon Optimal design was 
selected with an overall one-side type I error of 10% and 90% power to detect the difference 
between unacceptable Paclitaxel treatment completion rate (75%) and desirable completion rate 
(85%).  
 
Primary endpoint 
• Paclitaxel treatment completion omitting Neulasta™(pegfilgrastim)  using pre-specified 
safety rules within 7 weeks (from D1of cycle 1 of Paclitaxel to D1 of cycle 4 of 
Paclitaxel) 
 
 
This study will enroll up to 125 patients eligible for the primary analysis.  (We estimated that 5% 
of patients who started AC will not proceed to Paclitaxel).2 
 
The secondary endpoints include: 
• Utilization of Neulasta™ (pegfilgrastim)  using pre-specified safety rules in patients 
receiving dose dense Paclitaxel,  
• Safety of omitting Neulasta™ (pegfilgrastim)  support using pre-specified safety rules in 
patients receiving dose dense Paclitaxel,  
• Impact on schedule of omitting Neulasta™ (pegfilgrastim)  support using pre-specified 
safety rules in patients receiving dose dense Paclitaxel  
• Impact on costs of omitting Neulasta™ (pegfilgrastim)  support using pre-specified safety 
rules in patients receiving dose dense Paclitaxel,  
• Safety of simplify the pre-medication used for the Paclitaxel portion of the regimen,  
 
13.2 
Sample Size/Accrual Rate 
 
If 85% patients completed Paclitaxel treatment within 7 weeks, the Neulasta™ (pegfilgrastim)   
intervention would be considered worthy of further study. A true rate of 75% or less would not 
be of clinical interest. The sample size was chosen to have high power (90%) with a Type I error 
no more than 10%.  
 
In the first stage, 51 evaluable patients will be enrolled. If during the first stage, at any point, a 
total of 12 or more patients do not complete treatment within 7 weeks the trial will be closed 
permanently.  Among the 51 patients enrolled after the first stage, if at least 40 patients 
completing treatment without dose delay, accrual will continue to the third stage where an 
additional 74 evaluable patients will be enrolled.  If there are at least 100 among the 125 
evaluable patients completing treatment without dose delay, the regimen will be considered 


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33 
worthy of further study.  If during the second stage, at any point, a total of 26 patients do not 
complete treatment within 7 weeks the trial will be closed permanently and the study 
intervention would not be of clinical interest.  
 
In addition, observation of 3 FN will trigger the DSMC to make a decision whether the trial 
should be closed to further treatment and enrollment of patients. 
 
If the true response rate is 75%, the chance the regimen is declared ineffective is 91% (exact 
alpha = 0.094) and if the true response rate is 85% the chance that the regimen is falsely declared 
ineffective is 10% (exact power = 0.899). 
  
Based on historical rates of treatment at the DF/HCC, accrual is estimated to be 6-8 per month 
and will be completed between 16-21 months. 
 
Throughout the course of the trial, two patients were registered, but did not move forward with 
participating in the trial. Since the study endpoint is powered to assess feasibility of completion 
of paclitaxel without neulasta, there is statistical justification to replace these two patients so that 
we have 125 evaluable participants for the primary endpoint. As such, we will raise the overall 
accrual to 127. 
 
13.3 
Data analysis and Primary Objective 
 
For this phase II trial, the analysis population is all patients who initiate Paclitaxel. All patients 
who receive at least one dose of Paclitaxel will be evaluable for duration of treatment from the 
time of their first treatment. The primary analysis will evaluate the percent of patients who 
complete Paclitaxel treatment within 7 weeks using a pre-specified algorithm and the decision 
rules give in 13.2.  We will estimate this percentage and a corresponding 95% confidence 
interval (CIs) will be calculated.  
 
13.4 
Statistical considerations for Secondary objectives  
 
13.4.1 Utilization of Neulasta™ (pegfilgrastim)  using pre-specified safety rules in patients 
receiving dose dense Paclitaxel 
 
The proportion and corresponding 95% CI of Neulasta™ (pegfilgrastim)   utilization per cycle 
will be tabulated. If the primary endpoint is met, this study will be considered successful if, in 
addition a substantial of savings is achieved (omission of 25% Neulasta™ (pegfilgrastim)   
without additional expenses, or the equivalent; we will calculate total costs and compare them 
with costs of an historical matched cohort of patients treated with Neulasta™ (pegfilgrastim)).  
 
13.4.2 Safety of omitting Neulasta™ (pegfilgrastim)  support using pre-specified safety rules in 
patients receiving dose dense Paclitaxel 
 
Safety data that will be evaluated include AEs, clinical laboratory results and vital signs.  
Abnormal laboratory values will be flagged.  Treatment-emergent AEs (TEAEs) will be analyzed.  
AEs will be regarded as TEAEs if they started on or after the date and time of administration of 


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34 
the first dose of study treatment or if they were present before the administration of the first dose 
of study treatment and increased in severity during the study.  AEs that are not treatment emergent 
will be listed. 
 
AEs will be graded using CTCAE v 4.0 (Appendix A). Investigators will collect all CTCAE grades 
for all AEs (to assess both increasing and decreasing severity).  AEs will be coded from verbatim 
terms using Medical Dictionary for Regulatory Activities (MedDRA) version 10.0 or above and 
grouped by system organ class (SOC) and preferred term (PT).  Events will be summarized by 
frequency and percentage. 
 
The incidence of TEAEs will be summarized by SOC, PT, CTCAE grade, and relatedness to study 
treatment.  Although a MedDRA term may be reported more than once for a subject, that subject 
will be counted only one time in the incidence count for that MedDRA term by the highest CTCAE 
grade (in the summary by CTCAE grade) and by the closest causal relationship to study treatment 
(in the summary by relatedness to study treatment). 
 
13.4.3 Impact on schedule of omitting Neulasta™ (pegfilgrastim)  support using pre-specified 
safety rules in patients receiving dose dense Paclitaxel 
 
Results will be tabulated appropriately, including the median chemotherapy cycle length, the rate 
of chemotherapy dose reductions, the percentage of patients who receive 85% of planned 
chemotherapy doses, the percentage of patients who receive all planned cycles of chemotherapy 
and reasons for treatment delays (defined as schedule/preference, absolute neutrophil count 
(ANC) < 1,000/mm3, hypersensitivity, neurotoxicity, transaminitis, other). 
 
13.4.4 Impact on costs of omitting Neulasta™ (pegfilgrastim)  support using pre-specified safety 
rules in patients receiving dose dense Paclitaxel 
 
 
We will compare charges/payments for study patients versus a matched set of non-study patients 
who were treated with dose-dense paclitaxel and also received peg-filgrastim at DFCI from 
2012-present. 12  Peg-filgrastim patients will have had reimbursement for this agent, either as a 
facility administered medication or prescription, within the one-year observation window. Study 
and non-study patients will be matched based on their propensity to receive peg-filgrastim; the 
propensity score will be derived from a logistic regression model that includes age, race, co-
morbidity and stage as covariates. Total charges/payments will be calculated during the year 
after diagnosis, adjusted for inflation, and expressed as 2016 $US. We will also assess 
charges/payments for specific services, including facility administered medications (i.e., 
chemotherapy), ED/inpatient hospitalizations, ambulatory clinic visits, and prescriptions.  
 
 
13.4.5 Safety of simplify of the pre-medication used for the Paclitaxel portion of the regimen 
 
We will estimate the rate of grade 3-4 HSR in cycle 3-4.  As a safety stopping rule, we will 
evaluate the rate of grade 3-4 HSR after enrolling 51 patients. If the rate of grade 3-4 HSR in 
cycle 3-4 >10%, omitting steroid as pre-medicine for Paclitaxel in cycle 3-4 would be considered 


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too toxic.  If 2 out of 51patients experienced a grade 3-4 HSR in cycle 3-4, the rate of grade 3-4 
HSR is 4% (90% CI 1-12%). If 2 or more patients experienced a grade 3-4 HSR in cycle 3-4, the 
regimen would be considered too toxic, and this sub-study will be terminated due to safety 
concern. For the remaining study steroid standard regimen across the 4 cycles will be use. 
 
14. PUBLICATION PLAN 
 
14.1 
Publication of Results 
 
We plan to submit the results of this study within 12 months of the first analysis being available.  
 
14.2 
Disclosure and Confidentiality 
 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study.  These obligations of confidentiality and nonuse shall in no way diminish 
such obligations as set forth in the Confidentiality Agreement between the sponsor and the 
investigator. All persons assisting in the performance of this study must be bound by the 
obligations of confidentiality and nonuse set forth in the Confidentiality Agreement. 
 
 
 


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15. REFERENCES 
 
1. 
(EBCTCG) EBCTCG: Effects of chemotherapy and hormonal therapy for 
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. 
Lancet 365:1687-717, 2005 
 
2. 
Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-
dense versus conventionally scheduled and sequential versus concurrent combination 
chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first 
report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 
21:1431-9, 2003 
 
3. 
Bonilla L, Ben-Aharon I, Vidal L, et al: Dose-dense chemotherapy in 
nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled 
trials. J Natl Cancer Inst 102:1845-54, 2010 
 
4. 
Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: a phase III trial 
comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58-
64, 2015 
 
5. 
Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of pegfilgrastim and 
darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer 
chemotherapy. J Clin Oncol 23:8340-7, 2005 
 
6. 
Kuderer NM, Dale DC, Crawford J, et al: Impact of primary prophylaxis 
with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer 
patients receiving chemotherapy: a systematic review. J Clin Oncol 25:3158-67, 2007 
 
7. 
Lyman GH, Dale DC, Wolff DA, et al: Acute myeloid leukemia or 
myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with 
granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 28:2914-24, 2010 
 
8. 
Vaz-Luis I, Hughes ME, Cronin AM, et al: Variation in type of adjuvant 
chemotherapy received among patients with stage I breast cancer: A multi-institutional study. 
Cancer, 2015 
 
9. 
Shulman LN, Berry DA, Cirrincione CT, et al: Comparison of doxorubicin 
and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in 
women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol 32:2311-7, 
2014 
 
10. 
Sugarman S, Wasserheit C, Hodgman E, et al: A pilot study of dose-dense 
adjuvant paclitaxel without growth factor support for women with early breast carcinoma. Breast 
Cancer Res Treat 115:609-12, 2009 
 
11. 
Singh AK, Malhotra A, Lemke SM: A retrospective study of dose-dense 
adjuvant paclitaxel without G-CSF support in patients with breast cancer. J Clin Oncol 31, 2013 
(suppl; abstr e20547), 2013 
 
12. 
Paes F, Vaz Luis I, Losk K, et al: Variation in the use of granulocyte-
colony stimulating factor (G-CSF) for dose dense paclitaxel: A single institution retrospective 
study., 2015 
 
13. 
Lyman GH, Kuderer NM, Crawford J, et al: Predicting individual risk of 
neutropenic complications in patients receiving cancer chemotherapy. Cancer 117:1917-27, 2011 
 
14. 
Wiernik PH, Schwartz EL, Strauman JJ, et al: Phase I clinical and 
pharmacokinetic study of taxol. Cancer Res 47:2486-93, 1987 
 
15. 
Albanell J, Baselga J: Systemic therapy emergencies. Semin Oncol 
27:347-61, 2000 


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16. 
Shepherd GM: Hypersensitivity reactions to chemotherapeutic drugs. Clin 
Rev Allergy Immunol 24:253-62, 2003 
 
17. 
Markman M, Kennedy A, Webster K, et al: Paclitaxel-associated 
hypersensitivity reactions: experience of the gynecologic oncology program of the Cleveland 
Clinic Cancer Center. J Clin Oncol 18:102-5, 2000 
 
 


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16. APPENDICES 
 
 
16.1 
APPENDIX A:  NATIONAL CANCER INSTITUTE COMMON TOXICITY 
CRITERIA  
 
The National Cancer Institute’s CTCAE v 4.0 published 28 May 2009 provides descriptive 
terminology to be used for AE reporting in clinical trials.  A brief definition is provided to clarify 
the meaning of each AE term.  To increase the accuracy of AE reporting, all AE terms in 
CTCAE version 4.0 have be correlated with single-concept, MedDRA® terms. 
Grades in CTCAEs v 4.0 refer to the severity of the AE.  Grades of 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline: 
 
Grade 
Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.* 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL.** 
4 
Life-threatening consequences: urgent intervention indicated. 
5 
Death related to AE. 
ADL = Activities of Daily Living 
*:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Cancer Therapy Evaluation Program, NCI CTCAE v 4.0.  Available from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev 4.pdf.Error! Bookmark not d
efined. 
For further details regarding MedDRA, refer to the MedDRA website at: 
http://www.meddramsso.com.  CTCAE v 4.0 is available online at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev 4.pdf. 
 
 
 
 
 
 
 
 


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16.2 
APPENDIX B:   PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.