Clinical trial NCT01036087
Conditions: Breast Cancer
Keywords: Inflammatory Breast Cancer IBC Primary breast carcinoma HER2 negative overexpression Panitumumab Vectibix Nab-paclitaxel Paclitaxel Abraxane Carboplatin Paraplatin PNC 5-fluorouracil 5-FU Adrucil Efudex Epirubicin Ellence Cyclophosphamide Cytoxan Neosar FEC
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-11-01; Completion date: 2022-08-09
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn how effective the combination of chemotherapy including both panitumumab, Abraxane (nab-paclitaxel), and carboplatin (PNC) and fluorouracil, epirubicin, and cyclophosphamide (FEC) used before surgery for the treatment of IBC is. The safety of PNC combination will also be studied.

Detailed description:
Study Drugs:

Panitumumab is designed to prevent or slow down the growth of tumor cells by blocking the proteins on the surface the cancer cell, called the epidermal growth factor receptor (EGFR).

Nab-paclitaxel is designed to kill tumor cells by binding a chemotherapy drug paclitaxel to albumin, a protein made by the liver. The albumin gets into the cancer cell and releases the paclitaxel directly to the tumor.

Carboplatin is designed to stop or slow cancer cells from growing by damaging the RNA or DNA (the genetic material of cells) that tells the tumor cells to grow.

5-fluorouracil, epirubicin, and cyclophosphamide each work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Study Drug Administration:

On Day 1 of Week 1, you will receive panitumumab through a needle in your vein over 60 minutes.

After Week 1, you will receive a total of 4 cycles of PNC. Each cycle is 4 weeks.

During Cycles 1-3 (Weeks 2-13), you will receive PNC by vein once a week for 3 weeks, followed by a week of rest. You will receive PNC through a needle in your vein. The infusion will take 90 minutes.

During Cycle 4 (Week 14 to 17), you will receive PNC on Day 1 of Weeks 14 and 15. On Day 1 of Week 16, you will receive only carboplatin and nab-paclitaxel.

Starting on Day 1 of Week 18, you will receive FEC through a needle in your vein. The infusion will take 90 minutes. You will receive a total of 4 cycles, each 3 weeks long, over 12 weeks.

Surgery:

After you have completed both PNC and FEC treatments, you will have the standard of care surgery performed. You will be given a separate consent form to read and sign.

During surgery, breast tissue samples will be collected to identify tumors as routine procedure.

Study Visits:

Each week that you receive PNC or FEC therapy, before each dose of chemotherapy, blood (about 1 1/2 tablespoons) will be drawn for routine tests.

Before Week 2, an optional breast core biopsy will be performed to collect tumor samples for biomarker testing

On Week 2, every 4 weeks after that until the end of PNC, and again before FEC, the following tests and procedures will be performed before each dose of chemotherapy.

* You will have a physical exam, including measurement of your vital signs and weight, and breast exam.
* Blood (about 1 1/2 tablespoons) will be drawn for routine tests.
* You will be asked how well you are able to perform the normal activities of daily living (performance status).

During Weeks 2 and 9, and before FEC therapy, the study doctor will take pictures of both of your breasts.

Before FEC (after Cycle 4 of PNC) and again before surgery, the following tests and procedures will be performed:

* To check the status of the disease, imaging studies including mammogram, breast MRI, breast ultrasound, and digital photograph will be performed.
* You will have a physical exam, including vital signs, weight, and breast exam
* Blood (about 3 tablespoons) will be drawn for routine tests.
* You will be asked about any symptoms that you may have.
* The ECGs and ECHO/MUGA scans will be repeated, when the doctor thinks it is necessary.

This schedule may be changed if the study doctor thinks that it is necessary.

Length of the study:

You may remain on study treatment for up to 10 months. You will be taken off study early if the disease gets worse or you experience intolerable side effects.

This is an investigational study. Panitumumab is FDA approved and commercially available for the treatment of EGFR-expressing metastatic colorectal cancer with disease progression. It's use in this study is considered to be investigational.

Nab-paclitaxel is FDA approved and commercially available for the treatment of breast cancer after the failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. The use of Nab-paclitaxel in this study is considered to be investigational.

Carboplatin is FDA approved and commercially available for the treatment of IBC.

FEC is FDA approved for breast cancer in general, but not specifically for inflammatory breast cancer.

The use of PNC and FEC together before surgery is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: PNC = Panitumumab + Nab-paclitaxel + Carboplatin, and

FEC = 5-fluorouracil, epirubicin, and cyclophosphamide
Interventions: intervention 1: Panitumumab intervention 2: Nab-paclitaxel intervention 3: Carboplatin intervention 4: 5-Fluorouracil intervention 5: Epirubicin intervention 6: Cyclophosphamide
Intervention descriptions: intervention 1: 2.5 mg/kg IV on Day 1 of Week 1 over 60 minutes, followed by 2.5 mg/kg weekly Weeks 2-12. intervention 2: 100 mg/m2 IV over 30 min on Day 1 of Weeks 2-13 over 30 minutes. intervention 3: AUC 2 IV over 30 min on Day 1 of Weeks 2-13 after completion of Abraxane through separate IV line. intervention 4: 500 mg/m2 IV every 3 weeks, starting on Day 1 of Week 14 (4 cycles, each 3 weeks long, over 12 weeks). intervention 5: 100 mg/m2 IV over 30 min every 3 weeks starting on Day 1 of Week 14 (4 cycles, each 3 weeks long, over 12 weeks). intervention 6: 500 mg/m2 IV every 3 weeks starting on Day 1 of Week 14 (4 cycles, each 3 weeks long, over 12 weeks).

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 1 of 44 
 
 
Phase II Study of Panitumumab, Nab-paclitaxel, and Carboplatin for Patients with Primary 
Inflammatory Breast Cancer (IBC) without HER2 Overexpression 
 
ABSTRACT 
1.0 
OBJECTIVES  
 
 
 
 
 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
 
 
 
 
 
3.0 
PRODUCT INFORMATION 
 
 
 
 
 
 
 
4.0 
PATIENT ELIGIBILITY  
 
 
 
 
 
 
 
5.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
6.0 
PRETREATMENT EVALUATION 
 
 
 
 
 
 
 
7.0 
EVALUATION DURING STUDY  
 
 
 
 
 
 
8.0 
CRITERIA FOR RESPONSE 
 
 
 
 
 
 
 
9.0 
CRITERIA FOR REMOVAL FROM THE STUDY 
10.0 
CORRELATIVE STUDIES 
 
 
 
 
 
 
11.0 
STUDY CALENDAR 
12.0 
ADVERSE EVENTS (AE) 
13.0 
STATISTICAL CONSIDERATIONS 
14.0 
REFERENCES  
 
 
 
 
 
 
 
 
15.0 
LIST OF APPENDICES  
 
 
 
 
 
 
 
 
Appendix I 
 
Dermatologic toxicities 
 
Appendix II 
 
Panitumumab Pharmacy Guide 
 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 2 of 44 
 
 
Coordinating Center:  
 
The University of Texas M. D. Anderson Cancer Center. 
 
*Principal Investigator:             Name: Naoto T. Ueno 
Address: 1515 Holcombe Blvd. Unit 1354, Houston, TX 77030 
Telephone: 713-792-8754 
Fax: 713-794-4538 
E-mail address: nueno@mdanderson.org 
 
Responsible  Research Nurse: 
Name: Charla Parker 
 
Address: 1515 Holcombe Blvd. Unit 1354, Houston, TX 77030 
Telephone: 713-745-1042 
 
Fax: 713-794-4358 
 
E-mail address: cparker@mdanderson.org  
 
 
 
Protocol Type / Version Date: Final /Version Date: 10-30-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 3 of 44 
 
 
 
1.0 
OBJECTIVES: 
1.1 
Primary Objectives is to determine the pathologic complete response (CR) rate in patients with 
primary inflammatory breast cancer (IBC) without HER2 overexpression by Panitumumab, Nab-
paclitaxel, and Carboplatin (PNC) and FEC preoperative systemic chemotherapy. 
 
1.2 
Secondary Objectives 
1.2.1 
To determine the disease-free survival (DFS) produced by PNC regimens. 
1.2.2 
To determine the overall survival (OS) produced by PNC regimens. 
1.2.3 
To determine the disease-free survival (DFS) produced by PNC regimens among patients with triple 
negative breast cancer. 
1.2.4 
To determine the overall survival (OS) produced by PNC regimens patients with triple negative 
breast cancer. 
1.2.5 
To determine the safety and tolerability by PNC regimens. 
1.2.6 
To determine whether pathologic response rate correlates with EGFR expression level. 
 
1.3 
Exploratory 
1.3.1 
To identify molecular markers predictive of pathologic CR rate by analysis of multilayer 
immunohistochemical staining (IHC) 
1.3.2 
To identify molecular marker by gene profiling and proteinomics 
 
2.0 
BACKGROUND AND RATIONALE: 
2.1 
Inflammatory breast cancer (IBC) is the most aggressive form of primary breast carcinoma and has 
distinctive biological features. The outcome for patients with IBC is bleak despite multimodality 
treatment approaches; 3-overall survival (OS) rates after combined chemotherapy, surgery, and 
radiation are only 40% compared to 80% for non-inflammatory breast cancer (Cristofanilli et al., 
2007; Ueno et al., 1997). Current treatment modalities are inadequate for IBC, and a better 
understanding of the biological features of the disease is necessary if more effective interventions 
are to be developed. Pathological CR rate determines the long-term outcome (DFS as well as 
overall survival) of inflammatory breast cancer. Thus, we will use pathological CR rate produced by 
preoperative chemotherapy as a primary endpoints of this study. 
 
2.2 
Clinical Characteristics of IBC. Inflammatory breast cancer is defined by a rapid onset of diffuse skin 
erythema, edema involving more than 2/3 of the breast resulting in a pitted appearance (peau 
d’orange), as well as tenderness, induration and warmth of the involved breast (Cristofanilli et al., 
2003). At the time of initial diagnosis most IBC patients have lymph node involvement and 
approximately 30% have distant metastases (Liauw et al., 2004). 
 
2.3 
Pathology of IBC. This type of breast cancer frequently demonstrates dermal lymphatic invasion by 
tumor emboli, which contributes to the rapid engorgement of the breast and clinical features of 
“inflammation.” However, absence of dermal lymphatic invasion does not exclude the diagnosis if 
the clinical signs are present (Giordano and Hortobagyi, 2003). In fact, the AJCC does not consider 
the presence of dermal lymphatic invasion without characteristic clinical features to be sufficient to 
diagnose IBC. When a retrospective analysis was performed in patients diagnosed with IBC based 
on clinical criteria, with or without pathologic evidence of dermal lymphatic invasion, patients with 
clinical symptoms had a poorer prognosis, including a shorter DFS and OS compared to patients 
with only pathologic findings of dermal lymphatic invasion (Amparo et al., 2000). These findings 
support the importance of clinical features in the initial diagnosis of IBC. 
 
2.4 
Molecular changes of IBC. These tumors are characterized by high histologic grade, high 
proliferation rate (e.g., elevated MIB1 expression, high S-phase proportion, or high thymidine-
labeling index), aneuploidy, and high levels of expression of p53 and MUC1, RhoC, E-cadherin, and 
growth factor receptors such as HER2 and EGFR. IBC is often associated with a “basal-like” 
phenotype, high intratumoral microvessel density, high levels of tumor angiogenesis- and 
lymphangiogenesis-related factors such as vascular endothelial growth factors (VEGF) -A, -C, and -
D, Flt-1, KDR, Tie-1, and Tie2, and high expression of chemokines such as CCL3/MIP1A and 


Protocol 2008-0372 
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CCL5/RANTES. We recently undertook an IHC analysis of 44 cases of IBC diagnosed between 
1994 and 2002 and found HER2 overexpression in 21 patients (48%) and EGFR overexpression in 
12 of 40 patients (30%). Significantly, EGFR overexpression was the only factor predictive of worse 
outcome: the 5-year OS rate was significantly lower for women with EGFR-positive disease than for 
women with EGFR-negative disease (P=0.01). Moreover, tumors that expressed EGFR, alone or in 
combination with CXCR4, were associated with a relatively higher incidence of bone recurrence 
(Cabioglu et al., 2007; Cristofanilli et al., 2007). The association of EGFR overexpression and 
increased risk of recurrence and death indicates that EGFR may represent a potential therapeutic 
target in IBC. 
  
2.5 
Treatment of IBC. Surgery was the first therapeutic modality used to treat IBC, but produced 
disappointing results. The mean survival of patients treated with mastectomy alone ranged from 12-
32 months (Cristofanilli et al., 2003) with a 5-year OS rate <5% (Ueno et al., 1997). Radiation 
therapy alone appears to have little impact on survival, with median overall survival rates ranging 
from 4 to 28 months in studies with very small patient populations (Chittoor, 1998). An extensive 
review of IBC data at the M.D. Anderson Cancer Center conducted by Ueno and colleagues (Ueno 
et al., 1997) concluded that surgery plus radiotherapy as opposed to radiotherapy alone did not 
have an impact on DFS or OS. Cristofanilli and colleagues reported that the addition of radiotherapy 
improved locoregional control rate, but the combination had no significant effect on survival 
(Cristofanilli et al., 2003). At this time, combined-modality treatment (neoadjuvant chemotherapy, 
mastectomy, adjuvant chemotherapy, and radiotherapy) is considered to be a standard of care for 
IBC (Ueno et al., 1997). Further, pathological CR in surgical samples after preoperative systemic 
chemotherapy is the most important prognostic factors to determine the long-term outcome of IBC. 
Twenty-eight percent of patients using this modality remained disease-free beyond 15 years when 
compared with single modality treatments that yielded only 5%.  
 
Anthracyclines (FEC; 5-FU, epirubicin, cyclophosphamide or FAC; 5-FU, adriamycin, 
cyclophosphamide) and taxanes (paclitaxel or docetaxel) are the most effective cytotoxic agents in 
the management of primary breast cancer and have demonstrated their importance in the 
management of early breast cancer and IBC (Cristofanilli et al., 2003).  
 
Despite improvements in survival with the implementation of aggressive multi-modality induction 
therapies, women with IBC still have far lower survival rates than those with non-IBC. Furthermore, 
the quality of life of patients with refractory or relapsed IBC is often negatively impacted by pain, 
erythema, edema and cosmetic appearance of uncontrolled chest wall disease. Thus, there is a 
need for novel treatment for primary IBC before recurrence of disease. This is why new combination 
chemotherapy (panitumumab, nab-paclitaxel, carboplatin) will be added to standard anthracycline 
regiments (FEC). New combination chemotherapy is added to standard FEC x 4 cycles which allows 
us to compare the pathological CR rate to the historical pathological CR rate [paclitaxel followed by 
FEC]. 
 
2.6 
Lapatinib study in IBC (Study EGF103009). We recently completed a phase II trial testing lapatinib 
(TYKERB, a dual EGFR and HER2 inhibitor) in combination with paclitaxel as preoperative systemic 
chemotherapy for primary IBC. The results of that study indicated that lapatinib had optimal activity 
in HER2-overexpressing IBC but limited response in EGFR overexpressing by IBC. We recently 
showed that lapatinib has very limited activity against EGFR-overexpressing tumors (Zhang et al., 
2008). Thus, there is an urgent need for new EGFR-targeted therapy. Interestingly, panitumumab 
(see below for details) has been shown to be active in breast cancer preclinical model using MDA-
MB-468, which overexpresses EGFR by both IHC and FISH [Amgen, preclinical study]. Further, 
EGFR tyrosine kinase inhibitor such as erlotinib does have an anti-tumor activity against human 
inflammatory breast cancer cells [Ueno’s lab]. At last, in colorectal cancer, relationship between 
EGFR expression level and antitumor response remains controversial (Sartore-Bianchi et al., 2007; 
Van Cutsem et al., 2007). Thus, in this clinical trial, we will treat all patients with negative HER2-
expressing IBC by panitumumab. 
  
2.7 
Panitumumab. This drug is previously known as ABX-EGF. It is a high affinity (Kd = 5 x 10-11 M) 


Protocol 2008-0372 
Revised Date: 10-30-2018  
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fully human IgG2 monoclonal antibody directed against human EGFR. Panitumumab blocks the 
ligands EGF and TGF binding to EGFR, inhibits tumor growth, and elicits both tumor regression 
and eradication of established tumors in murine xenograft tumor models (Yang et al., 1999). The 
antineoplastic effects of panitumumab in vivo have been demonstrated using human xenograft 
mouse models including breast cancer. Panitumumab has been shown to inhibit the growth of 
human epidermoid carcinoma A431 xenografts in athymic mice resulting in the complete regression 
of large (up to 1.2 cm3) established A431 tumors, regardless of initial tumor size. Lower doses of 
panitumumab administered twice weekly for 3 weeks inhibited growth of preexisting solid tumors. 
Furthermore, a single injection of panitumumab (1 mg) resulted in significant and prolonged tumor 
inhibition.  
 
Preclinical Toxicology and Pharmacokinetics. Results of panitumumab toxicology studies (1- and 3-
month duration) have identified diarrhea and skin rash as the principal toxicities, of which the skin 
rash was considered related to the pharmacological action of panitumumab. Pharmacokinetics was 
shown to be nonlinear, and the production of monkey anti-human antibodies (MAHA) against 
panitumumab in animals caused a significant decrease in exposure over the course of the 3-month 
study. In a 6-month toxicology study where panitumumab was administered IV at weekly doses of 
7.5, 15, and 30 mg/kg to cynomolgus monkeys, skin rash and diarrhea were observed in several 
animals in all dose groups; both of these toxicities were considered to be related to the 
pharmacological action of panitumumab. Additionally, several animals showed decreased food 
consumption and body weight loss (Panitumumab Toxicology Study 103419).  
 
2.8 
Nab-paclitaxel. In this protocol, paclitaxel will be replaced with Nab-paclitaxel for paclitaxel with 
carboplatin regimen. Nab-paclitaxel (Abraxane, ABI-007, albumin-bound paclitaxel) is a Cremophor 
EL-free, albumin-bound form of paclitaxel with a mean particle size of approximately 130 
nanometers. 
 
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 (Desai et al., 
2006). A protein specifically secreted by the tumor (SPARC) binds and entraps the albumin, 
allowing release of the hydrophobic drug to the tumor cell membrane (Desai et al., 2006). 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. 
 
Clinical Studies with nab-paclitaxel 
 
Every 3 Weeks Schedule. 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 (Gradishar et al., 2005). 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 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 6 of 44 
 
 
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).  At the time of these analyses (October 2004), the median censoring time for overall patient 
survival was 103 weeks for the Nab-paclitaxel group and 101 weeks for the paclitaxel group. 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). 
 
The incidence of hypersensitivity reactions (any Gr) was low for both arms (1% for Nab-paclitaxel 
and 2% for paclitaxel). No severe (Gr III or IV) treatment-related hypersensitivity reactions occurred 
in any of the patients in the Nab-paclitaxel group despite the absence of premedication. In contrast, 
Gr III hypersensitivity reactions occurred in the paclitaxel group despite standard premedication 
(chest pain, two patients; allergic reaction, three patients). Per protocol, corticosteroids and 
antihistamines were not administered routinely to patients in the Nab-paclitaxel group; however, 
premedication was administered for emesis, myalgia/arthralgia, or anorexia in 18 patients (8%) in 
the Nab-paclitaxel group in 2% of the treatment cycles, whereas 224 patients (> 99%) in the 
paclitaxel group received premedication in 95% of the cycles. 
 
Although the patients in the Nab-paclitaxel group received an average paclitaxel dose-intensity 49% 
greater than that received by patients in the paclitaxel group, the incidence of treatment-related Gr 
IV 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 Gr III 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 Gr II 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 Gr III sensory neuropathy was the same (n = 
4) in both study arms. No episodes of motor neuropathy or Gr IV sensory neuropathy were reported 
in either group.  
 
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 years old in both groups. Of the patients  65 years old, the incidences of the following 
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. 
 
Weekly Schedule. 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 weekly nab-
paclitaxel 100 mg/m2  (Blum JL, et al. J Clin Oncol 22:14S, abstract 543:2004). This regimen was 
well tolerated. 91% of patients were treated at the full dose of 100 mg/m2 of nab-paclitaxel without 
dose reductions.  
 
Based on these favorable toxicities, another trial was conducted to determine the activity and safety 


Protocol 2008-0372 
Revised Date: 10-30-2018  
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profile of nab-paclitaxel followed by FEC in women with LABC. Between 7/05 and 5/06, 65 women 
with LABC initiated preoperative nab-paclitaxel 100 mg/m2 weekly for 12 consecutive weeks 
followed by (a) 4 cycles of FEC-100 q3wks (F:500 mg/m2, E:100 mg/m2, C:500 mg/m2) if their 
cancer was HER2 negative or (b) 4 cycles of FEC-75 q3wks (F:500 mg/m2, E:75 mg/m2, C:500 
mg/m2) if their cancer was HER2+ and they received trastuzumab.  Trastuzumab could be co-
administered with nab-paclitaxel and FEC-75 on a standard weekly schedule at the discretion of the 
investigator in patients with HER2+ disease.  Primary endpoint will be pathologic complete response 
rate following completion of FEC.  Secondary endpoints include complete clinical response rate 
assessed at the completion of nab-paclitaxel and safety. 
 
The median age was 47 years (range: 28-70).  Stage IIB disease was present in 31%, IIIA in 46%, 
and IIIB in 24%.  Tumors were ER+ in 54% and HER2+ in 28%.  Preliminary toxicity data with nab-
paclitaxel reported in the first 44 patients shows the most frequent toxicities have been diarrhea (Gr 
II/3-16%/7%), fatigue (Gr II/3-30%/5%), and sensory neuropathy (Gr II/3-9%/5%).  No Grade 4 or 5 
toxicities and only one Gr 3 neutropenia have been reported.   All 12 doses of nab-paclitaxel were 
administered to 29 of the first 32 patients, and 28 of these completed the 12 doses in 12-14 weeks. 
Thus, weekly nab-paclitaxel has minimal toxicity in chemotherapy naive patients with LABC. 
 
2.9 
Combination of paclitaxel with carboplatin in breast cancer. New non-anthracycline regimens have 
been used for both primary and metastatic breast cancer. Carboplatin as a single agent produces 
response rates of 20–35% in untreated metastatic breast cancer. Further, when combined with 
carboplatin and taxanes (paclitaxel, docetaxel) therapy was active and reasonably well tolerated in 
the first-line treatment of metastatic breast cancer, producing objective response rates of 53%–
62%—substantially higher rates than those seen in other phase II trials of either drug alone. At last, 
phase III data suggest that adding carboplatin to a paclitaxel/trastuzumab regimen produces 
superior efficacy than paclitaxel/trastuzumab alone for patients with HER2+ metastatic disease. This 
regimen was used in preoperative systemic chemotherapy with equivalent efficacy (DFS and OS) 
with adriamycin/cyclophosphamide followed by paclitaxel/trastuzumab without equivalent toxicities. 
Thus, incorporation of carboplatin as a standard agent in first-line treatment of primary 
breast cancer has support from these recent studies. 
 
 
2.10 
Biomarker Development. No biomarkers have been established with which to identify patients who 
might benefit from this type of treatment which include EGFR targeted therapy. Thus, secondary 
objective of this study is to determine whether pCR rate correlates with EGFR expression level by 
immunohistochemical (IHC) staining and fluorescence in situ hybridization (FISH). Both techniques 
(IHC, FISH) for measuring EGFR expression level have been standardized at M. D. Anderson.  
 
To further understand the biological effect of panitumumab as a single agent and to discover novel 
biomarkers, we will administer the first dose administer as a single agent. Then, perform a biopsy of 
the breast tumor before the second dose of panitumumab, which will be combined with chemotherapy. 
 
We will use a new tool, layered peptide arrays, to perform multilayer IHC staining of a single section 
of paraffin blocks of breast tumor that has been collected. This new tool allows testing of up to 20 
biomarkers. Current plans are to test the phosphorylation status of p27, EGFR, PEA15, and ERK, all 
of which are thought to modulate EGFR-targeting drug activities. 
 
At last, we will collect frozen tumors for protein and mRNA profiling, and serum by registering the 
patient on inflammatory breast cancer registration study (2006-1072). 
 
 
2.11 
Rationale. The hypothesis underlying this protocol is that preoperative chemotherapy with a 
combination of anti-EGFR monoclonal antibody (panitumumab), carboplatin, and nab-paclitaxel with 
FEC will produce higher pathologic complete response rates among patients with IBC than the 
historical rate (about 13%). We propose here a prospective, single-arm, phase II protocol to confirm 
the importance of EGFR as a therapeutic target in IBC and to show that use of an anti-EGFR 


Protocol 2008-0372 
Revised Date: 10-30-2018  
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antibody such as panitumumab can modulate the sensitivity of IBC to chemotherapy, as indicated 
by an improved pathologic CR rate. Taxanes and carboplatin have known activity in breast cancer 
and synergistic effects with modulators of the EGF family. In particular, nab-paclitaxel is far superior 
to the standard formulation in metastatic breast cancer. 
 
 
3.0 
PRODUCT INFORMATION 
3.1 
Panitumumab 
3.1.1 
Therapeutic Classification: Antineoplastic Agent, Monoclonal Antibody 
3.1.2 
Mechanism of Action: Recombinant human IgG2 monoclonal antibody which binds specifically to the 
epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of 
epidermal growth factor (EGF) and other ligands. Binding to the EGFR blocks phosphorylation and 
activation of intracellular tyrosine kinases, resulting in inhibition of cell survival, growth, proliferation 
and transformation 
3.1.3 
Pharmaceutical Data: 
 
Half-life elimination: 7.5 days (range: 4-11 days) 
3.1.4 
Solution Preparation: Panitumumab is a protein and should be handled gently to avoid foaming, 
which may lead to denaturation of the protein product. This precaution applies not only to 
panitumumab stored in the vial, but also for diluted panitumumab prepared in the IV bag. It is, 
therefore, essential to avoid medication delivery methods, particularly pneumatic tube systems, 
which could potentially lead to excessive shaking or vibration, which would potentially lead to 
particulate formation in the protein product. Panitumumab must be prepared as an intravenous (IV) 
infusion using aseptic techniques. The dose of panitumumab will be 2.5 mg/kg and will be based 
upon the subject’s baseline weight. The dose of panitumumab is required to be recalculated only 
when the subject’s body weight increases or decreases by > 10% from the original 
screening/baseline weight. This weight will be considered the new baseline weight from which a + 
10% variance is allowed before another recalculation is necessary. The calculated amount of 
panitumumab (may be rounded to the nearest ten milligrams [e.g., 456 mg rounded to 460 mg or 
312 mg rounded to 310 mg]) will be removed from the vials and added to a minimum volume of 100 
mL of pyrogen-free 0.9% sodium chloride solution USP. Doses higher than 1000 mg should be 
diluted to 150 mL with 0.9% sodium chloride injection, USP. The maximum concentration of the 
diluted solution to be infused should not exceed 10 mg/mL. In the event a subject’s actual body 
weight requires greater than a 150-mL volume infusion, panitumumab will be administered over 60 
to 90 + 15 minutes, as tolerated. The panitumumab will be infused within 6 hours of dilution and will 
be labeled per site pharmacy standard operating procedures. The bag should be labeled per site 
pharmacy standard operating procedures and promptly forwarded to the clinic center for infusion.  
3.1.5 
Stability and Storage Requirements:  
 
Each vial of panitumumab will contain 10 mL of a sterile protein solution containing a 20-mg/mL 
solution of panitumumab. The vial will contain approximately 200 mg of panitumumab and is for 
single dose use only. Each vial of panitumumab will be labeled in accordance with current ICH GCP, 
FDA and specific national requirements. 
 
The supplied investigational drug must be stored at 2-8° C in a secured area upon receipt. As 
panitumumab contains no preservatives, vials are designed for single use only. Exposure of the 
material to excessive temperature above or below this range should be avoided. Do not allow 
panitumumab to freeze and do not use if contents freeze in transit or in storage. If vials fall out of 
specified temperature requirement, please contact Amgen for instructions. Records of the actual 
storage condition during the period of the study must be maintained (i.e., records of the date and 
time and initials of person checking, and the “working day” temperature of the refrigerator used for 
storage of trial supplies, continuous temperature recordings, or regularly maintained temperature 
alarm systems used in conjunction with temperature recording). 
 
Supply and Return: At study initiation and as needed thereafter, panitumumab will be shipped to a 
responsible person (e.g., a pharmacist) at the Investigator’s institution, who will check the amount 
and condition of the drug and enter these data into the Proof of Receipt Form and Investigational 
Product Accountability record. The Proof of Receipt Form should then be returned to Amgen, and 
the original retained at the site. At the end of the study, or as directed, all panitumumab supplies, 
including unused, partially used, or empty containers, will be destroyed at the site. 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 9 of 44 
 
 
 
Panitumumab Accountability: An Investigational Product Accountability Record for panitumumab 
must be kept current and should contain: 
 
The dates and quantities of panitumumab received from Amgen 
 
Manufacturing batch or lot numbers for product for product received 
 
Subject’s identification (subject number) 
 
Dose preparation records 
 
Date and quantity of drug dispensed and returned to the investigator/pharmacy, if appropriate 
Authorized sponsor representative(s) and regulatory agency inspector(s) must make these 
inventories available for inspection. The investigator is responsible for the accountability of all used 
and unused trial supplies 
3.1.6 
Route of Administration: IV infusion only. 
3.1.7 
Usual Dosage Range:  
3.1.7.1 Adults: Adults: Colorectal cancer: 6 mg/kg every 2 weeks 
3.1.7.2 Dosing adjustment for toxicity: 
 
Infusion reactions, mild-to-moderate (grade 1 or 2): Reduce the infusion rate by 50% for the duration 
of infusion 
 
Infusion reactions, severe (grade 3 or 4): Immediately and permanently discontinue treatment 
 
Skin toxicity (grade 3 or 4): Withhold treatment; if skin toxicity does not improve to ≤ grade 2 within 1 
month, permanently discontinue. If skin toxicity improves to ≤ grade 2 within 1 month (with patient 
missing ≤2 doses), resume treatment at 50% of the original dose. Dose may be increased in 
increments of 25% of the original dose (up to 6 mg/kg) if skin toxicities do not recur. For recurrent 
skin toxicity, permanently discontinue. 
3.1.7.3 Dosage adjustment in renal impairment: Has not been studied 
3.1.7.4 Dosage adjustment in hepatic impairment: Has not been studied 
3.1.8 
Side Effects:  
3.1.8.1 The below referenced studies reflect the reported adverse events at the time of the last 
Panitumumab Investigator’s Brochure (Version 7.0, 10June2008).  Please refer to the current 
version of the Panitumumab Investigator’s Brochure as well as the updated safety information 
contained in the Investigational New Drug safety letters for further updates. 
3.1.8.2 Safety analyses from 16 clinical studies in subjects with a variety of solid tumors (n = 1599 receiving 
panitumumab) indicated that panitumumab is generally well tolerated.  Among these studies, 11 
enrolled subjects with mCRC (n = 1052 receiving panitumumab as a single agent).  In these 
subjects, dermatologic-related toxicities were the most frequently reported adverse events (91% of 
subjects), with most events being mild to moderate.  Relatively few subjects (2%) permanently 
discontinued panitumumab due to dermatologic adverse events.  Infusion reactions to panitumumab 
(defined as any reported allergic reaction, anaphylactoid reaction, chills, fever, or dyspnea, 
occurring within 24 hours of the first dose that were not otherwise designated as either 
anaphylactoid or allergic reaction) were infrequent (3% of subjects; < 1% severe); particularly 
considering that premedication was not mandated in study protocols.  Panitumumab antigenicity, as 
measured by enzyme-linked immunosorbent assay (ELISA) and Biacore assay, was very low and 
was not associated with clinical sequelae. 
3.1.8.3 Panitumumab Monotherapy Studies  
An integrated analysis of the safety of panitumumab has been conducted for 1052 subjects with 
mCRC receiving panitumumab monotherapy (mCRC Monotherapy Set).  Subjects primarily received 
panitumumab doses of 2.5 mg/kg once weekly (15%) or 6.0 mg/kg every 2 weeks (82%). 
Consistent with the published data on subjects treated with EGFr inhibitors (ie, class/target effect) 
(Perez-Soler and Saltz, 2005), the most commonly reported treatment-related adverse events in 
subjects treated with panitumumab were associated with the skin, including pruritus (52%), 
acneiform dermatitis (51%), erythema (50%), and rash (38%).  Most subjects (833 of 1052 subjects, 
79%) with any dermatologic toxicity had events that were considered to be mild or moderate.  Only 
3% of subjects permanently discontinued panitumumab administration for dermatologic toxicities.  
Dermatologic toxicities typically were observed after initiation of panitumumab, with a median time to 
first integument toxicity (of any severity) of 10 days (95% CI: 8, 11).   
Other common treatment-related adverse events (ie, subject incidence  10%) included fatigue 
(15%) and diarrhea (13%). 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 10 of 44 
 
 
Subjects in the wild-type KRAS subset received a higher number of panitumumab infusions 
compared with subjects in the mutant subset (mean [median] 10.0 [8.0] and 4.9 [4.0], respectively).  
More treatment-related adverse events occurred in the wild-type KRAS subset compared with the 
mutant KRAS subset, presumably due to the greater number of panitumumab infusions received.  
These adverse events were mainly skin toxicities (erythema, pruritus, dermatitis acneiform) likely 
reflecting the increased duration of exposure to panitumumab.  No qualitative differences in overall 
adverse events were observed between the wild-type KRAS subset, the mutant KRAS subset and 
the overall population, however, treatment related grade 3 adverse events were reported for 25% of 
subjects in the wild-type KRAS subset compared with 12% of subjects in the mutant KRAS subset.  
Two percent of wild-type KRAS subjects and 1% of mutant KRAS subjects withdrew for 
panitumumab-related events. 
Infusion reactions to panitumumab were infrequent even though premedication was not mandated in 
the panitumumab clinical program.  Overall, 1% of subjects had an infusion reaction reported by the 
investigator as an adverse event.  Using a definition consistent with the Vectibix USPI (2007), 3% of 
panitumumab-treated subjects had a potential infusion reaction; < 1% of subjects had a potential 
infusion reaction by this definition ≥ grade 3.   
3.1.8.4 Panitumumab Combination Chemotherapy Studies 
To date, panitumumab has been evaluated in combination with chemotherapy in subjects with CRC, 
NSCLC, and SCCHN.   
In the mCRC setting in combination with IFL (Study 20025409), the incidence of grade 3 or 4 
diarrhea (58%) was notably higher than that historically expected for this already highly GI-toxic 
chemotherapy regimen, and 1 subject had an episode of grade 4 diarrhea that was also considered 
serious.  Of note, panitumumab in combination with the FOLFIRI regimen using the same agents 
but different doses/infusion times was better tolerated with an incidence of grade 3 or 4 diarrhea 
similar to that expected from the literature for this chemotherapy regimen alone (25%) (Andre et al, 
1999; Saltz et al, 2000).  These data suggest that the potential for additive toxicities in the 
gastrointestinal tract exists when panitumumab is administered in combination with GI toxic 
chemotherapy.  However, these toxicities could be managed by appropriate selection of the 
concomitant chemotherapy regimen.   
No clear additive effects were observed in the NSCLC setting where panitumumab was combined 
with carboplatin/paclitaxel (Study 20025404).  One case of pulmonary fibrosis was reported in a 
subject treated with this combination.  Although subjects with evidence of interstitial pneumonitis or 
pulmonary fibrosis were excluded from clinical studies (from 2004 onward), this subject, who had a 
previous history of underlying idiopathic pulmonary fibrosis, was enrolled before the protocol 
exclusions were implemented.   
Amgen study 20040249 (PACCE) is an open-label, controlled study of bevacizumab and 
chemotherapy administered with and without panitumumab as first-line treatment of subjects with 
mCRC.  Chemotherapy included oxaliplatin-or irinotecan-based regimens.  Based on the results of a 
planned interim analysis (conducted after 257 progression or death events had occurred), adding 
panitumumab to bevacizumab and oxaliplatin-based chemotherapy did not prolong progression-free 
survival and contributed increased toxicity to the multi-agent regimens.  Panitumumab treatment 
was discontinued from the study at that time (22 March 2007).   
A final analysis of on-treatment efficacy and safety was performed based on available data as of 31 
May 2007.  The addition of panitumumab to bevacizumab and oxaliplatin-based chemotherapy 
showed an unfavorable benefit-to-risk profile with shorter progression-free survival time and 
increased toxicity.  Although panitumumab treatment in the irinotecan-based chemotherapy stratum 
was also prematurely discontinued, there was no evidence of significant benefit with the addition of 
panitumumab to bevacizumab and irinotecan-based chemotherapy in first-line treatment of mCRC.  
Given the unfavorable benefit-to-risk outcome, the PACCE study as designed did not support the 
use of panitumumab with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy as first-
line treatment of metastatic colorectal cancer. 
3.1.8.5 Please refer to the current Panitumumab Investigator’s Brochure for further details. 
3.1.8.6 Panitumumab Combination Radiotherapy with or without Chemoradiotherapy Studies 
An open-label, dose-finding study (Study 20040235) of AMG 706 or panitumumab when 
administered with induction chemotherapy (IC) and/or chemo-radiotherapy (CRT) in the treatment of 
subjects with loco-regionally advanced squamous cell carcinoma of the head and neck is ongoing.  


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 11 of 44 
 
 
Five dose cohorts are currently planned for this study.  As of the data cut-off date (18 May 2007), 5 
subjects were enrolled in cohort A [TPF (T – docetaxel 75 mg/m2; P  cisplatin 75 mg/m2; F – 5-
fluorouracil 750 mg/m2 days 1 to 5) induction chemotherapy followed by chemoradiotherapy + 
panitumumab 1.5 mg/kg QW (n = 7) and 2.5 mg/kg (n = 3), and 4 subjects were enrolled in cohort B 
(TPF induction chemotherapy followed by chemoradiotherapy + AMG 706).  Of the 9 subjects 
enrolled in cohorts A and B, 8 had completed study and 1 had treatment ongoing (data on file at 
Amgen Inc).  Safety data was available for all 9 subjects. 
At least 1 treatment-emergent adverse event was reported for all 9 subjects (100%) in cohorts A and 
B.  Two subjects in cohort A1 experienced a DLT (one each grade 3 and 4 mucositis).  
Subsequently, the protocol was amended to modify the DLT definition for mucositis to limit it to 
grade ≥ 3 toxicity that occurred in the first 5 weeks of radiotherapy or led to a 5-day radiotherapy 
delay.  There were no further DLTs.  The most common grade ≥ 3 AE during the panitumumab + 
chemoradiotherapy phase was mucositis (n = 6).  There was 1 event each of grade 3 esophagitis, 
dysphagia, and odynophagia, all reported as unrelated to panitumumab.  One subject also 
experienced grade 3 radiation dermatitis that was considered related but did not meet the criteria of 
a DLT.  The most common grade ≥ 3 adverse events during induction chemotherapy were febrile 
neutropenia (n = 5) and mucositis (N = 4).  No subjects in cohort A have died within 30 days of last 
dose of investigational product (data on file at Amgen Inc) 
 
 
3.2 
Nab-paclitaxel (Abraxane) 
3.2.1 
Therapeutic Classification: Antimicrotubular; Antineoplastic Agent, Natural Source (Plant) Derivative 
3.2.2 
Mechanism of Action: Paclitaxel promotes microtubule assembly by enhancing the action of tubulin 
dimers, stabilizing existing microtubules, and inhibiting their disassembly, interfering with the late G2 
mitotic phase, and inhibiting cell replication. In addition, the drug can distort mitotic spindles, 
resulting in the breakage of chromosomes. Paclitaxel may also suppress cell proliferation and 
modulate immune response. 
3.2.3 
Pharmaceutical Data: 
 
Drug Distribution 
Abraxane® will be distributed by Celgene. No supplies will be shipped to any site until 
regulatory approval has been obtained.  Investigational sites will be supplied with Abraxane® 
upon identification and screening of a potential trial subject.   
Upon identification of a potential subject, sites must fax a completed Drug Request Form to 
Celgene. Allow at least 5 working days for drug shipment.  There are no shipments on Fridays 
or holidays. 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene at 908-393-
8304. 
 
Drug Return and Destruction 
If the investigational site does not have a policy, procedure or SOP detailing the process to 
follow for study drug destruction, the study drug must then be returned to Celgene using the 
Drug Return Form provided in the package containing the study drug.  The following information 
must be recorded on the site’s pharmacy drug accountability log: quantity of vials to be returned, 
expiration date and lot number.  A copy of the Drug Return Form and the study drug should be 
returned to Celgene using the mailing address on the packaging slip that came with the original 
study drug order.  A copy of the Drug Return Form should be retained at the clinical site.  In the 
event of study completion or termination, a copy of all pharmacy records (drug dispensing log, 
drug accountability log and any destruction memos) must be mailed Celgene. 
If the investigational site has a policy, procedure or SOP detailing the process to follow for study 
drug destruction, the pharmacist or designee can choose to destroy the study drug on site.  The 
following information must be recorded on the site’s pharmacy drug accountability log: quantity 
of vials destroyed, expiration date and lot number.  The pharmacist must document that the 
study drug was destroyed in accordance with their institution’s drug destruction policy or SOP.  
A drug destruction memo and the site’s drug destruction SOP/policy should be sent to Celgene.  
A copy of the drug destruction memo should be retained at the clinical site.  In the event of study 
completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene.   


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 12 of 44 
 
 
 
 
Distribution: Vd: 632 L/m2  
 
Protein binding: 89-98% 
 
Metabolism: Hepatic via CYP3A4 (to minor metabolites) and 2C8 (primarily to 6-alpha-
hydroxypaclitaxel) 
 
Half-life elimination: 27 hours 
 
Excretion: Urine (4% as unchanged drug, 1% as metabolites); feces (20%) 
 
Clearance 15 L/hour/m2 
3.2.4 
Storage and Stability: Unreconstituted Abraxane should be stored at controlled room temperature 
(20 – 25 °C or 68 – 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 – 8 °C (38 – 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. 
3.2.5 
Solution Preparation: 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 Injection, powder for 
reconstitution: 100 mg contains human albumin 900 mg. 
 
Reconstitution and use of Abraxane  
 
1. Calculate the patient’s body surface area at the beginning of the study and if the weight changes 
by > 10% by using the formula provided in the study manual.  
 
2. Calculate the total dose (in mg) to be administered by:  
Total Dose (mg) = BSA x (study dose mg/m2)  
 
3. Calculate the total number of vials required by:  
Total Number of Vials = Total Dose (mg) / 100 (mg/vial)  
Round up the number of vials to be reconstituted to the next higher whole number when a fractional 
number of vials is obtained by the above formula (eg, if the total number of vials = 4.05 or 4.5, then 
5 vials would be reconstituted).  
 
4. Using sterile technique, prepare the vials for reconstitution.  
 
5. Swab the rubber stoppers with alcohol.  
 
6. Reconstitute each Abraxane 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.  


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 13 of 44 
 
 
  
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 Abraxane 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 Abraxane 
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 Abraxane 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 Abraxane in a 
refrigerator for no longer than 8 hours.  
 
3.2.6 
Route of Administration: IV infusion only. IV: Administer over 30 minutes; use of DEHP-free 
containers or administration sets is not necessary; do not use an in-line filter 
3.2.7 
Usual Dosage Range:  
3.2.7.1 Adults: Adults: Breast cancer: 260 mg/m2 every 3 weeks 
3.2.7.2 Dosage adjustment for toxicity: 
 
Severe neutropenia (<500 cells/mm3) ≥1 week: Reduce dose to 220 mg/m2 for subsequent courses 
 
Recurrent severe neutropenia: Reduce dose to 180 mg/m2 
 
Severe sensory neuropathy: Reduce dose to 180 mg/m2 
 
Sensory neuropathy grade 3 or 4: Hold treatment until resolved to grade 1 or 2, then resume with 
reduced dose 
3.2.7.3 Dosage adjustment in renal impairment: Safety not established for serum creatinine >2 mg/dL; use 
with caution 
3.2.7.4 Dosage adjustment in hepatic impairment: Effects of hepatic dysfunction (serum bilirubin >1.5 
mg/dL) unknown; dosage adjustment recommendations are not available. 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. 
3.2.7.5 Administration of Study Drug to Patients with Abnormal Hematologic Function. Abraxane dosing 
should not be administered at the start of each cycle until the absolute neutrophil count returns to 
≥1.5 x 10^9 cells/L and the platelet count returns to >100 x 10^9 cells/L.  
3.2.7.6 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 severe hypersensitivity reactions to Abraxane should not be re-challenged. 
3.2.7.7 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). 
3.2.8 
Drug Interactions Substrate (major) of CYP2C8, 2C9, 3A4; Induces CYP3A4 (weak) 
Anthracyclines (e.g. doxorubicin, epirubicin): Paclitaxel may increase anthracycline levels/toxicity; 
administration of anthracycline at least 24 hours prior to paclitaxel may reduce interaction. 
Carboplatin, cisplatin, oxaliplatin (platinum derivatives): When administered as sequential infusions, 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 14 of 44 
 
 
taxane derivatives should be administered before platinum derivatives to limit myelosuppression and 
to enhance efficacy. 
Cardiac glycosides: Paclitaxel may decrease the absorption of cardiac glycosides (may only affect 
digoxin tablets); monitor. 
CYP2C8 inducers: May decrease the levels/effects of paclitaxel. Example inducers include 
carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital. 
CYP2C8 inhibitors may increase the levels/effects of paclitaxel. Example inhibitors include 
gemfibrozil, ketoconazole, montelukast, and ritonavir. 
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of paclitaxel. Example 
inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, 
and rifamycin. 
CYP3A4 inhibitors: May increase the levels/effects of paclitaxel. Example inhibitors include azole 
antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, 
nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil. 
3.2.9 
Side Effects:  
3.2.9.1 >10% 
 
Cardiovascular: EKG abnormal (60%) 
 
Dermatologic: Alopecia (90%) 
 
Gastrointestinal: Nausea (30%; grades 3/4: 3%), diarrhea (27%; grades 3/4: <1%), vomiting (18%; 
grades 3/4: 4%) 
 
Hematologic: Neutropenia (80%; grade 4: 9%), anemia (33%; grades 3/4: 1%) 
 
Hepatic: AST increased (39%), alkaline phosphatase increased (36%), GGT increased (grades 3/4: 
14%) 
 
Neuromuscular & skeletal: Sensory neuropathy (71%; grades 3/4: 10%; dose dependent; may be 
cumulative), weakness (47%), myalgia/arthralgia (44%) 
 
Ocular: Vision disturbance (13%; severe [keratitis, blurred vision]: 1%) 
 
Respiratory: Dyspnea (12%) 
Miscellaneous: Infection (24%; primarily included oral candidiasis, respiratory tract infection, and 
pneumonia 
3.2.9.2 1% to 10%: 
 
Cardiovascular: Edema (10%), hypotension (5%), cardiovascular events (grades 3/4: 3%; included 
chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary 
thromboembolism, pulmonary emboli, and hypertension) 
 
Gastrointestinal: Mucositis (7%; grades 3/4: <1%) 
 
Hematologic: Bleeding (2%), neutropenic fever (2%), thrombocytopenia (2%; grades 3/4: 1%) 
 
Hepatic: Bilirubin increased (7%) 
 
Neuromuscular and skeletal: Peripheral neuropathy (grade 3: 10%) 
 
Renal: Creatinine increased (11%; severe 1%) 
 
Respiratory: Cough (7%) 
 
Miscellaneous: Hypersensitivity reaction (4%) 
3.2.9.3 <1% (Limited to important or life-threatening): <1%: Bradycardia, cardiac ischemia, cerebrovascular 
attack, cranial nerve palsies, embolism, erythema, hand-foot syndrome (in patients previously 
exposed to capecitabine), injection site reaction, maculopapular rash, MI, motor neuropathy, nail 
discoloration, nail pigmentation changes, photosensitivity reaction, pneumothorax, pruritus, radiation 
recall, stroke, thrombosis, transient ischemic attack 
3.2.9.4 It is contraindicated with hypersensitivity to paclitaxel or any component of the formulation; baseline 
neutrophils <1500/mm3 
3.2.9.5 Adverse reactions reported with paclitaxel, which may occur with paclitaxel (protein bound): 
Autonomic neuropathy, cellulitis, conjunctivitis, extravasation recall, fibrosis, hepatic necrosis, 
hepatic encephalopathy, induration, intestinal obstruction, intestinal perforation, interstitial 
pneumonia, ischemic colitis, lacrimation increased, lung fibrosis, necrosis, neutropenic enterocolitis 
(typhlitis), optic nerve damage (persistent), pancreatitis, paralytic ileus, phlebitis, radiation 
pneumonitis with concurrent radiation therapy, skin exfoliation, Stevens-Johnson syndrome, toxic 
epidermal necrolysis 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 15 of 44 
 
 
3.3 
Carboplatin 
3.3.1 
Therapeutic Classification: Alkylating Agent; Platinum 
3.3.2 
Mechanism of Action: Carboplatin is an alkylating agent, which covalently binds to DNA; possible 
cross-linking and interference with the function of DNA 
3.3.3 
Pharmaceutical Data: 
 
Injection: 50 mg, 150 mg, 450 mg 
 
Distribution: Vd: 16 L/kg 
 
Protein binding: 0%; platinum is 30% irreversibly bound.  
 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
 
Half-life elimination: Terminal: 22-40 hours; CrCl >60 mL/minute: 2.5-5.9 hours 
 
Excretion: Urine (60-90%) within 24 hours 
3.3.4 
Solution Preparation:  Maximum concentration: 10 mg/mL. Standard IVPB Fluid: 250 mL D5W. 
3.3.5 
Stability and Storage Requirements:  
 
Room temperature stability: 36 hours; extrapolated stability policy considering % drug lost over time 
 
Refrigeration stability after dilution: 5 days 
3.3.6 
Route of Administration: IV infusion only. 
3.3.7 
Usual Dosage Range:  
3.3.7.1 Adults: Single agent: 360 mg/m2 once every 4 weeks; dose is then adjusted on platelet count and 
neutrophil count values; Carboplatin may also be prescribed by formula-based dosing using the 
AUC method as per the Calvert-based equations. Carboplatin, as a single agent, has been shown to 
be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 
every 4 weeks. In general, however, single intermittent courses of carboplatin should not be 
repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100 K. The dose 
adjustments in the table below were recommendations from LexiComp and are modified from a 
controlled trial in previously treated patients with ovarian carcinoma. Blood counts were done 
weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil 
value.  
 
Carboplatin Dosage Adjustment Based on Pretreatment Platelet Counts 
Platelets (cells/L) 
Neutrophils 
(cells/L) 
Adjusted Dose 
(From Prior 
Course) 
> 100 x 109 
> 2 x 109 
125% 
50-100 x 109 
0.5-2 x 109 
No adjustment 
< 50 x 109 
< 0.5 x 109 
75% 
3.3.7.2 Dosing in renal impairment: Creatinine clearance (CrCl) < 60 mL/minute are at increased risk of 
severe bone marrow suppression. In renally impaired patients who received single agent carboplatin 
therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% 
when the following dosage modifications have been used: CrCl 41-59 mL/minute: Recommended 
dose on day 1 is 250 mg/m2, CrCl 16-40 mL/minute: Recommended dose on day 1 is 200 mg/m2, 
The data available for patients with severely impaired kidney function (CrCl <15 mL/minute) are too 
limited to permit a recommendation for treatment. These dosing recommendations apply to the initial 
course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance 
based on the degree of bone marrow suppression. 
3.3.8 
Side Effects:  
3.3.8.1 >10% 
 
Dermatologic: Alopecia 
 
Endocrine & metabolic: Hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia; less severe 
than those seen after cisplatin (usually asymptomatic).  
 
Gastrointestinal: Nausea, vomiting, stomatitis.  
 
Hematologic: Myelosuppression (dose related and dose-limiting); thrombocytopenia (37-80%); 
leukopenia (27-38%). Nadir: 21 days following a single dose.  
 
Hepatic: Alkaline phosphatase increased, AST increased (usually mild and reversible).  
 
Otic: Hearing loss at high tones (above speech ranges, up to 19%); clinically important ototoxicity is 
not usually seen.  


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 16 of 44 
 
 
 
Renal: Increases in creatinine and BUN have been reported. 
3.3.8.2 1% to 10%: 
 
Gastrointestinal: Diarrhea, anorexia 
 
Hematologic: Hemorrhagic complications 
 
Local: Pain at injection site 
 
Neuromuscular & skeletal: Peripheral neuropathy (4-6%; up to 10% in older and/or previously-
treated patients) 
 
Otic: Ototoxicity 
3.3.8.3 <1% (Limited to important or life-threatening): Neurotoxicity, urticaria, rash, nephrotoxicity, 
secondary malignancies, anaphylaxis, malaise, and hypertension 
3.3.8.4 Special Precautions:  Increased toxicity can be observed with: Nephrotoxic drugs; aminoglycosides 
increase risk of ototoxicity, and Docetaxel, paclitaxel (taxane derivatives): When administered as 
sequential infusions, taxane derivatives should be administered before platinum derivatives to limit 
myelosuppression and to enhance efficacy. 
3.3.8.5 Carboplatin is a vascular irritant.  
3.3.8.6 It is contraindicated with history of severe allergic reaction to cisplatin, carboplatin, other platinum-
containing formulations, mannitol, or any component of the formulation; pregnancy 
 
3.4 
Epirubicin 
3.4.1 
Therapeutic Classification: Anthracycline; Antineoplastic Agent 
3.4.2 
Mechanism of Action: Epirubicin is an anthracycline antibiotic; known to inhibit DNA and RNA 
synthesis by steric obstruction after intercalating between DNA base pairs; active throughout entire 
cell cycle. Intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. 
Also inhibits DNA helicase, and generates cytotoxic free radicals. 
3.4.3 
Pharmaceutical Data: 
 
Injection: 2 mg/mL (50 mg/25 mL; 200 mg/100 mL) 
 
Distribution: Vss 21-27 L/kg 
 
Protein binding: 77% to albumin 
 
Metabolism: Extensively via hepatic and extrahepatic (including RBCs) routes 
 
Half-life elimination: Triphasic; Mean terminal: 33 hours 
 
Excretion: Feces; urine (lesser extent) 
3.4.4 
Solution Preparation: Stability and Storage Requirements:  
 
Room temperature stability:  
 
Refrigeration stability:  
3.4.5 
Route of Administration: IV infusion only. 
3.4.6 
Usual Dosage Range:  
3.4.6.1 Adults: Single agent:  
 
Recommended starting dose: 100-120 mg/m2. Epirubicin is given in repeated 3- to 4-week cycles 
with the total dose given on day 1 of each cycle or divided equally and given on days 1 and 8 of 
each cycle. Patients receiving the 120 mg/m2 regimen should also receive prophylactic antibiotics 
with TMP-SMX or a fluoroquinolone.  
 
As a component of adjuvant therapy in patients with axillary-node positive breast cancer:  
 
CEF-120: 60 mg/m2 on days 1 and 8 of cycle (in combination with cyclophosphamide and 5-
fluorouracil); cycle is repeated every 28 days for 6 cycles  
 
FEC-100: 100 mg/m2 on day 1 of cycle (in combination with 5-fluorouracil and cyclophosphamide); 
cycle is repeated every 21 days for 6 cycles  
 
3.4.6.2 Dosing in hepatic impairment:  
 
Bilirubin 1.2-3 mg/dL or AST 2-4 times the upper limit of normal: 50% of recommended starting dose  
 
Bilirubin >3 mg/dL or AST >4 times the upper limit of normal: 25% of recommended starting dose  
 
3.4.6.3 Dosage adjustment in bone marrow dysfunction:  
 
Patients with heavy pretreatment, pre-existing bone marrow depression, or the presence of 
neoplastic bone marrow infiltration: Consider lower starting doses of 75-90 mg/m2  
 
Dosage modifications after the first treatment cycle: Nadir platelet counts  


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 17 of 44 
 
 
 
<50,000/mm3, ANC <250/mm3, neutropenic fever, or grades 3/4 non hematologic  
 
Toxicity: Reduce day 1 dose in subsequent cycles to 75% of the current cycle. Day 1 chemotherapy 
in subsequent courses of treatment should be delayed until platelet counts are ≥100,000/mm3, ANC 
≥1500/mm3, and non hematologic  
 
Toxicities have recovered to ≤grade 1.  
 
In addition, for patients receiving divided dose (day 1 and day 8) regimen:  
 
Day 8 platelet counts 75,000-100,000/mm3 and ANC 1000-1499/mm3: Day 8  
 
Dose should be 75% of the day 1 dose  
 
Day 8 platelet counts <75,000/mm3, ANC <1000/mm3, or grade 3 or 4  
 
Non hematologic toxicity: Omit day 8 dose  
 
Dosage adjustment in renal impairment: Severe renal impairment (serum creatinine >5 mg/dL): 
Lower doses should be considered  
 
3.4.7 
Side Effects:  
3.4.7.1 >10% 
 
Central nervous system: Lethargy (1-46%)  
 
Dermatologic: Alopecia (69-96%)  
 
Endocrine & metabolic: Amenorrhea (69-72%), hot flashes (5-39%)  
 
Gastrointestinal: Nausea/vomiting (83-92%), mucositis (9-59%), diarrhea (7-25%)  
 
Hematologic: Leukopenia (50-80%; grades 3/4: 2-59%), neutropenia (54-80%; grades 3/4: 11-67%; 
nadir: 10-14 days; recovery: 21 days), anemia (13-72%; grades 3/4: 6%), thrombocytopenia (5-49%; 
grades 3/4: 5%)  
 
Local: Injection site reactions (3-20%)  
 
Ocular: Conjunctivitis (1-15%)  
 
Miscellaneous: Infection (15-21%)  
 
3.4.7.2 1% to 10%: 
 
Cardiovascular: CHF (0.4-1.5%), decreased LVEF (asymptomatic) (1-2%); recommended maximum 
cumulative dose: 900 mg/m2  
 
Central nervous system: Fever (1-5%)  
 
Dermatologic: Rash (1-9%), skin changes (1-5%)  
 
Gastrointestinal: Anorexia (2-3%)  
 
Hematologic: Neutropenic fever (grades 3/4: 6%)  
 
3.4.7.3 <1% (Limited to important or life-threatening):  
 
Post-marketing, case reports, and/or frequency not defined: Acute lymphoid leukemia; acute 
myelogenous leukemia (0.3% at 3 years, 0.5% at 5 years, 0.6% at 8 years); anaphylaxis, 
atrioventricular block, bradycardia, bundle-branch block, cardiomyopathy, ECG abnormalities, 
hypersensitivity, myelodysplastic syndrome, photosensitivity, premature menopause, premature 
ventricular contractions, pulmonary embolism, radiation recall, sinus tachycardia, skin and nail 
hyperpigmentation, ST-T wave changes (nonspecific), tachyarrhythmias, thromboembolism, 
thrombophlebitis, transaminases increased, urticaria, ventricular tachycardia  
3.4.7.4 Drug interaction:  
 
Bevacizumab: May enhance the cardiotoxic effect of anthracycline antineoplastic agents.  
 
Cimetidine: May increase the levels/effects of epirubicin.  
 
Trastuzumab: May enhance the cardiotoxic effect of anthracycline antineoplastic agents.  
3.4.7.5 U.S. Boxed Warning 
 
Potential cardiotoxicity, particularly in patients who have received prior anthracyclines, prior or 
concomitant radiotherapy to the mediastinal/pericardial area, or who have pre-existing cardiac 
disease, may occur. Acute toxicity (primarily arrhythmias) and delayed toxicity (CHF) have been 
described. Delayed toxicity usually develops late in the course of therapy or within 2-3 months after 
completion, however, events with an onset of several months to years after termination of treatment 
have been described. The risk of delayed cardiotoxicity increases more steeply with cumulative 
doses >900 mg/m2, and this dose should be exceeded only with extreme caution. (The risk of CHF 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 18 of 44 
 
 
is ~0.9% at a cumulative dose of 550 mg/m2, ~1.6% at a cumulative dose of 700 mg/m2, and ~3.3% 
at a cumulative dose of 900 mg/m2.) Toxicity may be additive with other anthracyclines or 
anthracenediones, and may be increased in pediatric patients. Regular monitoring of LVEF and 
discontinuation at the first sign of impairment is recommended especially in patients with cardiac risk 
factors or impaired cardiac function.  
 
Myelosuppression (severe) may occur; neutropenia is the dose-limiting toxicity; severe 
thrombocytopenia or anemia may occur. Thrombophlebitis and thromboembolic phenomena 
(including pulmonary embolism) have occurred.  
 
Reduce dosage and use with caution in mild-to-moderate hepatic impairment or in severe renal 
dysfunction (serum creatinine >5 mg/dL). May cause tumor lysis syndrome or radiation recall.  
 
Treatment with anthracyclines may increase the risk of secondary leukemias.  
 
For IV administration only, severe local tissue necrosis will result if extravasation occurs.  
 
Women ≥70 years of age should be especially monitored for toxicity; women of childbearing age 
should be advised to avoid becoming pregnant.  
 
Should be administered under the supervision of an experienced cancer chemotherapy physician. 
Safety and efficacy in children have not been established. 
 
3.4.8 
Contraindication: Hypersensitivity to epirubicin or any component of the formulation, other 
anthracyclines, or anthracenediones; previous anthracycline treatment up to maximum cumulative 
dose; severe myocardial insufficiency, severe arrhythmias; recent myocardial infarction; severe 
hepatic dysfunction; baseline 
 
3.5 
Cyclophosphamide 
3.5.1 
Therapeutic Classification: Antineoplastic Agent, Alkylating Agent 
3.5.2 
Mechanism of Action: Mechanism of Action Cyclophosphamide is an alkylating agent that prevents 
cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase 
nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. 
Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver. 
3.5.3 
Pharmaceutical Data: 
 
Injection: Vd: 0.48-0.71 L/kg; crosses placenta; crosses into CSF (not in high enough concentrations 
to treat meningeal leukemia) 
 
Protein binding: 10-60% Metabolism: Hepatic to active metabolites acrolein, 4-aldophosphamide, 4-
hydroperoxycyclophosphamide, and nor-nitrogen mustard Bioavailability: >75% 
 
Elimination: 3-12 hours Time to peak, serum. 
 
Excretion: (<30% as unchanged drug, 85-90% as metabolites) 
3.5.4 
Solution Preparation: Stability and Storage Requirements:  
 
Room temperature stability: Store intact vials of powder at room temperature of 15°C to 30°C (59°F 
to 86°F).  
 
Refrigeration stability: Reconstituted solutions are stable for 24 hours at room temperature and 6 
days under refrigeration 2°C to 8°C (36°F to 46°F). Further dilutions in D5W or NS are stable for 24 
hours at room temperature (25°C) and 6 days at refrigeration. 
3.5.5 
Route of Administration: IV infusion only. 
3.5.6 
Usual Dosage Range:  
3.5.6.1 Adults: Single agent:  
 
400-1000 mg/m2 in divided doses over 4-5 days as intermittent therapy IV:  
 
Single doses: 400-1800 mg/m2 (30-50 mg/kg) per treatment course (1-5 days) which can be 
repeated at 2-4 week intervals Continuous daily doses: 60-120 mg/m2 (1-2.5 mg/kg) per day  
 
Autologous BMT: IVPB: 50 mg/kg/dose x 4 days or 60 mg/kg/dose for 2 days; total dose is usually 
divided over 2-4 days  
3.5.6.2 Dosing in renal impairment:  
 
Some authors recommend no dose adjustment unless severe renal insufficiency (CrCl <20 
mL/minute) CrCl >10 mL/minute: Administer 100% of normal dose CrCl <10 mL/minute: Administer 
75% of normal dose  
 
Hemodialysis: Moderately dialyzable (20-50%); administer dose post hemodialysis CAPD effects: 
Unknown CAVH effects: Unknown Dosing adjustment in hepatic impairment: The pharmacokinetics 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 19 of 44 
 
 
of cyclophosphamide are not significantly altered in the presence of hepatic insufficiency. No 
dosage adjustments are recommended. 
 
3.5.7 
Drug Interaction 
Substrate of CYP2A6 (minor), 2B6 (major), 2C9 (minor), 2C19 (minor), 3A4 (major); Inhibits 
CYP3A4 (weak); Induces CYP2B6 (weak), 2C8 (weak),  
2C9 (weak)  
Allopurinol may cause increase in bone marrow depression and may result in significant elevations 
of cyclophosphamide cytotoxic metabolites.  
Anesthetic agents: Cyclophosphamide reduces serum pseudocholinesterase concentrations and 
may prolong the neuromuscular blocking activity of succinylcholine; use with caution with halothane, 
nitrous oxide, and succinylcholine.  
Cardiac glycosides: Cyclophosphamide may decrease the absorption of digoxin tablets.  
CYP2B6 inducers: May increase the levels/effects of acrolein (the active metabolite of 
cyclophosphamide). Example inducers include carbamazepine, nevirapine, phenobarbital, 
phenytoin, and rifampin.  
CYP2B6 inhibitors: May decrease the levels/effects of acrolein (the active metabolite of 
cyclophosphamide). Example inhibitors include desipramine, paroxetine, and sertraline.  
CYP3A4 inducers: CYP3A4 inducers may increase the levels/effects of acrolein (the active 
metabolite of cyclophosphamide). Example inducers include aminoglutethimide, carbamazepine, 
nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycin.  
CYP3A4 inhibitors: May decrease the levels/effects of acrolein (the active metabolite of 
cyclophosphamide). Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, 
diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, 
protease inhibitors, quinidine, and verapamil.  
Etanercept: May enhance the adverse/toxic effects of cyclophosphamide.  
Mivacurium: Cyclophosphamide may increase the levels/effects of mivacurium.  
Phenytoin: May decrease the levels/effects of cyclophosphamide; may increase the levels/effects of 
4-hydroxycyclophosphamide.  
Succinylcholine: Cyclophosphamide may increase the levels/effects of succinylcholine. 
3.5.8 
Side Effects:  
3.5.8.1 >10% 
 
Dermatologic: Alopecia (40-60%) but hair will usually regrow although it may be a different color 
and/or texture. Hair loss usually begins 3-6 weeks after the start of therapy.  
 
Endocrine & metabolic: Fertility: May cause sterility; interferes with oogenesis and spermatogenesis; 
may be irreversible in some patients; gonadal suppression (amenorrhea)  
 
Gastrointestinal: Nausea and vomiting (usually beginning 6-10 hours after administration); anorexia, 
diarrhea, mucositis, and stomatitis are also seen  
 
Genitourinary: Severe, potentially fatal, acute hemorrhagic cystitis or urinary fibrosis (7-40%)  
 
Hematologic: Thrombocytopenia and anemia are less common than leukopenia. Onset: 7 days. 
Nadir: 10-14 days. Recovery: 21 days  
 
3.5.8.2 1% to 10%: 
 
Cardiovascular: Facial flushing  
 
Central nervous system: Headache  
 
Dermatologic: Skin rash  
 
Renal: SIADH may occur, usually with doses >50 mg/kg (or 1 g/m2); renal tubular necrosis, which 
usually resolves with discontinuation of the drug, is also reported  
 
Respiratory: Nasal congestion occurs when IV doses are administered too rapidly; patients 
experience runny eyes, rhinorrhea, sinus congestion, and sneezing during or immediately after the 
infusion.  
 
3.5.8.3 <1% (Limited to important or life-threatening):  
Post-marketing, and/or case reports: High-dose therapy may cause cardiac dysfunction manifested 
as CHF; cardiac necrosis or hemorrhagic myocarditis has occurred rarely, but may be fatal. 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 20 of 44 
 
 
Interstitial pneumonitis and pulmonary fibrosis are occasionally seen with high doses. 
Cyclophosphamide may also potentiate the cardiac toxicity of anthracyclines. Other adverse 
reactions include anaphylactic reactions, darkening of skin/fingernails, dizziness, hemorrhagic 
colitis, hemorrhagic ureteritis, hepatotoxicity, hyperuricemia, hypokalemia, jaundice, malaise, 
neutrophilic eccrine hidradenitis, radiation recall, renal tubular necrosis, secondary malignancy (eg, 
bladder carcinoma), SAIDH, Stevens-Johnson syndrome, toxic epidermal necrolysis, weakness.  
3.5.8.4 Special Precautions:  
 
Cardiotoxicity: May cause cardiotoxicity (CHF, usually with higher doses).  
 
Fertility effects: May impair fertility; interferes with oogenesis and spermatogenesis. Hemorrhagic 
cystitis: May occur; increased hydration and frequent voiding is recommended.  
 
Immunosuppression: Monitor for infections; immunosuppression may occur.  
 
Secondary malignancies: With use secondary malignancies (usually delayed) have been reported.  
 
Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may 
be needed.  
 
Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be 
needed.  
 
May potentiate the cardiotoxicity of anthracyclines. 
 
3.6 
Fluorouracil 
3.6.1 
Therapeutic Classification: Antineoplastic Agent, Antimetabolite (Pyrimidine Antagonist) 
3.6.2 
Mechanism of Action: Action A pyrimidine antimetabolite that interferes with DNA synthesis by 
blocking the methylation of deoxyuridylic acid; fluorouracil inhibits thymidylate synthetase (TS), or is 
incorporated into RNA. The reduced folate cofactor is required for tight binding to occur between the 
5-FdUMP and TS. 
3.6.3  Pharmaceutical Data: 
 
Injection: IV Irritant. Direct IV push injection (50 mg/mL solution needs no further dilution) or by IV 
infusion. Doses >1000 mg/m2 are usually administered as a  
 
24-hour infusion. Giving the drug as a constant infusion may reduce toxicity. Bolus doses may be 
administered by slow IVP or IVPB. 
 
Distribution: Vd: ~22% of total body water; penetrates extracellular fluid, CSF, and third space fluids 
(eg, pleural effusions and ascitic fluid). 
 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; FU must be metabolized to be active 
 
Half-life elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have 
prolonged half-lives depending on the type of tissue 
 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 hours 
3.6.4 
Solution Preparation: Stability and Storage Requirements:  
 
Room temperature stability:  
 
Refrigeration stability:  
3.6.5 
Route of Administration: IV infusion only. 
3.6.6 
Usual Dosage Range:  
3.6.6.1 Adults: 
IV bolus: 500-600 mg/m2 every 3-4 weeks or 425 mg/m2 on days 1-5 every 4 weeks Continuous IV 
infusion: 1000 mg/m2/day for 4-5 days every 3-4 weeks or 2300-2600 mg/m2 on day 1 every week 
or 300-400 mg/m2/day or 225 mg/m2/day for 5-8 weeks (with radiation therapy) 
3.6.6.2 Dosing in renal impairment:  
Hemodialysis: Administer dose following hemodialysis. Dosage adjustment for hepatic impairment: 
Bilirubin >5 mg/dL: Omit use.  
 
3.6.7 Side Effects:  
3.6.7.1 Common 
 
Cardiovascular: Angina, myocardial ischemia, nail changes  
 
Central nervous system: Acute cerebellar syndrome, confusion, disorientation, euphoria, headache, 
nystagmus  
 
Dermatologic: Alopecia, dermatitis, dry skin, fissuring, palmar-plantar erythrodysesthesia syndrome, 
pruritic maculopapular rash, photosensitivity, vein pigmentations  


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 21 of 44 
 
 
 
Gastrointestinal: Anorexia, bleeding, diarrhea, esophagopharyngitis, nausea, sloughing, stomatitis, 
ulceration, vomiting  
 
Hematologic: Agranulocytosis, anemia, leukopenia, pancytopenia, thrombocytopenia  
 
Myelosuppression: Onset: 7-10 days Nadir: 9-14 days Recovery: 21-28 days  
 
Local: Thrombophlebitis Ocular: Lacrimation, lacrimal duct stenosis, photophobia, visual changes 
Respiratory: Epistaxis Miscellaneous: Anaphylaxis, generalized allergic reactions, nail loss. 
 
3.6.7.2 Special Precautions:  
 
Hand-foot syndrome: Palmar-plantar erythrodysesthesia (hand-foot) syndrome has been associated 
with use.  
 
Toxicity: Discontinue if intractable vomiting, diarrhea, precipitous fall in leukocyte or platelet counts, 
myocardial ischemia, hemorrhage, or stomatitis occur.  
 
Dihydropyrimidine dehydrogenase deficiency (DPD): Administration to patients with genetic DPD 
has been associated with increased toxicity following administration (diarrhea, neutropenia, and 
neurotoxicity). Systemic toxicity normally associated with parenteral administration has also been 
associated with topical use, particularly in patients with DPD; discontinue if symptoms of DPD occur.  
 
Hepatic impairment: Use with caution in patients with hepatic impairment.  
 
Renal impairment: Use with caution in patients with renal impairment.  
 
Alkylating agents: Use with caution in patients who have had previous use of alkylating agents.  
 
4.0 
PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria 
4.1.1 
Histological confirmation of breast carcinoma. Pathologic evidence of dermal lymphatic invasion 
should be noted but not required. 
4.1.2 
Clinical diagnosis of IBC (presence of inflammatory changes in the involved breast, including diffuse 
erythema, heat, ridging, and peau d’orange). 
4.1.3 
 Age 18 
4.1.4 
ECOG performance status ≤ 1  
4.1.5 
Adequate hematologic function 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
Platelet count  100 x 109/L  
 
Hemoglobin  9.0 g/dL  
4.1.6 
Adequate cardiac function (LVEF  45%) 
4.1.7 
Adequate Renal function 
 
Creatinine (Cr)  1.5 mg/dL x ULN 
 
Creatinine clearance (CrCl)  50 mL/min calculated by the Cockroft-Gault method as follows: Male 
creatinine clearance = (140 - age) x (weight in Kg) / (serum Cr x 72) Female CrCl = (140 - age) x 
(weight in Kg) x 0.85 / (serum Cr x 72) 
4.1.8 
Adequate Hepatic function 
 
Aspartate aminotransferase (AST)  2.5 x ULN 
 
Alanine aminotransferase (ALT)  2.5 x ULN 
 
Alkaline phosphatase (Alp)  2.5 x ULN 
 
Total bilirubin  1.5 x ULN 
4.1.9 
Ability and willingness to sign an informed consent form for this protocol 
4.1.10 If female of childbearing potential (women who are post-menopausal < 1 year, not surgically 
sterilized, or not abstinent), urine pregnancy test is negative, and agrees to be consistent and 
correct use of one of the following acceptable methods of birth control: male partner who is sterile 
prior to the female subject’s entry into the study and is the sole sexual partner for that female 
subject; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral 
contraception, or barrier methods, including diaphragm or condom with a spermicide. 
4.1.11 Patients who have metastatic disease, if the metastatic sites are amendable for local therapy (i.e. 
radiation and/or surgery), and are candidates for breast surgery will be eligible. 
4.2 
Exclusion Criteria 
4.2.1 
History of radiation or chemotherapy 
4.2.2 
HER2-positive breast carcinoma (IHC staining more than 3+ or HER2 gene amplification by FISH) 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 22 of 44 
 
 
4.2.3 
Recurrent breast cancer 
4.2.4 
History of other malignancies (except for cured non-melanomatous skin cancer or cured cervical 
carcinoma in situ, or malignancies with no evidence of disease and no treatment for >5 years)  
4.2.5 
Known positive test(s) for human immunodeficiency virus infection, hepatitis C virus, acute or 
chronic active hepatitis B infection 
4.2.6 
History of extensive interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or any evidence 
of extensive interstitial lung disease on baseline chest CT scan  
4.2.7 
Patient with other significant medical or psychiatric condition that would make assessment of toxicity 
or efficacy difficult. 
4.2.8 
Uncontrolled intercurrent illness including, but 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. 
4.2.9 
Peripheral neuropathy ≥ Gr II 
 
 
5.0 
TREATMENT PLAN 
5.1 
General: All patients shall be registered in CORe. 
5.2 
Information on histological diagnosis of malignancy, nuclear grade, estrogen and progesterone 
receptor, HER, flow cytometry will be collected if available 
5.3 
Preoperative systemic chemotherapy PNC. 
5.3.1 
All chemotherapy will be given based on actual body weight-derived body surface area (BSA). No 
dose adjustment should be made based on weight gain due to fluid retention. 
 
5.3.2 
First week of treatment will be only panitumumab. Panitumumab 2.5 mg/kg IV over 60 min by pump. 
Please see section 2.10 for rationale. An optional core  Biopsy of the breast will be done (1 week) 
after this first dose but before 2nd dose.  
 
5.3.3 
Starting week 2 (day 1 of cycle 1), patients will receive 4 cycles of weekly combination of 
panitumumab, carboplatin, and nab-paclitaxel on a 3-week on and 1-week off schedule.   During 
Cycle 4, patients will receive 2 weekly doses of panitumumab and 3 weekly carboplatin and nab-
paclitaxel.  Assuming bone marrow recovery (absolute granulocyte count >/= 1,000 and platelets >/= 
100,000 per mm3 before each dosing) Panitumumab—2.5 mg/kg IV over 30 min (If no reaction to 
the 1st dose), Abraxane—100 mg/m2 IV over 30 min, Carboplatin—AUC 2 IV over 30 min Table 1.  
If the dose of panitumumab dose is higher than 1000 mg, it will be infused over 90 min. 
 
Dosage of PNC (Table 1) 
 
Premedications;* 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Panitumumab 
Not required for 
routine infusions 
2.5 
mg/kg 
If no reaction to the first dose 
of Panitumumab, 30 min for 
subsequent dose 
Wk 1; 
C1-3 wklyX3, 1 wk off;  
C4 wklyX2 
 
Nab-paclitaxel 
Not required for 
routine infusions 
100 
mg/m2 
IV over 30 min after 
completion of Agent 
Panitumumab through 
separate IV line 
C1-4 wklyX3, 1 wk off 
  
Carboplatin 
Not required for 
routine infusions 
2 
AUCa 
IV over 30 min after 
completion of Abraxane 
through separate IV line
C1-4 wklyX3, 1 wk off 
 
* Only for hypersensitivity, anti-emetic should be given accordinglya. Total Dose (mg) = (target AUC) X 
(GFR+25) 
The GFR used in the Calvert formula to calculate AUC-based dosing should not exceed 125mL/min 
Maximum CARBOplatin AUC 2 should not exceed 300mg 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 23 of 44 
 
 
 
 
 
 
Dose-De-escalation Schedule (Table 2a) 
If toxicities are deemed to be related to Panitumumab, dose of Panitumumab will be reduced. 
Dose Level 
Panitumumab (mg/kg) 
 
Starting dose 
 
2.5 
Level -1 
2.0 
Level -2 
1.5 
 
DC Panitumumab* 
* If Panitumumab is discontinued due to panitumumab-related toxicities, patient may continue on Nab-
paclitaxel and Carboplatin. 
 
 
Dose-De-escalation Schedule (Table 2b) If toxicities are deemed to be related to chemotherapy 
(Nab-paclitaxel and/or Carboplatin), chemotherapy dose will be reduced. 
 
Dose Level 
 
Starting dose 
Dose*
Nab-paclitaxel 
(Abraxane) 
100 mg/m2 
Carboplatin 
AUC 2 
Level -1 
80 
1.6 
Level -2 
60 
1.2 
 
Off study* 
Off study* 
* If Nab-paclitaxel and/or Carboplatin continue to cause chemotherapy related toxicities at dose level -2 , 
patient will be off study. 
 
 
5.3.4 
Panitumumab Dosage, Administration and Schedule: The starting panitumumab dose is 2.5 mg/kg. 
The total dose may be rounded up or down by no greater than 10 mg. The panitumumab dose will 
be calculated based on the subject’s actual body weight at baseline and will not be re-calculated 
unless the actual body weight changes by at least 10%. Panitumumab will be diluted in a minimum 
of 100 mL of pyrogen-free 0.9% sodium chloride solution USP/PhEur (normal saline solution, 
supplied by the site). The maximum concentration of the diluted solution to be infused should not 
exceed 10 mg/mL. The volume of normal saline should be increased as needed to ensure the 
maximum concentration of the diluted solution does not exceed 10 mg/mL. Panitumumab will be 
administered IV by an infusion pump through a peripheral line or indwelling catheter using a 0.2 or 
0.22-micron in-line filter infusion set-up over 1 hour  15 minutes by a trained healthcare 
professional. If the first infusion is well tolerated (i.e. without any serious infusion-related reactions) 
all subsequent infusions may be administered over 30  10 minutes. In the event a subject’s actual 
weight requires greater than 150 mL volume infusion, panitumumab will be administered over 90 
minutes  15 minutes, as tolerated. If the filter extension set is not compatible with the infusion set-
up at the study center, Amgen should be contacted immediately. Strict adherence to aseptic 
technique should be used during panitumumab preparation and administration. The bag should be 
labeled per site pharmacy Standard Operating Procedures and promptly forwarded to the clinical 
research center for infusion. The effects of overdose of panitumumab are not known. See Section 
3.0 Pharmacy Guide for information on panitumumab packing and formulation, labeling, storage, 
preparation, supply/return, and accountability. 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 24 of 44 
 
 
 
5.3.5 
Pre-medication for Panitumumab: Panitumumab specific pre-medication is not required for routine 
panitumumab infusions. If, during or after any infusion, a reaction occurs, pre-medication may be 
used for subsequent panitumumab infusions according to institutional guideline or investigator’s 
discretion as listed in the standard Panitumumab order set. 
 
5.3.6 
Interruption of Panitumumab Infusion: Subjects who experience any serious infusion reaction during 
panitumumab administration will have the infusion stopped. Continuation of dosing will be based on 
the severity and resolution of the event and will be at the discretion of the investigator. Suspected 
infusion reactions should be reported as an adverse event. All subjects who experience such an 
event will be followed for safety. 
 
 
5.3.7 
Toxicity Assessment: Toxicities will be recorded as AEs on the Adverse Event case report form and 
must be graded using The National Cancer Institute’s Common Toxicity Criteria (NCI-CTC) version 
3.0 (Appendix A), with the exception of skin- or nail-related toxicities, which must be graded using 
NCI-CTC version 3.0 with modifications (see Appendix I). 
 
5.3.8 
Panitumumab Dosage Adjustments: For subjects who experience panitumumab-related Gr III and IV 
toxicities (no hematologic toxicities) while on study, one or more doses of panitumumab may need 
to be withheld, delayed, or reduced. If Panitumumab is withheld, or delayed for up to two cycles, on 
resolution of toxicity, two attempts to reduce panitumumab doses will be allowed (Table 2). If 
Panitumumab is withheld for more than 2 cycles or after 2nd dose reduction and patients remain to 
have panitumumab-related Gr III and IV non-hematological toxicities, panitumumab will be 
discontinued. Patient may continue Nab-paclitaxel and carboplatin as clinically indicated. 
 
Panitumumab Dose Reductions (Table 3) 
 
Starting Dose 
1st Dose 
Reduction 
2nd Dose 
Reduction 
Percentage (%) 
100 
80 
60 
mg/kg 
2.5 
2.0 
1.5 
 
 
5.3.9 
Criteria for Withholding a Dose of Panitumumab  
5.3.9.1 Skin- or nail-related toxicities:  
 
Symptomatic skin- or nail-related toxicity requiring narcotics, systemic steroids, or felt to be 
intolerable by the subject.  
 
Skin or nail infection requiring IV antibiotic or IV antifungal treatment.  
 
Need for surgical debridement.  
 
Any skin- or nail-related serious adverse event 
5.3.9.2 Non-skin- or nail-related toxicities: Any Gr III or IV toxicity with the following exceptions: 
 
Panitumumab will only be withheld for symptomatic hypomagnesemia and/or hypocalcemia that 
persists despite aggressive magnesium and/or calcium replacement 
 
Panitumumab will only be withheld for Gr III or IV nausea, diarrhea, or vomiting that persists despite 
maximum supportive care (see Section 5.4.1 for diarrhea management guidelines) 
 
Panitumumab will only be withheld for Gr ≥ III anemia or Gr IV thrombocytopenia that cannot be 
managed by transfusion(s) or cytokine therapy 
5.3.10 Criteria for re-treatment with panitumumab: 
5.3.10.1 
Skin- or nail-related toxicities: Panitumumab administration may recommence once: The adverse 
event has improved to ≤ Grade 2 or returned to baseline, or; The subject has recovered to the point 
where symptomatic skin- or nail-related toxicity is felt to be tolerable; or, Systemic steroids are no 
longer required, or IV antibiotic or IV antifungal treatment is no longer required 
5.3.10.2 
Non-skin- or nail-related toxicities:  Panitumumab administration may recommence once the 
adverse event has improved to ≤ Grade 1 or returned to baseline. 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 25 of 44 
 
 
5.3.11 Infusion-related reaction: Reduce infusion rate by 50% in patients experiencing a mild or moderate 
(grade 1 or 2) infusion reaction for the duration of that infusion. Immediately and permanently 
discontinue Vectibix infusion in patients experiencing severe (grade 3 or 4) infusion reactions. 
 
5.3.12 Dose Modification Schedule: Subjects should be assessed for toxicity before each dose. Dose 
modification should be performed according to the schedule described below and outlined in Figure 
1.  Subjects who develop a toxicity that does not meet the criteria for withholding a dose of 
panitumumab (Section 5.3.9) should continue to receive panitumumab and their symptoms should 
be treated. Re-treatment with panitumumab will be allowed if panitumumab-related toxicity should 
return to</=1 or complete resolution. 
 
5.3.13  For subjects who experience a toxicity that meets the criteria for withholding a dose of 
panitumumab:  
5.3.13.1 
Subjects receiving either 100% of the starting dose of panitumumab are allowed to have up to 2 
subsequent doses withheld for toxicity. However a second dose should only be withheld if the 
toxicity has not resolved by the time that the subsequent dose is due.  
5.3.13.2 
Subjects treated at the 100% dose level whose toxicity resolves after 1 dose of panitumumab is 
withheld should be re-started at the 100% dose level (recommended but not required, reduction to 
the 80% dose is allowed as an alternative to re-challenge with the 100% dose).  
5.3.13.3 
If toxicity recurs, subjects treated at the 100% dose or 80% dose should be re-started at the 80% 
dose or 60% dose, respectively, when the toxicity resolves after withholding 1 or 2 doses of 
panitumumab. 
5.3.13.4 
Subjects treated at the 100% dose level whose toxicity resolves only after 2 subsequent doses of 
panitumumab are withheld should be re-started at the 80% dose level.  
5.3.13.5 
Subjects treated at the 80% dose level whose toxicity resolves after withholding 1 or 2 doses of 
panitumumab should be re-started at the 60% dose level.  
5.3.13.6 
Subjects who experience toxicity at the 60% dose level will not be re-treated with panitumumab.  
5.3.13.7 
It is recommended that panitumumab doses will be escalated in subjects whose toxicity resolves 
to the degree that meets the criteria for re-starting a dose of panitumumab (Section 5.3.9). Dose 
escalations are recommended but not required. Dose escalations should occur in the following 
manner: 
5.3.13.8 
Subjects treated at the 80% dose level whose toxicity does not recur should receive the 100% 
dose level at the next dose unless a previous attempt to re-escalate to the 100% dose level was not 
tolerated (re-initiation of the 80% dose is allowed as an alternative to dose escalation).  
5.3.13.9 
Subjects treated at the 60% dose level whose toxicity does not recur should receive the 80% 
dose at the next dose unless a previous attempt to re-escalate to the 80% dose level was not 
tolerated (re-initiation of the 60% dose is allowed as an alternative to dose escalation). 
5.3.13.10 Subjects who miss more than 5 consecutive (6 weeks) scheduled doses due to toxicity or are 
unable to receive a dose of panitumumab within 6 weeks of having received their previous dose of 
panitumumab due to toxicity will be considered unable to tolerate panitumumab and will not be 
retreated with panitumumab. 
5.3.13.11 If a subject demonstrates a clinical benefit with a documented response of stable disease, partial 
response or complete response and there are reasons that the dose modification rules above 
cannot be implemented, the investigator should contact and discuss these reasons with Amgen. The 
investigator must obtain written agreement from Amgen before any changes in the dose 
modification rules can be implemented, Sponsor Approval (ORERM) will also be obtained. 
5.3.13.12 Panitumumab Delayed- or Missed-Doses  
5.3.13.12.1 Panitumumab should be given on the first day of each treatment period. Delays of 
panitumumab administration beyond 3 weeks from the previous dose of panitumumab are not allowed.  
5.3.13.12.2 Reasons to withhold a dose of panitumumab are described in Section 5.3.9. More than 5 
total missed doses are not allowed. Missed panitumumab doses will not be made up. 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 26 of 44 
 
 
Figure 1. Panitumumab Dose Modification Algorithm for Toxicity 
Severity of Toxicity
Withhold panitumumab for 1 dose
Toxicity resolved?
Continue per protocol  
(Symptoms should be treated per 
protocol)
 
Life Threatening or
Disabling Toxicity
No/Mild/Moderate Toxicity
Severe Toxicity* 
Discontinue 
Panitumumab
Administer panitumumab @ 100% of original dose
(recommended but not required)
YES
Administer panitumumab @ 80% of original dose
NO
Administer panitumumab @ 100% of original dose 
(recommended but not required)
OR
Maintain at 80% of original dose 
(if a previous attempt to dose escalate to 100% was not 
tolerated)
YES
Toxicity recurs?*
NO
Administer panitumumab @ 60% of original dose
YES
NO
Discontinue 
Panitumumab
Discontinue 
Panitumumab
Discontinue 
Panitumumab
Toxicity resolved?
Withhold panitumumab for 1 or 2 
doses‡ 
Toxicity resolved?
If toxicity recurs*, withhold panitumumab 
for 1 or 2 doses‡
NO
YES
Discontinue 
Panitumumab
Toxicity recurs?*
YES
NO
Withhold an additional dose of panitumumab
Toxicity resolved?
YES
NO
 Assess toxicity before each cycle. Toxicity resolved = meets the  criteria for restarting panitumumab (see section 4.1.7).                 
   Subjects from whom > 2 subsequent cycles of panitumumab are required to be withheld should not be re-treated with        
   panitumumab.
* Assess toxicity before each cycle. Toxicity recurs =  meets the criteria for withholding a dose of panitumumab at any time during    
   the study (See Section 4.1.6). 
ą Up to 2 subsequent doses of panitumumab may be withheld but panitumumab may not be withheld longer than 6 weeks from 
   the previous dose.  The second dose should only be withheld if the toxicity has not resolved by the time that the 
  
   subsequent cycle of chemotherapy is due.
Maintain at 60% of original 
dose (if a previous attempt 
to dose escalate to 80% 
was not tolerated)
If toxicity recurs* at the 60% 
of the original dose, 
discontinue panitumumab
Escalate to 80% of original dose  
(recommended but not required)
If toxicity recurs*, withhold 
panitumumab until toxicity 
resolves and maintain at 60% of 
the original dose
OR
 
5.3.14 Discontinuation of Panitumumab: Panitumumab will be continued as scheduled (week 1 to week 
12).  Subjects will be taken off study if they are unable to tolerate panitumumab, disease 
progression, death, or study withdrawal by the subject, investigator, or sponsor.  
5.3.15 Nab-paclitaxel and Carboplatin will be continued as scheduled if clinically indicated. The dose 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 27 of 44 
 
 
adjustment is based on the following. 
 
5.4 
Nab-paclitaxel and Carboplatin Dose Adjustments: 
5.4.1 
Every effort will be made to administer the full dose regimen. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Toxicities will be graded using the 
NCI-CTC in Appendix A. If toxicity occurs, the appropriate treatment will be used to ameliorate 
signs and symptoms including antiemetics for nausea and vomiting, antidiarrheals for diarrhea, and 
antipyretics and antihistamines for drug fever, before toxicity grade is determined. 
5.4.2 
Dose adjustments for toxicity should be made according to guidelines, which follow.  
5.4.2.1 Doses, which have been reduced for toxicity, must not be re-escalated back to starting level.  
5.4.2.2 Treatment may be delayed no more than 3 weeks to allow recovery from acute toxicity, and no more 
than 4 weeks to allow recovery from chronic toxicity (except for alopecia, skin changes and anemia).  
5.4.2.3 If toxicities are related to Nab-Paclitaxel and Carboplatin, a maximum of two dose reductions will be 
allowed per patient. If NC is discontinued due to toxicity before 6th cycles can be administered, the 
patient will be removed from the study. The investigator should attempt to obtain follow-up 
information on such patients.  
5.4.2.4 Depending upon the toxicity, dose reduction may occur for only one drug or for both drugs [Nab-
paclitaxel or Carboplatin] together. If the investigator is unsure of the cause, both drugs should be 
reduced. One dose reduction will consist of decreasing the dose to the next lower dose level in 
which the dose of the specified drug(s) actually is (are) reduced (see Table 2). If the toxicity 
indicates that only one drug should be reduced, the other drug should remain at the original dose 
level. If potentially dangerous toxicities are observed, the investigator and sponsor will discuss the 
need for dose reductions.  
5.4.3 
Myelosuppression 
5.4.3.1 In the event of severe myelosuppression (platelet count < 25,000 for any length of time) the dose of 
Nab-paclitaxel and Carboplatin will be reduced by 1 level for both drugs. 
5.4.3.2 Grade I-III myelosuppression (anemia, neutropenia, thrombocytopenia) and Gr IV neutropenia 
except as defined above, with recovery within 7 days, does not require dose modification. 
5.4.3.3 Patients with Gr III-IV neutropenia associated with fever (one reading of oral temperature >38.5 C, 
or 3 readings of oral temperature > 38.0 C in a 24-hour period) or documented infection requiring 
hospitalization and/or oral or intravenous antibiotics will be retreated after recovery at the same 
dose of PNC (in order to maximize dose density/intensity); including prophylactic G–CSF during 
subsequent cycles. However, levofloxacin 500 mg PO qd x 7 days starting on day 5 will be added. 
In addition, patients may have 1 level dose reduction if they experience severe neutropenic 
complications requiring prolonged hospitalization and/or ICU care. If Gr IV neutropenia of > 7 days 
duration, or Gr III-IV neutropenia associated with fever (as defined above) or infection occur again 
despite the use of G–CSF and levofloxacin, the patient should be retreated at 1 lower dose level for 
both drug in all subsequent cycles. Therapy with G-CSF will be allowed if clinically indicated in the 
management of complicated symptomatic neutropenia.  
5.4.4 
Neurotoxicity: If Gr IV, the patient will not receive additional nab-paclitaxel and will be off study. If Gr 
III, patient should be retreated upon recovery (not to exceed 4 weeks) to a < Gr I toxicity with a dose 
reduction of 1 dose level of Nab-paclitaxel. 
 
5.5 
Preoperative Chemotherapy FEC 
5.5.1 
Standard of care FEC chemotherapy will be administered after completion of 13 weeks of PNC 
regimen. Dose modification of the FEC is based on standard of care. 
 
5.5.2 
Then, it will consist of 4 cycles of FEC (5-FU, epirubicin, cyclophosphamide), to be repeated at 
three-week intervals, assuming bone marrow recovery (absolute granulocyte count >/= 1,000 and 
platelets >/= 100,000 per mm3 before the next cycle is begun).  
 
5.5.3 
Dose modification of FEC chemotherapy will be based on standard of care practice. 
 
Dosage of FEC (Table 4) 
 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 28 of 44 
 
 
Fluorouracil 
Use institutional 
guideline
500 
mg/m2
IV 
Every 3 
weeks
Epirubicin 
Use institutional 
guideline
100 
mg/m2
IV over 30 min 
Every 3 
weeks
Cyclophosphamide 
Use institutional 
guideline
500 
mg/m2
IV 
Every 3 
weeks
 
 
 
5.6 
Definition of Toxicity: Toxicities will be graded according to the National Cancer Institute’s NCI-
CTC v3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf)  
 
5.7 
Duration of Therapy: In the absence of treatment delays due to AEs, treatment continues until one 
of the following criteria applies or completion of scheduled PNC and FEC: 
 
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unexpected serious adverse event(s), 
 
 
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. 
 
5.8 
Other Agent(s), Other Modality(ies) and/or Procedures 
5.8.1 
Surgery will be based on standard of the care at the time of patient treatment. 
5.8.2 
Patients with tumors expressing the estrogen or progesterone receptor will be given hormonal 
therapy after the completion of surgery and radiation therapy.  Hormonal therapy drug choice and 
duration will be based on standard of the care at the time of patient treatment. 
5.8.3 
Adjuvant radiation therapy will be started after the completion surgery based on current standards 
and is not part of the protocol therapy. 
5.8.4 
Adjuvant chemotherapy is at the discretion of the investigator if clinically indicated. 
 
 
6.0 
PRETREATMENT EVALUATION  
6.1 
Complete history and physical examination including breast examination, vital signs, height, weight, 
demographics, and adverse events.  
6.2 
Documentation of Performance status [PS] (See Appendix D), menopausal status, date of last 
menstrual period, duration of mass or symptoms. 
6.3 
Careful clinical measurement of the breast and description of the breast finding of the involved area. 
Location and size of tumor, axillary and supraclavicular node status, clinical TNM stage. 
Measurements should be bi-dimensional and expressed in cm.  
6.4 
Digital Photography of both breasts 
6.5 
Complete blood count (CBC), differential count, and platelet count;  
6.6 
Comprehensive metabolic profiles-SMA (Na, K, Cl, HCO3,  BUN, creatinine, Mg, calcium, SGOT [AST], 
SGPT [ALT], glucose, LDH,  total billirubin) 
6.7 
ECG, Cardiac ejection fraction [EF] (by echocardiography or MUGA) 
6.8 
Urine pregnancy test if female patient is of childbearing potential. 
6.9 
Tumor staging (Imaging Studies) 
6.9.1 
Chest x-ray 
6.9.2 
PET/CT or Chest and Abdominal CT scan (as clinically indicated). 
6.9.3 
Bone scan 
6.9.4 
Bilateral mammography 
6.9.5 
Breast MRI for involved breast 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 29 of 44 
 
 
6.9.6 
Breast sonography with axillary assessment 
6.9.7 
Breast Core biopsy for frozen section and paraffin block. This is mandatory for baseline evaluation. 
However, if a patient is consented for both 2006-1072 (IBC registry) and 2008-0372, core needle 
biopsy will be performed in one setting and tissues will be collected separately for both studies. If 
core biopsy is already performed for protocol 2006-1072, and patient is subsequently consented for 
2008-0372, we will follow the procedures below: 
 
If optimal samples from the core biopsy were collected for 2006-1072, a portion of the 
samples will be used for biomarker testing as described in protocol 2008-0372. Core 
biopsy will not be repeated for the purpose of protocol 2008-0372. 
 
If optimal samples are not available from protocol 2006-1072, patient will be subject to 
repeat core biopsy. 
6.10      Data management: The data from diagnostic tests, physical exam, vital signs, weight, concomitant   
medication, history of biopsy, radiation at screening/baseline will be documented as standard of 
care, but not for protocol purpose, so these data will not be entered into PDMS/CORe for this study. 
 
 
7.0 
EVALUATION DURING STUDY (See Section 11.0) The window for all assessments and therapies 
can be within +/- 3 days.  
7.1 Evaluation during PNC treatment (Cycles 1 to 4):  
7.1.1 
Within 2 days before day 1 of cycle 1, an optional core biopsy will be performed for frozen 
sections and paraffin block. 
7.1.2 
Patients will have CBC, differential and platelet counts before each dosing.  
 
 
Patients may repeat CBC, differential and platelet counts until recovery of these measures before 
next cycle (absolute granulocyte counts >/= 1,000 and platelets >/= 100,000 per mm3).  
7.1.3 
Medical history and physical examination with vital signs, weight, PS before each cycle ,  
7.1.4 
Digital photography at weeks before cycles 1, 3,  
7.1.5 
Toxicities will be assessed before each cycle  
7.1.6 
SMA ( Na, K, Cl,  HCO3,  BUN, creatinine, Mg, calcium, SGOT [AST], SGPT  
 
 
[ALT], glucose, LDH,  total bilirubin,) will be performed before each cycle ,  
7.1.7 
ECG and ECHO or MUGA will be repeated when clinically indicated.  
 
 
7.2 Evaluation during preoperative chemotherapy (FEC):  
 
7.2.1 Prior to FEC, minimum 1 week after cycle 4 of PNC:  
7.2.1.1 Mammography of involved breast 
7.2.1.2 Breast MRI if clinically indicated 
7.2.1.3 Ultrasound of the involved breast/regional lymphatic chains 
7.2.1.4 SMA (as above), CBC,  
7.2.1.5 Digital photography of the breast 
7.2.1.6 Careful clinical breast measurement (if measurable, ruler should be measure the size of the 
tumor) of the breast and description of the breast finding of the involved area.  
7.2.1.7 Medical history and physical examination, with vital signs, weight, PS performance 
7.2.1.8 Toxicity Evaluation 
 
 
7.2.2 During EFC 
7.2.2.1 Assessments during EFC are standard of care, including physical examination, vital signs, 
weight, PS, CBC with diff, platelet counts, SMA and toxicity prior to each cycle. 
7.2.2.2   Careful clinical breast measurement (if measurable, ruler should be measure the size of the 
tumor) of the breast and description of the breast finding of the involved area before each cycle. 
7.2.2.3 ECG, ECHO/MUGA will be repeated as clinically indicated. 
 
 
7.3 Evaluation before surgery  
After 4th cycles of FEC [minimum of 3 week after 4th cycle of FEC and prior to surgery] 
7.3.1 
Mammography of involved breast 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 30 of 44 
 
 
7.3.2 
Breast MRI if clinically indicated. 
7.3.3 
Ultrasound of the involved breast/regional lymphatic chains 
7.3.4     SMA(as above),CBC, 
7.3.5 
Digital photography of the breast 
7.3.6  
Careful clinical measurement (if measurable, ruler should be measure the size of the tumor) of 
the breast and description of the breast finding of the involved area.  
7.3.7 
Medical history and physical examination, with vital signs, weight, PS performance 
7.3.8 
PET/CT or Chest and Abdominal CT scan before surgery (as clinically indicated). 
7.3.9 
Toxicity evaluation 
7.3.10 ECG, ECHO/MUGA will be repeated as clinically indicated. 
 
 
 
7.4 Evaluation during surgery.  
7.4.1 
Breast pathologist will be notified before the surgery and they will handle resected specimen. 
Every attempt will be made to identify any residual tumor. If tumor is not identified grossly the 
area previously identified by mammogram will be extensively sampled.  
 
7.5 Post-Surgery Follow-up:  
Post-surgery follow-up and evaluation will be a part of standard of care, only survival data will be 
recorded for study purpose. 
       
7.6 Data management 
The data from diagnostic tests, physical exam, vital signs, weight, concomitant   medication, biopsy 
during study, before FEC and before surgery, will be documented as standard of care, but not for 
protocol purpose, so these data will not be entered into PDMS/CORe. Only the chemotherapy, 
toxicity and treatment response will be entered into PDMS/CORe for this study. 
 
 
8.0 
CRITERIA FOR RESPONSE  
8.1 
All tumor measurements (clinical breast exam) must be recorded in centimeters and must have the 
longest diameter, and its perpendicular applied at the widest portion of the tumor, as well as the 
depth recorded, if clinically possible. Clinical breast exam will be performed before weeks 2,  5,  8 
and 11, of PNC, and before each cycle of FEC. Response Criteria: 
 
8.1.1 
Complete Response [CR] 
8.1.1.1 CLINICAL CR: Disappearance of all clinical evidence of active tumor by clinical evaluation, 
mammogram and ultrasound. The patient must be free of all symptoms. 
8.1.1.2 PATHOLOGICAL CR: No evidence of residual invasive tumor, including no residual tumor in the 
axillary lymph nodes. 
 
8.1.2 
Partial Response[PR]: 50% or greater decrease for a minimum of 4 weeks in the measurable 
lesion as determined by the product of the perpendicular diameters of the lesion. Every lesion need 
not regress to qualify as a partial response. However, if any lesion progresses or if new lesions 
appear, the response cannot be classified as a partial response. 
 
8.1.3 
Minor Response [MR]: Decreases in tumor masses insufficient to qualify as a partial remission, i.e. 
<50%. 
 
8.1.4 
Stable Disease [SD]: Between MR and PD 
 
8.1.5 
Progressive Disease [PD]: Increase in the size by 25% of any measured lesion. Appearance of 
new lesions will also constitute increasing disease. Mixed responses will be considered PD. 
 
8.2 
The following patient categories will be considered inevaluable for response: 
8.2.1 
Early Deaths: Those patients who die within the 1st two weeks from the initiation of drug therapy 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 31 of 44 
 
 
due to intercurrent disease, but will be considered as failures in the intent to treat analysis. 
8.2.2 
Lost to Follow-up:  Those patients in whom there is inadequate information to judge tumor response 
because of loss of contact with our institution (>2 months after missed appointment) and with 
referring physician in spite of repeated attempts to try to locate them. These patients will be 
considered failure in the intent to treat analysis. 
8.2.3 
Major Protocol Violation:  Patients in whom there is a significant deviation from the treatment 
program by either adding or deleting another agent or another therapeutic maneuver or by modifying 
substantially the dosage and schedule of the drug under evaluation. Patients who do not fulfill the 
requirements outlined under Patient Eligibility (item 4.0) are also included in this category. 
8.2.4 
Downstaging is defined as change in tumor extent that results in reclassification of the primary 
tumor and/or regional lymph node metastases into a different (lower) T, N, or M subgroup. 
8.3 
All subjective toxicities encountered during the study will be evaluated according to the NCI-CTC 
grading system (0-4) in Appendix A. Objective toxicities will be considered as the maximum 
numerical deviation from the normal range. 
8.4 
The survival of patients will be measured from the date of registration. Disease-free survival will be 
measured from the date of surgery. 
8.5 
Patients will be followed minimally for 1 year after removal from study or until death, whichever 
occurs first. Patients removed from study for unacceptable AEs will be followed until resolution or 
stabilization of the adverse event. 
 
 
9.0 
CRITERIA FOR REMOVAL FROM THE STUDY  
9.1 
Any patient showing distant metastatic disease or progressive disease will be removed from the 
study. 
9.2 
The development of unacceptable toxicity (irreversible Gr III or IV) 
9.3 
Death. 
9.4 
Patients’ refusal to continue participation in the study. 
 
10.0 
CORRELATIVE STUDIES 
10.1.1 EGFR FISH 
10.1.1.1 Collection of Specimen(s): Breast Core Biopsy 
10.1.1.2 Handling of Specimens(s): Savitri Krishnamurthy, MD 
10.1.1.3 Shipping of Specimen(s): 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.1.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
 
10.1.2 EGFR Immunohistochemical staining 
10.1.2.1 Collection of Specimen(s): Breast Core Biopsy 
10.1.2.2 Handling of Specimens(s): Savitri Krishnamurthy, MD 
10.1.2.3 Shipping of Specimen(s); 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.2.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
 
10.1.3 Multiplex immunohistochemical staining 
10.1.3.1 Collection of Specimen(s): Breast Core Biopsy 
10.1.3.2 Handling of Specimens(s): Naoto T. Ueno, MD, PhD 
10.1.3.3 Shipping of Specimen(s): 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.3.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
 
10.1.4 
Compare Normal Cell Interactions and EGFR signaling in the normal tissue adjacent to breast 
tumor. 
10.1.4.1. Normal tissue will be requested from the patient paraffin embedded mastectomy samples, and 
unstained slides will be prepared. 
10.1.4.2. Dr. Wendy Woodward’s lab will perform the analysis.   
 
10.1.5 Immunohistochemical staining of other molecules 
10.1.5.1 Collection of Specimen(s): Breast Core Biopsy 
10.1.5.2 Handling of Specimens(s): Naoto T. Ueno, MD, PhD; Savitri Krishnamurthy, MD 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 32 of 44 
 
 
10.1.5.3 Shipping of Specimen(s); 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.5.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
In our preclinical studies, we found that 1) COX-2 expression levels were upregulated in IBC 
SUM149 cells following EGF stimulation and notably downregulated when stably transfected 
with EGFR shRNA or treated with PmAb and erlotinib, suggesting that the regulation of COX-2 
can be mediated via EGFR signaling in IBC. 2) EMT is a biological process in which epithelial 
cells are polarized to undergo multiple biochemical changes to mesenchymal cells, resulting in 
enhanced migratory capacity, invasiveness, and acquired resistance to apoptosis. Zhang et al. 
reported that EGFR targeted therapy (erlotinib) exhibits extracellular signal-regulated kinase 
(ERK)-dependent antiproliferative activity in IBC. Furthermore, this therapy reversed the 
mesenchymal phenotype of IBC cell lines to an epithelial phenotype in three-dimensional 
culture. 3) The inhibition of the EGFR pathway using panitumumab or erlotinib reduced the CSC 
population in IBC cells. We identified Nodal, a member of the TGFβ superfamily, as a potential 
driver of EGFR/COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Based 
on these results, we will determine the expression of COX-2, PGE2, and PGF2α, EMT markers 
including E-cadherin and vimentin, CSC markers including Nodal and ALDH. 
We will conduct immunohistochemical staining of candidates identified from NGS/RNA 
microarray analysis in tumor tissues collected from the pre- and post- panitumumab treatment 
(10.1.6. NSG/RNA microarray).  
The scoring and data analysis of these molecules will be performed in collaboration with Dr. 
Savitri Krishnamurthy. We will correlate the expression of these molecules with patient outcome. 
 
10.1.6 NGS/RNA microarray 
10.1.6.1 Collection of Specimen(s): Breast Core Biopsy  
10.1.6.2 Handling of Specimens(s): Naoto T. Ueno, MD, PhD 
10.1.6.3 Shipping of Specimen(s): 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.6.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
To identify biomarkers that predict the response to panitumumab treatment, we will conduct 
differential gene expression analysis using patient tissues collected from the pre- and post- 
panitumumab treatment. Typically, 8 to 10 unstained sections from a core biopsy are required if 
the core has reasonable cellularity and >30% purity (sections may have a mixture of tumor cells, 
stromal cells, inflammatory cells, etc). For an RNA microarray, the ideal sample type is an entire 
fresh core kept in RNAlater® solutions. Paraffin sections may be used, but the quality of RNA is 
suboptimal. 
We will conduct immunohistochemical staining of candidates identified from NGS/RNA 
microarray analysis in tumor tissues collected from the pre- and post-panitumumab treatment as 
described in 10.1.5 Immunohistochemical staining of other molecules).  
 
10.1.7 Immunophenotyping 
10.1.7.1 Collection of Specimen(s): Blood and Breast Core Biopsy 
10.1.7.2 Handling of Specimens(s): Naoto T. Ueno, MD, PhD 
10.1.7.3 Shipping of Specimen(s): 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.7.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
Using a novel IBC SUM149 immunocompetent mouse model, we showed that panitumumab 
treatment enhances antitumor immunity in IBC by increasing cytotoxic T cells and reducing 
immunosuppressive Tregs and subsequently reduces IBC tumor growth. So we will measure the 
populations of CD8+ T cells, CD4+ T cells, Tregs, macrophages in patient blood and tissue samples 
collected from the pre- and post- panitumumab treatment using flow cytometry, CyTOF, 
immunohistochemical staining, and multiplexing imaging. These samples will be obtained from IBC 
registry 2006-1072. 
 
 
10.1.8 Cytokines/chemokines 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 33 of 44 
 
 
10.1.8.1 Collection of Specimen(s): Blood sample  
10.1.8.2 Handling of Specimens(s): Naoto T. Ueno, MD, PhD; James Reuben, PhD 
10.1.8.3 Shipping of Specimen(s): 1515 Holcombe Blvd. Unit 448, Houston, TX 
10.1.8.4 Site(s) Performing Correlative Study: M. D. Anderson Cancer Center 
By conducting panitumumab treatment in IBC SUM149 immunocompetent mouse model, we also 
identified several cytokines whose expressions were changed by panitumumab treatment. These 
cytokines including CXCL10, CXCL9, CCL5, CCL4, CCL20, CXCL5, CCL2, OPG, VEGF, and IL-8 
are involved in immune response and are linked with progression of a variety of cancers. We will 
measure the expression of these cytokines in patient blood samples collected from the pre- and 
post- panitumumab treatment using Luminex Multiplex Bead Array assay (Luminex) or enzyme-
linked immunoassay (ELISA). These samples will be obtained from IBC registry 2006-1072. 
 
 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 34 of 44 
 
 
11.0 STUDY CALENDAR 
Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy. Core 
biopsy tissue can be collected any time before therapy. Scans and x-rays must be done <4 weeks 
prior to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
During PNC 
   
 
Pre- 
Study
 
Wk
1
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
 
 
Wk
2
 
Wk
3
 
Wk 
4
 
Wk
5
 
Wk
6
 
Wk
7
 
Wk
8
 
Wk
9
 
Wk
10
 
Wk
11
 
Wk
12
 
Wk
13
Wk
14
Wk
15 
Wk
16 
Wk
17
 
Before 
FEC
Panitumumab 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Carboplatin, nab-
paclitaxel 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History  
X g 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Physical exam, vital 
signs, height, weight,  
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
AEs 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Clinical breast exam, 
lymph nodes status 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Digital Photography of 
bilateral breasts 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PS 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, Pltb, 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
SMA (Serum 
chemistry) a 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG, ECHO or 
MUGA c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging Studies 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
Breast Core Bxh 
X 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Na, K, Cl, HCO3,  BUN, creatinine, Mg, calcium, SGOT [AST], SGPT [ALT], glucose, LDH,  total bilirubin, . 
b: Before each cycle, may repeat until recovery (ANC>/=1.0, Platelets >/=100,000 per mm3. A portion of the blood samples 
obtained from IBC registry 2006-1072 will be utilized for correlative testing as described in protocol 2008-0372 correlative 
section. 
c.  EKG, ECHO/MUGA will be repeated as clinically indicated 
d. CXR, bone scan, Bilateral mammography, Breast MRI, Breast US with axillary, PET/CT or Chest and Abdominal CT scan 
(as clinically indicated).   
e. Mammography of involved breast, breast MRI, US of involved breast with regional lymphatic chains,  
f. Optional. 1-2 passes will be obtained.  
g. including menopausal status, date of last menstruation, Duration of mass or symptoms at baseline only 
h. At baseline, if a patient is consented for both 2006-1072 (IBC registry) and 2008-0372, core needle biopsy will be 
performed in one setting and tissues will be collected separately for both studies. If core biopsy is already performed for 
protocol 2006-1072, and patient is subsequently consented for 2008-0372, we will follow the procedures below: 
 
If optimal samples from the core biopsy were collected for 2006-1072, a portion of the samples will be 
used for biomarker testing as described in protocol 2008-0372. Core biopsy will not be repeated.  
 
If optimal samples are not available from protocol 2006-1072, patient will be subject to repeat core 
biopsy. 
 
 
 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 35 of 44 
 
 
 
 
 
During and after FEC 
 
 
 
*  Mammography, breast MRI, and Ultrasound of the involved breast/regional lymphatic chains. 
PET/CT or Chest and Abdominal CT scan (as clinically indicated) can be any time after last dose of 
FEC and before surgery. 
 
12.0 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS. The ongoing review of safety 
data will include review of clinical AEs and SAEs including skin-related and neurological toxicity 
assessment and laboratory studies. The NCI-CTC version 3.0 will be used to grade all AEs, except 
panitumumab-related skin toxicity, which will be graded by modified NCI-CTC version 3.0 
Dermatology Skin Assessment. Appendix I. An AE is an undesirable medical occurrence (sign, 
symptom, or diagnosis) or worsening of a pre-existing medical condition (diabetes, congestive heart 
failure, rheumatoid arthritis) that occurs after initiation of investigational product whether or not 
considered to be investigational product related. A worsening of an existing medical condition is one 
that was present at baseline (e.g., cancer, diabetes, migraine headaches,gout) and became more 
severe, more frequent, or increased in duration during investigational product treatment. 
 
12.1 
REPORTING PROCEDURES FOR ALL AES. All  AEs (>/=2 non-hematological and >/=3 
hematological AEs) occurring after informed consent signing observed by the investigator or 
reported by the subject (whether or not attributed to investigational product), will be documented to 
the medical record then entered into the case report form. Abnormal laboratory values should not be 
reported as AEs; however, any clinical consequences of the abnormality should be reported as AEs. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) need not be considered AEs and should not be recorded as 
an AE. Disease progression should not be recorded as an AE. The Investigator is responsible for 
verifying and providing source documentation for all adverse events and assigning attribution for 
each event for all subjects enrolled on the trial 
12.2 
Serious Adverse Event Reporting (SAE) 
  
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Before surgery 
FEC 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Physical exam, 
Vital signs, 
weight, 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
PS 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts
 
X
 
X
 
X
 
X
SMA (as above) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
EKG, ECHO, 
MUGA  (as 
indicated) 
 
 
 
 
 
 
 
 
 
 
 
 
Digital 
photography of 
bilateral breasts
  
X 
Clinical breast 
exam, 
 
 
x 
 
 
X 
 
 
X 
 
 
X 
Imaging Study 
 
 
 
 
 
 
 
 
 
 
 
X* 
AEs 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Surgical sample 
collection 
 
X during 
surgery 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 36 of 44 
 
 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
Death 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on 
Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, regardless of 
attribution (within 5 working days of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have 
a written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office.  
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting 
to the IND Office and MDACC IRB.  
 
Serious adverse events will be captured from the time of the first protocol-specific intervention, until 
30 days after the last dose of drug, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been acceptable resolution of the 
event.  
Additionally, any serious adverse events that occur after the 30 day time period that are related to 
the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND 
Office) according to 21 CFR 312.32. 
 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 37 of 44 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Investigator Communication with Supporting Companies: 
 
All SAEs (Death, A life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, a congenital 
anomaly/birth defect. 
must be reported to Amgen and Celgene Drug Safety within 1 working day of discovery or 
notification of the event. Initial SAE information and all amendments or additions must be recorded 
on an SAE Report form and faxed to Amgen at: 
Amgen Global Safety 
Fax:  888-814-8653 
 
Safety Reporting Requirements and Timelines 
 
The Sponsor-Investigator will utilize the Celgene Drug Safety SAE Completion Form for the 
reporting of adverse events and follow up information to those events.  
 
All serious adverse events regardless of severity or relationship must be reported to Celgene Drug 
Safety within 24 hours of the investigational staff’s knowledge.   
 
 
To report adverse events on all Celgene (or legacy Abraxis) products, please use the email address 
provided below. Please email the completed SAE Forms to: 
 
U.S. Sites: drugsafety@celgene.com 
 
12.2.1 Pregnancy: Should a pregnancy occur, it must be reported in accordance with the following 
procedures: If your study has a patient that experiences a pregnancy while on a Celgene product a 
separate pregnancy SAE Initial and follow-up must be completed.  Pregnancy itself is not regarded 
as an AE unless there is a suspicion that the trial treatment under investigation may have interfered 
with the effectiveness of a contraceptive medication. However, the outcome of all pregnancies 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality) must be 
followed up and documented, even if the patient was discontinued from the trial. All reports of 
congenital abnormalities or birth defects are SAEs. Spontaneous miscarriages should also be 
reported and handled as SAEs. Elective abortions without complications should not be handled as 
AEs. 
 
IDENTIFICATION, RECORDING AND HANDLING AEs 
 
All staff involved in the study will have adequate procedural training regarding the identification, 
documentation, and reporting AEs as described in this protocol.  The principal investigator will be 
responsible for ensuring that adequate training is performed and documented for study staff 
members. 
 
 
Definitions and Types of Adverse Events 
 
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 AE 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 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 38 of 44 
 
 
electrocardiogram abnormalities.  
 
Causality  
The definition of an AE 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.  
 
Special Considerations for Laboratory Results 
Any NCI-CTC Gr III or IV hematology or biochemistry laboratory values not solely considered a 
result of disease progression will be considered an AE.  
 
Treatment Non-Response as an AE  
"Lack of efficacy" or treatment non-response for an unproven therapy will not generally considered 
an AE.  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. 
 
Types of AEs 
In the clinical study setting, AEs 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.  
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
The primary objective of the trial is to determine the pathological complete response rate (pCR), 
which will be assessed after patients have received PNC and FEC preoperative chemotherapy 
treatment. We plan to enroll up to 40 patients, with accrual estimated to be completed in 20 months. 
 
13.2 
Efficacy: We will enroll and evaluate a minimum of 10 patients and a maximum of 40 patients at a 
rate of 2 patients per month. Our primary outcome is pathologic complete response (pCR), which is 
assessed at 25 weeks following initiation of therapy. Our target pCR rate is at least 13% [Dawood et 
al., 2008]. Previous studies have shown that these IBC patients achieve a 13% pCR rate on the 
standard of care. Therefore, we assume a beta (0.26, 1.74) prior distribution for the pCR rate. This 
prior distribution has a mean of 13% and a standard deviation of 19%. 
 
13.3 
We will consider stopping the trial early if P (pCR rate ≥ 13% | data from the trial) < 0.01. That is, 
given the outcomes from the patients who have already been evaluated, if we determine that there 
is less than a 1% chance that the pCR rate is 13% or more we will consider stopping the trial. This 
decision rule gives the following stopping rule. Consider stopping the trial if [ # of pts with pCR / # of 
pts evaluated ] ≤ 0/17, 1/37. If none of the first 16 patients reached pCR, the accrual will be 
suspended until 17th patient has been evaluated.  The operating characteristics of this continuous 
monitoring rule are shown in Table 1 (Thall et al., 1996). 
13.4 
 
 
Table 5. Operating Characteristics for Efficacy Monitoring Rule 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 39 of 44 
 
 
 
 
Sample Size 
pCR Rate 
Probability of 
Stopping Early 
P
25 
P
50 
P
75 
0.03 
0.770 
17 
17 
37 
0.05 
0.555 
17 
37 
40 
0.07 
0.372 
17 
40 
40 
0.09 
0.252 
37 
40 
40 
0.11 
0.164 
40 
40 
40 
0.13 
0.113 
40 
40 
40 
0.15 
0.070 
40 
40 
40 
 
13.5 
Once we have completed the study we will estimate the pCR rate with a 90% credible interval. If we 
have pCR in 4 of the 40 patients (10%), then our 90% credible interval for the pCR rate will be 4.0-
19.6%. If we have pCR in 8 of the 40 patients (20%), then our 90% credible interval for the pCR rate 
will be 10.6-30.4%. We will also report the posterior probability that the pCR rate is 13% or more. 
For example, if we have pCR in 8 of the 40 patients (20%), then the probability that the pCR rate is 
13% or more is 0.869. 
13.6 
Toxicity: We will enroll a minimum of 10 and a maximum of 40 patients.  We will continue to enroll 
and evaluate these patients for toxicity (severe grade 4 organ toxicity or irreversible grade 3 toxicity 
during the 13 weeks of therapy) as long as we are sure that the toxicity rate is not more than 10%.  
We will employ the following monitoring rule for toxicity. We will consider stopping the trial if 
P(toxicity > 10% | data from the trial) > 0.95.  That is, given the outcomes from the patients who 
have already been evaluated, if we determine that there is more than a 95% chance that the toxicity 
rate is more than 10% we will consider stopping the trial.  This decision rule gives the following 
stopping rule.  We assume a beta (0.20, 1.80) prior distribution for the toxicity rate.  This prior 
distribution has mean 10% and standard deviation of 17%.  Consider stopping the trial if [ # of pts 
with toxicity / # of pts evaluated ] > 4/10, 5/15, 6/22, 7/28, 8/35 [Table 2]. 
The operating characteristics of this rule are shown in Table 2 
Table 6.  Operating Characteristics for Toxicity Monitoring Rule 
 
 
Sample Size 
Toxicity Rate 
Probability of 
Stopping 
P25 
P50
P75
0.050 
0.008 
40 
40 
40 
0.075 
0.033 
40 
40 
40 
0.100 
0.098 
40 
40 
40 
0.125 
0.210 
40 
40 
40 
0.150 
0.347 
26 
40 
40 
0.175 
0.496 
18 
40 
40 


Protocol 2008-0372 
Revised Date: 10-30-2018  
Page 40 of 44 
 
 
0.200 
0.646 
13 
26 
40 
0.250 
0.857 
11 
17 
27 
 
Once we have completed the study we will estimate the toxicity rate with a 90% credible 
interval.  If we have toxicity in 4 of the 40 patients (10%), then our 90% credible interval for 
the toxicity rate will be 3.7% to 18.5%.  If we have toxicity in 2 of the 40 patients (5%), then 
our 90% credible interval for the toxicity rate will be 1.1% to 11.8%. 
  
We will also report the posterior probability that the toxicity rate is 10% or less.  For example, 
if we have toxicity in 1 of the 40 patients (2.5%), then the probability that the toxicity rate is 
10% or less is 0.980. 
 
13.7 
Once we have completed the study we will estimate the toxicity rate with a 90% credible interval. If 
we have toxicity in 4 of the 40 patients (10%), then our 90% credible interval for the toxicity rate will 
be 3.5-18.1%. If we have toxicity in 2 of the 40 patients (5%), then our 90% credible interval for the 
toxicity rate will be 1.0-11.4%. 
 
13.8 
We will also report the posterior probability that the toxicity rate is 5% or less. For example, if we 
have toxicity in 1 of the 40 patients (2.5%), then the probability that the toxicity rate is 5% or less is 
0.960. 
 
13.9 
Secondary and Explanatory Objectives: Once the trial has been completed, we will determine the 
clinical response rate and present the rate with its corresponding 95% confidence interval.  
 
13.9.1 
We will investigate whether the pathological response rate is associated with the EGFR 
expression level. EGFR expression will be categorized as 1+, 2+, or 3+. A chi-square test, or 
Fisher’s exact test if cell sizes are small, will be used to determine if a significant association is 
present. Significance will be assessed at the 5% level.  
13.9.2 
We will estimate the effects of the therapy on the micrometastatic disease in the bone 
marrow and peripheral blood by measuring the numbers of CTCs. The estimated levels of CTCs in 
the bone marrow and peripheral blood will be presented along with 95% confidence intervals. 
13.9.3 
We will estimate the progression-free survival and overall survival as a whole group as 
well as patient with triple negative breast cancer. Triple negative breast cancer will be defined as ER 
negative (< 10% by immunohistochemical staining), PR negative (< 10% by immunohistochemical 
staining), and HER-2 negative by FISH. 
 
14.0 
References 
Amparo RS, Angel CD, Ana LH, Antonio LC, Vicente MS, Carlos FM et al (2000). 
Inflammatory breast carcinoma: pathological or clinical entity? Breast Cancer Res Treat 64: 
269-73. 
 
Cabioglu N, Gong Y, Islam R, Broglio K, Sneige N, Sahin A et al (2007). Expression of 
growth factor and chemokine receptors: new insights in the biology of inflammatory breast 
cancer. Ann Oncol. 
 
Cristofanilli M, Buzdar AU, Hortobagyi GN (2003). Update on the management of 
inflammatory breast cancer. Oncologist 8: 141-8. 
 
Cristofanilli M, Valero V, Buzdar AU, Kau SW, Broglio KR, Gonzalez-Angulo AM et al 
(2007). Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the 
biology of a unique disease.Cancer. 


Protocol 2008-0372 
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Page 41 of 44 
 
 
 
Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A et al (2006). Increased antitumor activity, 
intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, 
albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin 
Cancer Res 12: 1317-24. 
 
Giordano SH, Hortobagyi GN (2003). Inflammatory breast cancer: clinical progress and the 
main problems that must be addressed. Breast Cancer Res 5: 284-8. 
 
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P et al (2005). Phase III 
trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based 
paclitaxel in women with breast cancer. J Clin Oncol 23: 7794-803. 
 
Liauw SL, Benda RK, Morris CG, Mendenhall NP (2004). Inflammatory breast carcinoma: 
outcomes with trimodality therapy for nonmetastatic disease. Cancer 100: 920-8. 
 
Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G et al (2007). 
Epidermal growth factor receptor gene copy number and clinical outcome of metastatic 
colorectal cancer treated with panitumumab. J Clin Oncol 25: 3238-45. 
 
Thall PF, Simon R, Estey EH (1996). New statistical strategy for monitoring safety and 
efficacy in single-arm clinical trials. J Clin Oncol 14: 296-303. 
 
Ueno NT, Buzdar AU, Singletary SE, Ames FC, McNeese MD, Holmes FA et al (1997). 
Combined-modality treatment of inflammatory breast carcinoma: twenty years of 
experience at M. D. Anderson Cancer Center. Cancer Chemotherapy & Pharmacology 40: 
321-9. 
 
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B et al (2007). Open-
label phase III trial of panitumumab plus best supportive care compared with best 
supportive care alone in patients with chemotherapy-refractory metastatic colorectal 
cancer. J Clin Oncol 25: 1658-64. 
 
Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG, Jakobovits A (1999). Eradication of 
established tumors by a fully human monoclonal antibody to the epidermal growth factor 
receptor without concomitant chemotherapy. Cancer Res 59: 1236-43. 
 
Zhang D, Pal A, Bornmann WG, Yamasaki F, Esteva FJ, Hortobagyi GN et al (2008). 
Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing 
breast cancer cells. Mol Cancer Ther 7: 1846-50. 
 
Dawood et al. The medical treatment of inflammatory breast cancer. Semin Oncol (2008) 
vol. 35 (1) pp. 64-71 
 
 
 


Protocol 2008-0372 
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Page 42 of 44 
 
 
Appendix I.  Dermatology/Skin/Nail Assessment (from 
CTCAE version 3.0 with modifications) 
AE (Short Name) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nail changes (Nail 
changes) 
Discoloration; 
ridging 
(koilonychias; 
pitting) 
paronychia: 
intervention 
not indicated 
Partial or 
complete loss 
of nail(s); pain 
in nailbed(s), 
paronychia: 
intervention 
indicated 
 
Interfering with 
activities of daily 
living (ADL) 
___ 
Erythema 
(Erythema) 
Painless 
erythema 
Painful 
erythema 
Erythema with 
desquamation* 
Life-threatening; 
disabling 
Pruritis/itching 
(Pruritis) 
Mild or 
localized 
Intense or 
widespread 
Intense or 
widespread and 
interfering with ADL 
___ 
Rash: 
acne/acneiform 
(Acne) 
Intervention 
not indicated 
Intervention 
indicated 
Associated with 
pain requiring 
narcotic analgesics, 
ulceration, or 
desquamation* 
___ 
Rash/desquamation* 
(Rash) 
[Use for non-
acneiform rash or 
non-folliculitis rash] 
 
Macular or 
papular 
eruption or 
erythema 
without 
associated 
symptoms 
Macular or 
papular 
eruption or 
erythema with 
pruritis or other 
associated 
symptoms; 
localized 
desquamation* 
or other lesions 
covering < 
50% of body 
surface area 
(BSA) 
Severe, 
generalized 
erythroderma or 
macular, papular or 
vesicular eruption; 
desquamation* 
covering  50% 
BSA 
Generalized 
exfoliative, 
ulcerative, or 
bullous dermatitis 
Ulceration 
(Ulceration) 
___ 
Superficial 
ulceration < 2 
cm size; local 
wound care; 
medical 
intervention 
indicated 
Ulceration  2 cm 
size; operative 
debridement, 
primary closure or 
other invasive 
intervention 
indicated (eg, 
hyperbaric oxygen) 
Life-threatening 
consequences; 
major invasive 
intervention 
indicated (eg 
complete resection, 
tissue 
reconstruction, flap, 
or grafting) 
*Desquamation is defined as sloughing of skin and does not apply to dry flaking skin. 


Protocol 2008-0372 
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Page 43 of 44 
 
 
  
Appendix II.  Panitumumab Pharmacy Guide 
 
Packaging, Formulation, Labeling and Storage 
Panitumumab will be manufactured and packaged by Amgen and distributed using Amgen’s clinical 
trial drug distribution procedures.  Each vial of panitumumab will contain 10 mL of a sterile protein 
solution containing a 20-mg/mL solution of panitumumab.  The vial will contain approximately 200 
mg of panitumumab and is for single dose use only.  Each vial of panitumumab will be labeled in 
accordance with current ICH GCP, FDA and specific national requirements. 
The supplied investigational drug must be stored at 2-8° C in a secured area upon receipt.  As 
panitumumab contains no preservatives, vials are designed for single use only.  Exposure of the 
material to excessive temperature above or below this range should be avoided.  Do not allow 
panitumumab to freeze and do not use if contents freeze in transit or in storage.  If vials fall out of 
specified temperature requirement, please contact Amgen for instructions. 
Records of the actual storage condition during the period of the study must be maintained (ie, 
records of the date and time and initials of person checking, and the “working day” temperature of 
the refrigerator used for storage of trial supplies, continuous temperature recordings, or regularly 
maintained temperature alarm systems used in conjunction with temperature recording). 
 
Preparation 
NOTE: Panitumumab is a protein and should be handled gently to avoid foaming, which may 
lead to denaturation of the protein product.  This precaution applies not only to 
panitumumab stored in the vial, but also for diluted panitumumab prepared in the IV bag.  It 
is, therefore, essential to avoid medication delivery methods, particularly pneumatic tube 
systems, that could potentially lead to excessive shaking or vibration that would lead to 
particulate formation in the protein product.   
Panitumumab must be prepared as an intravenous infusion using aseptic techniques.  The dose of 
panitumumab will be 6 mg/kg (or 9mg/kg, depending on the study) and will be based upon the 
subject’s baseline weight.  The dose of panitumumab is required to be recalculated only when the 
subject’s body weight increases or decreases by > 10% from the original screening/baseline weight.  
This weight will be considered the new baseline weight from which a + 10% variance is allowed 
before another recalculation is necessary.  The calculated amount of panitumumab (may be 
rounded to the nearest ten milligrams [eg, 456 mg rounded to 460 mg or 312 mg rounded to 310 
mg]) will be removed from the vials and added to a minimum volume of 100 mL of pyrogen-free 
0.9% sodium chloride solution USP.  The maximum concentration of the diluted solution to be 


Protocol 2008-0372 
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Page 44 of 44 
 
 
infused should not exceed 10 mg/mL.  In the event a subject’s actual body weight requires greater 
than a 150-mL volume infusion, panitumumab will be administered over 60 to 90 + 15 minutes, as 
tolerated.  The panitumumab will be infused within 19 hours of dilution and will be labeled per site 
pharmacy standard operating procedures.  The bag should be labeled per site pharmacy standard 
operating procedures and promptly forwarded to the clinic center for infusion.  
Supply and Return 
At study initiation and as needed thereafter, panitumumab will be shipped to a responsible person 
(eg, a pharmacist) at the Investigator’s institution, who will check the amount and condition of the 
drug and enter these data into the Proof of Receipt Form and Investigational Product Accountability 
record.  The Proof of Receipt Form should then be returned to Amgen Inc., and the original retained 
at the site.  At the end of the study, or as directed, all panitumumab supplies, including unused, 
partially used, or empty containers, will be destroyed at the site.   
Panitumumab Accountability 
An Investigational Product Accountability Record for the panitumumab must be kept current and 
should contain: 
 
The dates and quantities of panitumumab received from Amgen Inc. 
 
Manufacturing batch or lot numbers for product received 
 
Subject’s identification (subject number) 
 
Date and quantity of panitumumab dispensed (and remaining, if from individual subject drug 
units) 
 
The initials of the dispenser 
 
Dose preparation records  
 
Date and quantity of drug returned to the investigator/pharmacy, if appropriate 
Any discrepancies must be documented and subsequently reported to Amgen Inc. immediately. 
These inventories must be made available for inspection by authorized sponsor 
representative(s) and regulatory agency inspector(s).  The investigator is responsible for 
the accountability of all used and unused trial supplies.