Women's Triple-Negative First-Line Study: A Phase II Trial of Panitumumab, Carboplatin and Paclitaxel (PaCT) in Patients With Localized Triple-Negative Breast Cancer (TNBC) With Tumors Predicted Insensitive to Standard Neoadjuvant Chemotherapy
Phase: PHASE2
Conditions: Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

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Women’s Triple-Negative First-Line Study: A Phase II Trial of Panitumumab, 
Carboplatin and Paclitaxel (PaCT) in Patients with Localized Triple-Negative Breast 
Cancer (TNBC) with Tumors Predicted Insensitive to Standard Neoadjuvant 
Chemotherapy 
 
 
 
Principal Investigator:  
Clinton Yam, MD 
 
 
Co-principal Investigator:  
Naoto T. Ueno, MD, PhD 
 
 
Collaborating Statistician:  
Roland Bassett Jr. 
 
 
 
Clinical Collaborators: Banu Arun, MD; Nuhad K. Ibrahim, MD; Jennifer Litton, MD; Rashmi 
Murthy, MD; Debasish Tripathy, MD; Wei Yang, MD ; Savitri Krishnamurthy, MD 
 
 
 
Laboratory Collaborators: Naoto Ueno, MD, PhD; Helen Piwnica-Worms, PhD; W. Fraser 
Symmans, MD 
   
 
Department: 
 
Breast Medical Oncology 
 
Phone: 
 
713-792-2817 
 
Fax: 
 
713-794-4385 
 
 
Protocol Type: 
 
Standard Protocol 
 
Protocol Phase: 
 
Phase II 
Version Status: 
 
16 

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Table of Contents 
1.0 Study Schema ............................................................................................................................. 3 
2.1 Introduction ................................................................................................................................. 3 
2.2 Rationale for Panitumumab therapy in TNBC ....................................................................... 7 
2.3 Rationale for Correlative Studies .......................................................................................... 8 
3.1 Objectives……………………………………………………………………………………………….10 
3.2 Primary Objective ................................................................................................................. 10 
3.3 Secondary Objectives: ......................................................................................................... 10 
3.4 Exploratory Objectives: ........................................................................................................ 10 
4.1 Selection of Patients……………………………………………………………………………………11 
4.2 Inclusion Criteria .................................................................................................................. 11 
4.3 Exclusion Criteria ............................................................................................................... 11 
5.0 Registration Procedures ............................................................................................................ 13 
6.1 Treatment Plan .......................................................................................................................... 14 
6.2 Treatment .......................................................................................................................... 14 
6.3 Drug Information ................................................................................................................ 15 
6.4 Administration .................................................................................................................... 15 
6.5 Toxicity and Dose modification ........................................................................................... 16 
7.0 Reporting of Adverse Events ..................................................................................................... 22 
8.0 Supportive Care ......................................................................................................................... 24 
9.0 Duration of Therapy ................................................................................................................... 24 
10.0 Duration of Follow-up ....................................................................................................... 24 
11.0 Protection of human subjects .................................................................................................. 25 
12.1 Scheduled evaluations............................................................................................................. 26 
12.2 Pretreatment Evaluation ................................................................................................... 26 
12.3 Evaluation During Study .................................................................................................. 26 
13.1 Measurement of Effect ............................................................................................................ 26 
13.2 Pathologic response ........................................................................................................ 26 
13.3 Radiographic Imaging ...................................................................................................... 27 
14.0 Correlative Studies .................................................................................................................. 27 
15.0 Statistical Considerations ........................................................................................................ 28 
16.0 Secondary Objectives and Correlative Studies: ....................................................................... 28 
17.0 Inclusion of Minorities .............................................................................................................. 28 
18.0 Study Calendar ......................................................................................................................... 29 
19.0 References .............................................................................................................................. 30 

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1.0 Study Schema: 
 
 
 
 
 
 
 
 
 
2.1 Introduction 
 
Patients with localized TNBC are preferably treated with systemic chemotherapy in the 
neoadjuvant setting (NACT) as this allows for close monitoring of response in the intact primary 
tumor and  often  results in ‘down-staging’ of tumors, which  increases  the feasibility of breast 
conserving surgery. The response to NACT at the time of surgical resection can be determined by 
measuring the amount of residual cancer remaining in the breast and draining lymph nodes during 
routine pathologic evaluation and is such a powerful indicator of prognosis that the Food and Drug 
Administration (FDA) has recognized significant improvement in complete response to neoadjuvant 
therapy as a pathway to drug approval. Investigators at MDACC have developed and validated a 
scoring system known as the Residual Cancer Burden (RCB) to quantify the extent of residual 
disease remaining after NACT and surgical resection.2 Approximately 50% of patients with 
localized TNBC treated with standard taxane/anthracycline-based NACT will have either pathologic 
compete response (pCR/RCB-0) or minimal residual disease (RCB-I) at the time of surgical 
resection and those patients have identical and exceptionally good long -term prognosis. 
Unfortunately, those with more extensive residual disease (RCB-II or RCB-III) have a much worse 
prognosis, with 50%-80% of patients developing distant metastatic disease within 3 years of initial 
diagnosis.3 Additionally, clinical trials of NACT in breast cancer have demonstrated that patients 
without response to their first chemotherapeutic regimen have very low chance (5%) of achieving 
pCR after their second neoadjuvant chemotherapy regimen.4  However, this has not been the case 
with targeted regimens such as trastuzumab in HER2+ tumors, suggesting that intrinsic resistance 
to chemotherapy can be overcome with appropriate targeted therapy.5  Though several  targeted  
agents  have  been  tested  for  treatment  in  TNBC,  so  far  none  have  been successful. The 
underlying causes of  this failure are commonly attributed to the molecular heterogeneity of tumors 
classified within the ‘catch all’ category of TNBC as well as the dilution effects of chemotherapy 
sensitive disease which requires clinical trials to enroll larger number of patients to show benefit  of 
combined  targeted  therapy/chemotherapy regimens over standard chemotherapy. Additionally, 
clonal selection of resistant cells with escape mechanisms also likely develops.  

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Recent advances in gene expression profiling have identified subgroups of triple-negative breast 
cancer (TNBC) with distinct molecular features that, if appropriately selected, may be more 
responsive to targeted therapy with existing FDA-approved drugs, leading to rapid improvement of 
outcomes in this high-risk breast cancer population.1,6-8 
 
Prediction of chemosensitivity and molecular aberrations 
associated with TNBC subtypes:  Our collaborator, Dr. 
Symmans, and his team have developed microarray-
based predictive signatures chemotherapy response using 
fresh primary tumor tissue obtained from a routine biopsy 
of breast cancer at the time of diagnosis or surgery. This 
approach has been retrospectively validated and tested for 
feasibility using a prospective registry study(MDACC 
clinical trial 2011-0007).9    The  proposed predictor was 
tested on an independent cohort of breast cancers 
irrespective of receptor  status  (N=198,  99%  with clinical  
Stage  II-III)  who  received  neoadjuvant  (N=180) or 
adjuvant (N=18) taxane-anthracycline chemotherapy. 
Predictions were accurate if ER+/HER2- (30% predicted 
sensitive, DRFS 97%, CI 91-100; ARR 11%, CI 0.1-21) or 
ER-/HER2- (26% predicted sensitive, DRFS 83%, CI 68-
100; ARR 26%, CI 4-48) (Fig  1).9 Predicted  treatment 
sensitivity  was significantly associated  with lower relapse 
risk (HR 0.19, CI0.07-0.55) in a multivariate model including 
ER status, tumor and nodal stage, grade, age, and type of 
taxane treatment (paclitaxel or docetaxel).
 

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As important as predicting chemosensitivity may be, outcomes for TNBC patients will not be 
improved unless targeted therapy is developed for patients with chemo-resistant disease. Recent 
advances in molecular profiling have identified subsets of TNBC (Fig. 2) with distinct molecular 
features targetable with existing FDA approved drugs.1,7,10,11 Basal- 
like TNBCs (BL1 and BL2) are heavily enriched in cell cycle and 
cell division pathways. Gene expression profiling has revealed that 
these tumors have high expression of proliferation genes such as 
aurora kinases, MYC, NRAS and PLK1 as well as elevated DNA 
damage response (BL1 subtype). These tumors may have higher 
rates of pCR to standard chemotherapy compared to other TNBC 
subtypes. The BL2 subset displays gene ontologies involving 
growth factor signaling such as EGFR and IGF1R pathways. Cell 
Figure 2: Classification of 75 
TNBC samples at MDACC 
using signatures published by 
Pietenpol et al.7 
lines classified as basal-like had high rates of sensitivity to cisplatin 
and relative resistance to PI3K directed therapy in both cell culture 
and xenograft models. Though most triple-negative breast cancers 
are classified as basal-like (BL1 and BL2) by microarray analysis, 
approximately 30% of triple negative tumors are molecularly 
distinct from basal-like breast cancers as they display mesenchymal features,  including 
enrichment in epithelial-to-mesenchymal transition (EMT) and stem-cell like characteristics. 
Subgroups with these features have been identified by independent investigators and have been 
termed mesenchymal (M), mesenchymal-stem cell like (MSL) and claudin-low. Mesenchymal-like 
TNBCs carry a high rate of molecular aberrations that activate the PI3K/Akt/mTOR axis 
suggesting that this subgroup may be responsive to therapeutic regimens targeting this pathway. 
Approximately 10-15% of TNBC are associated with expression of androgen receptor (AR+ or 
LAR) and approximately 20-25% are immune modulatory (IM), expressing genes associated with 
immune activation. Approximately 10-20% of patients with TNBC are carriers of germline 
BRCA1/2 mutations. When treated with NACT, pCR rates similar to slightly higher than non - 
carriers.12 
BRCA1 and BRCA2 are required for homologous recombination repair of DNA strand 
breaks leading to a defect in DNA repair in cancers harboring such mutations. As such, these 
tumors may be more sensitive to chemotherapy inducing DNA breaks or poly ADP-ribose 
polymerase (PARP) inhibitors. 
 
Notably, investigators at MDACC also determined that rates of pCR/RCB-I to standard NACT 
were not statistically different amongst the subtypes, though the lowest rates of pCR were seen in 
the BL-2 subtype and the highest rates of RCB-III disease was within the mesenchymal subtypes, 
further validating the need for both predictors of chemotherapy sensitivity as well as molecular 
characterization of predicted chemotherapy-insensitive disease to determine appropriate therapy 
for patients with localizedTNBC.12 
 
Given the disparity of treatment outcomes from NACT for TNBC, a molecular triaging protocol 
(MDACC 2014-0185) has been developed and IRB approved as a diagnostic platform to identify 
patients whose tumors are likely or 
unlikely to achieve pCR or RCB-I, in 
order to direct predicted responders 
toward standard chemotherapy and to 
direct 
predicted 
chemotherapy 
insensitive patients toward potentially 
more effective experimental therapies 
within clinical trials (Figure 3). Previously 
untreated patients with localized TNBC 
who 
are 
candidates 
for 
standard        
NACT       (anthracycline 
=>taxane 
based therapy) will 
be 
enrolled 
into 
2014-0185, 
a 
non- 
therapeutic, randomized trial where they 
will undergo biopsy of the primary tumor 
for molecular 
characterization within   

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the   MDACC   CLIA   certified 
Fig. 3 Clinical Trial Schema for 2014-0185 

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diagnostic lab, including predicted sensitivity to chemotherapy using gene signatures described 
above. Patients will be randomized 2:1 to know the results of the molecular characterization 
(given within 4-6 weeks after biopsy) or not know the results (treating physician blinded as well). 
All patients will be treated the same except for this randomization (Figure 3). 
 
All patients will then initiate a planned 4 cycles of standard neoadjuvant anthracycline based 
chemotherapy based upon physician’s choice (AC, dose-dense AC, FAC, EC or FEC are all 
allowed) with assessment of response by diagnostic imaging after 4 cycles of therapy (or at the 
time  of  progression  in  patients  who  develop  clinical  evidence  of  disease  progression  on 
chemotherapy). In our 
retrospective 
analysis 
of 
molecularly 
characterized 
patients 
with 
available 
diagnostic 
imaging, 
approximately 
10-15% 
of 
patients will have obvious, 
extreme discordance between 
volumetric measurement 
of 
tumor response by ultrasound 
after 4 cycles of NACT and 
response prediction by gene 
signature with  the diagnostic 
       imaging 
best 
predicting 
 
outcome in these extreme 
cases of response or lack thereof 
(parameters outlined in Fig. 3). As such, patients with discordant imaging/molecular predictor 
results will be ad vised of these results and counseled to proceed based upon imaging. After 
response assessment, all patients will be offered the option of continuing forward with standard 
taxane (paclitaxel or docetaxel) or participation in clinical trials (Figure 4). Molecular 
characterization of the tumor (if known) can also be used by the treating physician to select for 
clinical trials within the BMO neoadjuvant clinical trials portfolio (Figure 4). 
 
Additionally, because of the 2:1 randomization in 2014-0185 (Figure 3), a subgroup of patients 
molecularly profiled will not know the results for decision -making (control arm). Like the 
experimental arm, patients on the control arm will be allowed to choose between study 
participation or to receive standard chemotherapy with paclitaxel based regimen for 12 additional 
weeks. Essentially, those who do not know the results of the molecular profiling are offered the 
same options as those who do, they simply will not have the molecular analysis to guide their 
decision making. Since all patients enrolled in 2014-0185 have biopsies for molecular 
characterization and diagnostic imaging, for research purposes all patients can be characterized 
as chemosensitive or chemoresistant and further subtyped into the TNBC molecular subtypes 
mentioned above. As such, those patients characterized with chemoresistant, subtype specific 
disease that receive standard NACT with taxane-based regimens can be compared with matched 
patients treated on clinical trials with targeted agents, such as PaCT. Though this comparison will 
not be a randomized comparison, it will provide evidence as to whether patients treated on a 
single arm phase II trial of targeted therapy derive additional clinical benefit and the comparison 
can be used to provide more robust data for confirmatory phase III clinical trial design. While our 
hypothesis is PaCT would be the best regimen for basal like TNBC. Likewise, patients whose 
tumors do not have mesenchymal features can be enrolled on this protocol and receive PaCT, 
which will allow a control group of non-basal TNBCs to serve as a control to determine the 
predictive value of potential biomarkers to define the mesenchymal population. 
 
In summary, it is generally accepted that different subtypes of TNBC can be identified through 
modern molecular profiling techniques and that these subtypes contain potentially targetable 
molecular aberrations that would mandate different therapeutic approaches for each of the 
distinct subtypes. It is also generally accepted that the added toxicity associated with multi-drug 
therapeutic approaches necessitates exclusion of patients who are unlikely to benefit from an 
Figure 4: BMO Neoadjuvant Portfolio for Treatment of 
Chemotherapy Insensitive TNBC 

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investigational regimen. An unfortunate reality is that the modern molecular profiling techniques 
that have advanced our understanding of TNBC are not ready for use in patient selection to 
enrich for response in TNBC-subtype focused clinical trials, especially trials using archived 
paraffin embedded tissue as the source for analysis. As such, we are proposing an alternative 
strategy using an existing CLIA-compliant diagnostic test to identify patients with tumors that 
have basal like features (i.e. tumors with detectable EGFR staining). We are hopeful that this 
may help to further characterize which tumors are more likely to demonstrate response to the 
regimen. 
 
2.2 Rationale for Panitumumab therapy in TNBC: 
 
Epidermal growth factor receptor (EGFR) is overexpressed in all subtypes of breast cancer, with 
higher expression in TNBC.14-16 Suppression of EGFR signaling in breast cancer has shown 
efficacy in controlling cancers by three main mechanisms. First, in our own pre-clinical work as 
well as other researchers reported that the EGFR suppression in breast cancer induced 
suppression of stem cell population 17-19 Secondly, suppression of EGFR pathway induces 
enhanced apoptosis in cancer cells via downstream MAPK/PI3K pathways. 20,21 Lastly, our 
preclinical study suggested that suppression of EGFR reduced the epithelial-mesenchymal 
transition (EMT) markers in breast cancer cells which are known to increase the metastatic 
potential of breast cancer cells.22 Given the high rate of overexpression in TNBC, and the 
preclinical results on downstream effects of EGFR pathway suppression, we believe the 
suppression of EGFR in EGFR overexpression TNBC would have potential therapeutic potential. 
In recent study, when EGFR inhibiting small molecules were combined with genotoxic agents, the 
chemosensitivity of cells was enhanced. These researchers also reported that time-staggered 
EGFR inhibition, but not simultaneous co-administration, dramatically sensitizes a subset of triple- 
negative breast cancer cells to genotoxic drugs, such as doxorubicin and erlotinib respectively.23 
EGFR tyrosine kinase inhibitor such as erlotinib does have an anti-tumor activity against human 
inflammatory breast cancer cells, suggesting further benefit towards TNBC that harbors 
immunomodulatory pathway aberrations [Ueno’s lab]. Mueller KL et al showed that gefitinib, 
EGFR-TKi, suppressed the growth of TNBC SUM149 cells24. Taken together, EGFR targeted 
therapy might have a promising role in TNBC. 
 
Panitumumab is previously known as ABX-EGF. It is a fully humanized IgG2 monoclonal antibody 
with high affinity (Kd=5 x 10-11 M) that directly binds to the human EGFR. Panitumumab blocks the 
ligands EGF and TGFα binding to EGFR, inhibits the tumor growth, and elicits both tumor 
regression  and  eradication  of  established  tumors  in  murine  xenograft  tumor  models. The 
antineoplastic effects of Panitumumab in vivo have been demonstrated using human xenograft 
mouse models including breast cancers. Panitumumab has been shown to inhibit the growth of 
human epidermoid carcinoma A431 xenograft in athymic mice resulting in the complete regression 
of large (up to 1.2cm3) established A431 tumors, regardless of initial tumor size. Lower doses of 
panitumumab administered twice weekly for 3 weeks inhibited growth of pre-existing solid tumors. 
Furthermore, a single injection of panitumumab (1mg) resulted in significant and prolonged tumor 
inhibition. Panitumumab in combination with FEC100 (5 -fluorouracil, epirubicin, and 
cyclophosphamide; 500/100/500mg/m2) followed by docetaxel demonstrated with efficacious, 
acceptable toxicity as operable triple negative breast cancer in neoadjuvant setting.25 They 
determined that pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% 
[95% CI: 41.1% to 69.5%]. The complete clinical response rate was 37.5%. They also reported 
toxicity, neutropenia grade 4 and febrile neutropenia, in 20.5% and 3.6% of cycles. Non - 
hematological toxicities were grade 3 and 4 acneiform rashes (35% and 8.3%), grade 3 dry skin 
(10%), and erythema (5%). No toxic deaths were reported.  
Furthermore, the results of a clinical trial using panitumumab with weekly paclitaxel and 
carboplatin were reported32. Cowherd et al. conducted a single-arm phase II trial which enrolled 
metastatic or locally advanced TNBC using a treatment schedule of paclitaxel 80 mg/m2 and 
carboplatin AUC of 2 on days 1, 8, and 15 and panitumumab 6 mg/kg on days 1 and 15 for a cycle 
length of 28 days. The main result of this study was an overall response rate of 46%. The median 
time to best response was 2.4 months and median time to disease progression was 3.6 months. 

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Cowherd et al. concluded that the response rate and toxicity of panitumumab with carboplatin and 
paclitaxel was consistent with other reports using platinum based chemotherapy with targeted 
agents in metastatic TNBC.  
Simultaneously, in a review of EGFR targeted treatments for breast cancer by Lluch et al. reported 
that existing EGFR treatment has limited benefits for breast cancer patients including TNBC33. 
The response rate of combination of the monoclonal antibody cetuximab with a platinum agent is a 
15-20%. While the EGFR antibody gefitinib has some promising results in the ER positive 
population. It has not been identified as a predictive marker for the appropriate selection of the 
patients. Based on this information the selection of patients who may benefit from EGFR treatment 
needs to be refined with the help of biomarkers. 
 
We are performing a single arm phase II study in patients with primary IBC without HER2 over- 
expression treated with panitumumab,  Nab-paclitaxel,  and  carboplatin  and  FEC  preoperative  
systemic  chemotherapy (NCT01036087, institutional protocol #2008-0372). The median follow up 
time is 11.7 months (range; 8.7-33.9 months). This prospective study consists of 25 newly 
diagnosed IBC patients, 15 patients are ER/PgR+ and HER2- and 10 are TNBC. Nine patients 
achieved pCR; the response rate was 36% (95%CI; 0.18-0.58). Among 60% of TNBC, 20% of 
ER/PgR+ and HER2 - patients achieved pCR. The frequency of grade 3 or 4 hematological events 
were 18 (72%), grade 3 non-hematological toxic events were 5 (32%) and grade 4 was 0 during 
the panitumumab regimen (Data not published but submitted to ASCO). Higher proportion of 
TNBC patients who achieved pCR in this poor prognosis group of breast cancer patients further 
promoted the pursuit of EGFR inhibition in TNBC patients. We speculate such higher response in 
TNBC is due to higher expression of EGFR at baseline. Therefore, we hypothesize that EGFR 
overexpressing triple negative breast cancer will have a significant benefit from EGFR targeted 
therapy.  
 
 
2.3 Rationale for Correlative Studies 
 
EGFR suppression in breast cancer can induce several downstream changes. In addition to a 
routine - umbrella protocol based - molecular profiling of cancers, we propose to study such 
pathways that previously showed regulation by EGFR suppression. Suggested pathways are 
mainly 3, including stem cell population, EMT regulation, and apoptosis in addition to the 
confirmation of EGFR protein expression. To obtain more definitive biomarker changes 
induced by Panitumumab, we planned a one-week ”window” period of Panitumumab single 
agent treatment followed by a biopsy prior to the  start of the combination PaCT regimen. 
 
Immunohistochemistry (IHC): In lung cancer, where EGFR inhibitors are routinely used as 
predictive therapeutic biomarker, IHC for EGFR protein expression is the current standard of 
care. Patients who are enrolled in our study will have a baseline biopsy and an additional 
biopsy prior to initiation of the combination treatment that will be analyzed for EGFR gene 
expression/amplification. However, to confirm the convenient testing of EGFR using IHC 
technique, and consistency between gene amplification and protein expression in TNBC, we 
will also perform protein expression study using IHC for each sample. Additional IHC 
biomarkers that may be associated with response to neoadjuvant therapy including immune, 
cell cycle and oncogenic proteins such as PD-L1, Ki67, androgen receptor, PTEN, vimentin 
may be evaluated for correlative studies. 
 
Stem cell population: We will analyze the baseline molecular profile of tumors as well as 
targeted stem cell population on patients who received PaCT regimen using stem cell 
markers. Proposed stem cell markers include CD24, CD44, and ALDH. When the quantity of 
the sample is limited, we will use previously validated stem cell detection technique CD44 
variant antibody IHC staining to evaluate the proportion of stem cell within tumor sample. 
 
EMT markers: As a panel to evaluate the EMT markers, in addition to routine gene 
expression analysis, we will separately perform IHC staining using CLIA certified antibodies 
for E Cadherin, Vimentin, as well as experimental antibodies of Nodal, Axl to evaluate the 

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changes in EMT markers, in pre-and post-treatment samples in comparison. 
 
Apoptosis markers: To determine apoptosis activity induced by EGFR inhibition, cleaved 
caspase-8, caspase-3 will be stained by IHC technique, in pre-and post-treatment samples in 
comparison. 
 
PD-L1 glycosylation: Recent study by collaborator Dr. Hung showed EGF/EGFR induces the 
glycosylation of PD-L1, and suppression of PD-L1 either by sugar analogue or EGFR inhibitor 
enhances the efficacy of anti-PD-1 therapy. 
 
Blood Based Marker: In addition to tumor based analysis, peripheral blood can be collected to 
measure genomic changes. Serial monitoring of pharmacodynamics marker changes can reveal 
novel marker changes that cannot be detected by tumor response on short-term drug exposure. 
The TGIRT-Seq method was used to analyze plasma of metastatic breast patients by testing all 
RNA classes (mRNA and lincRNA, plus small ncRNAs such as Y RNA, tRNA and miRNA) 
together in one RNA-seq assay.  CTCs will be further analyzed for single cell based DNA 
mutation NGS. Initial studies of plasma and tissues from patients with breast cancer have been 
promising in illustrating the ability of this method to obtain clinically relevant information about 
transcript patterns than cannot be obtained by conventional methods using plasma. Novel 
proteomic assays such as O-link, where we detect protein of interest by double-antibody 
detection sandwich technique, thereby increase the sensitivity of protein detection to overcome 
the current limitation of many proteomic techniques  and Collaborative Enzyme Enhanced 
Reactive (CEER) assay, that enhances the detection of both intact and phosphorylated form of 
protein molecules therefore allowing detection of network-wide changes of small protein and 
phosphorylation changes that is induced by a drug, will be tested for proteomic landscape 
changes induced by the proposed treatment. These proteomic technologies are ultra-sensitive 
and highly specific protein measure assessment that can measure specific protein in the blood 
samples, while the exact sensitivity may need further validation. 
 
 

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Objectives 
 
3.1 Primary Objective: 
 
• 
To evaluate the pCR, RCB-0 and RCB-1 rates of patients with localized TNBC who were 
treated with PaCT in the neoadjuvant setting. 
 
3.2 Secondary Objectives: 
 
• 
To estimate progression free survival (PFS) distribution of localized TNBC patients who 
were non-responders to initial anthracycline and cyclophosphamide chemotherapy, and  
who  were treated with the PaCT regimen in the neoadjuvant setting. 
• 
Determine changes of EGFR downstream biomarkers one week after 1 dose of 
Panitumumab.  
• 
Determine response rate after 4 cycles of PaCT using radiographic imaging. 
• 
Correlate pathologic response with EGFR expression as measured by IHC.  
• 
Determine toxicity associated to 4 cycles of PaCT in the neoadjuvant setting. 
• 
Compare pathologic response to 4 cycles of PaCT in EGFR overexpressing tumors vs. 
non- EGFR overexpressing tumors. 
• 
Compare pathologic response in tumors to 4 cycles of PaCT vs. 12 weeks of weekly 
paclitaxel (using data collected in conjunction with protocol 2014-0185). 
• 
Determine pCR (RCB-0) alone as the response rate. 
 
3.3 Exploratory Objectives: 
 
• 
Determine the correlation between EGFR expression by IHC and the presence of 
enhanced EGFR gene signatures at the time of initial tumor biopsy prior to NACT (using 
gene expression data obtained from the protocol 2014-0185). 
 
• 
Determine rates of pCR in patients with EGFR overexpressed tumors identified by gene 
signatures (using gene expression data obtained from protocol 2014-0185) and compare 
to pCR rates in non-EGFR overexpressed tumors. 
 
• 
Determine the correlation between EGFR expression by IHC and the changes of EGFR 
downstream changes induced in surgery sample after completion of PaCT regimen. 
 
• 
Determine the change in PD-L1 glycosylation induced by Panitumumab, and correlation 
with efficacy. 
 
• 
Determine the change after treatment in blood-based markers, if any, and use these to 
predict a response to Panitumumab treatment. 
 
 

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4.0 Selection of Patients 
 
4.1 Inclusion Criteria: 
 
1) Patients must have an intact evaluable primary tumor, or biopsy proven axillary node 
involvement with at least 1.0 cm smallest dimension based on imaging after neoadjuvant 
anthracycline-based chemotherapy and prior to initiation of neoadjuvant chemotherapy under 
this protocol. Baseline measurements and evaluations must be obtained within 4 weeks of 
registration to the study. All areas of disease should be recorded in order to assess response 
and uniformity of response to therapy. 
2) Triple-negative breast cancer defined as ER<10%; PR<10% by immunohistochemistry (IHC) 
and HER2 0-1+ by IHC or 2+, FISH < 2, gene copy number < 4.  
3) Age ≥ 18 years. 
4) Patients must have an ECOG performance status of 0 or 1. 
5) Patients must have received at least one dose of an anthracycline based neoadjuvant 
regimen. Patients are eligible if therapy was discontinued due to disease progression or 
therapy intolerance. 
6) Baseline MUGA or echocardiogram showing LVEF >/= 50% within 12 weeks prior to initiation 
of neoadjuvant chemotherapy. 
7) Adequate organ function defined by the following parameters 
• 
Serum creatinine </= 1.5 mg/dl. Creatinine clearance (CrCl) >/= 50 mL/min calculated 
by the Cockroft-Gault method as follows: male creatinine clearance = (140 – age in 
years) x (weight in kg) / (serum Cr x 72); Female CrCl = (140 – age in years) x (weight 
in kg) x 0.85 / (serum Cr x 72). 
• 
ANC>/= 1500/mm3, platelets >/= 100,000/mm3 
• 
Hemoglobin >/=9.0 g/dL  
• 
SGOT (AST) and SGPT (ALT)< 3.0 x upper limit of normal 
• 
Alkaline phosphatase (Alp) </= 2.5 x ULN 
• 
Total bilirubin </=1.5 x ULN 
 
8) Signed informed consent. 
 
 
4.2 Exclusion Criteria 
 
1) Patient is unwilling or unable to sign and date the IRB approved informed consent. 
2) Patients with less than 1.0 cm measurable residual disease after neoadjuvant anthracycline 
based chemotherapy. 
3) Women that are pregnant or lactating. 
4) Patients with a history of prior malignancy within 5 years of study entry with the exception of curatively 
treated non-melanomatous skin cancer or carcinoma in situ of the cervix or breast. 
5) Patients with a history of stage IV or metastatic disease.  
6) Any serious medical illness, other than that treated by this study, which would limit 
survival to less than 1 month or psychiatric illness which would limit informed consent. 
7) Known positive test(s) for human immunodeficiency virus infection, hepatitis C virus, acute or 

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chronic active hepatitis B infection. 
8) Patients with a peripheral neuropathy > grade 1. 
9) Patients with a history of serious cardiac events defined as: New York Heart Association 
class 3 or 4 heart failure, or history of myocardial infarction, unstable angina or CVA within 6 
months of protocol registration. 
10) Patients with a history of PR prolongation or AV block. 
11) Patients with a history of prior therapy with paclitaxel and/or carboplatin. 
12) Patients who have received a cumulative dose of doxorubicin of greater than 360 mg/m2 or 
epirubicin of greater than 640 mg/m2.  
13) Patients who concurrently use hormonal therapy and/or concurrent radiation therapy. 
14) Patients who had prior radiation therapy of the primary breast carcinoma or axillary 
lymph nodes. 
15) Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception 
during the study and 8 weeks after. Highly effective contraception methods include 
combination of any two of the following: 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; 
• 
Total abstinence or; 
• 
Male/female sterilization. 
Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential. 
16) Male patients whose sexual partner(s) are WOCBP who are not willing to use 
adequate contraception, during the study and for 8 weeks after the end of treatment. 
17) Negative serum or urine pregnancy test for women within 72 hours of receiving the 
first dose of the study medication for women of childbearing potential. 
 
 
    
 
 

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5.0 Registration Procedures 
 
 Patients must not start protocol treatment prior to registration. 
  
 The following information will be requested: 
 
Protocol Number 
 
Investigator Identification 
 
Investigator’s name 
 
Patient Identification 
 
Initials 
    Patient Demographics 
    Sex 
    Birth Date (mm/yyyy) 
    Race 
    Ethnicity 
 
 
   Eligibility Verification 
 
Patients must meet all of the eligibility requirements listed in section 4.1 
 
 
 
   Additional Requirements: 
 
All patients must be provided with a signed and dated copy of the informed consent document. 
 
 
 
 
Instructions for Patients who Do Not Start Assigned Protocol Treatment 
 
If a patient does not receive any assigned protocol treatment, baseline and follow-up data will still 
be collected and must be submitted. The reason for not starting protocol treatment should be 
documented on one of the baseline forms. Also the date and type of the first non -protocol treatment 
that the patient receives should be documented. 

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6.0 Treatment Plan 
 
6.1 Treatment 
 
Patients will receive a single dose of Panitumumab, as a single agent, one week prior to the start 
of the treatment protocol. After this seven day “window period” patients will undergo an optional 
biopsy and correlative blood testing (+/- 1 day), then initiate the full PaCT combination (see Study 
Calendar). 
 
Patients will initiate therapy at the doses and schedules listed in table 1. Each cycle will be 
defined as 21 days of therapy. Patients will undergo a planned 4 cycles of therapy prior to 
surgical resection. Patients who are unable to receive 4 cycles of therapy due to toxicity will be 
recorded in the toxicity analysis, but will be replaced for the efficacy analysis. Patients who 
develop disease progression during therapy will be included in the efficacy analysis. For drug 
administration guidelines and dose reductions, see section 6.3. 
 
All patients will undergo surgical resection of their primary tumor unless they are deemed not fit 
for surgery after 4 cycles of therapy. Patients may undergo either lymph node sampling or 
complete axillary dissection as considered standard of care by their surgeon. 
 
 
Table 1. Dosage of panitumumab, carboplatin, paclitaxel 
Agent 
Premedication: 
*precautions 
Dose 
Route 
Schedule 
Panitumumab 
Not required for 
routine infusions 
2.5 
mg/kg 
If no reaction to the first 
dose of panitumumab, 30 
minutes for subsequent 
doses 
Once per week 
X12 
Paclitaxel 
10 mg IV 
Dexamethasone, 
15min prior. 
80 
mg/m2 
IV over 60 minutes after 
completion of 
Panitumumab, through 
separate IV line 
Once per week 
X12 
Carboplatin 
8 mg IV 
Ondansetron, 15 min 
prior 
4  
AUC** 
IV over 30 minutes after 
completion of paclitaxel 
through separate IV line 
Once every 3 
weeks X4 
* Only for hypersensitivity, antiemetic should be given accordingly. ** Total Dose (mg) = (target AUC) x 
(GFR+25) 
 
 
6.2 Drug Information 
 
For Paclitaxel/Carboplatin, please refer to package insert. 
 
Panitumumab (Vectibix®) 
  See Pharmacy guide in Appendix II. 
 
Do not administer panitumumab as an intravenous push or bolus. 
 
Preparation 
 

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Prepare the solution for infusion, using aseptic technique, as follows: 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Although panitumumab should be colorless, the solution may contain a 
small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab 
particulates (which will be removed by filtration; see below). Do not shake. Do not administer 
panitumumab if discoloration is observed. 
 
• 
Withdraw the necessary amount of panitumumab for a dose of 6 mg/kg. 
• 
Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses 
higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, 
USP. Do not exceed a final concentration of 10 mg/mL. 
• 
Mix diluted solution by gentle inversion. Do not shake. 
 
6.3 Panitumumab Administration 
 
 
• 
Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. 
Panitumumab must be administered via infusion pump. 
o 
Flush line before and after panitumumab administration with 0.9% sodium chloride 
injection, USP, to avoid mixing with other drug products or intravenous solutions. 
Do not mix panitumumab with, or administer as an infusion with, other medicinal 
products. Do not add other medications to solutions containing panitumumab. 
 
o 
Infuse doses of 1000 mg or lower over 60 minutes through a peripheral 
intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, 
administer subsequent infusions over 30 to 60 minutes. Administer doses higher 
than 1000 mg over 90 minutes. 
 
• 
Use the diluted infusion solution of panitumumab within 6 hours of preparation if stored at 
room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT 
FREEZE.  
• 
Discard any unused portion remaining in the vial. 
 
 
 
 
 
 
 
 
 
 
 
 
6.4 Toxicity and Dose modification 
 
 
Panitumumab 
 
Dermatologic and Soft Tissue Toxicity: In randomized trial of metastatic colorectal cancer 
(mCRC) patients, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC 
grade 3 and higher) in 15% of patients with mCRC receiving panitumumab. The clinical 
manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, 
skin exfoliation, paronychia, dry skin, and skin fissures. 
 

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Monitor patients who develop dermatologic or soft tissue toxicities while receiving panitumumab 
for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious 
complications including necrotizing fasciitis, abscesses, and sepsis have been observed in 
patients treated with panitumumab. Life-threatening and fatal bullous mucocutaneous disease 
with blisters, erosions, and skin sloughing has also been observed in patients treated with 
panitumumab. It could not be determined whether these mucocutaneous adverse reactions were 
directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens- 
Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue panitumumab for 
dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or 
infectious complications. 
 
Dose modification of Panitumumab: If the toxicities are deemed to be related to Panitumumab, 
two steps of dose reductions are permitted. Figure 6 provides guideline for reducing. The starting 
dose is 2.5 mg/kg. The panitumumab dose will be calculated based on the subject actual body 
weight at baseline and will not be re-calculated unless the actual body weight changes at least 
10%.
 
Electrolyte Depletion/Monitoring: Progressively decreasing serum magnesium levels leading to 
severe (grade 3-4) hypomagnesemia occurred in up to 7% of patients across clinical trials. 
Monitor patients for hypomagnesemia and hypocalcemia prior to initiating panitumumab 
treatment, periodically during panitumumab treatment, and for up to 8 weeks after the completion 
of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. 
Repletion magnesium and other electrolytes as appropriate is highly recommended. 
 
6.5.1.  Dose Modifications Panitumumab 
If the toxicities are associated with panitumumab, two levels of dose reductions are permitted 
(Table 2). The starting dose is 2.5 mg/kg. The panitumumab dose will be calculated based on the 
patient’s actual body weight at baseline and will not be re-calculated unless the actual body 
weight changes at least 10%. 
 
Table 2. Panitumumab de-escalation schedule 
Dose level 
Panitumumab dose (mg/kg) 
 
Starting dose 
 
2.5 
 
Level -1 
 
2.0 
 
Level -2 
 
1.5 
 
 
 
DC Panitumumab* 
 
* If panitumumab is discontinued due to panitumumab-associated toxicities, patient may 
continue to receive paclitaxel and carboplatin. 
 
For patients who experience panitumumab-associated grade 3 and grade 4 toxic effects while in 
the 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. If patients continue to experience panitumumab-
associated grade 3 or 4 toxicities after panitumumab is withheld for more than 2 cycles or after 
second dose reduction, panitumumab will be discontinued (Figure 6). 
 
 
 

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a. 
Criteria for withholding a dose of panitumumab 
1.1.1.a.1. 
Skin- or nail-related toxicities: 
• 
Symptomatic skin- or nail-related toxicity requiring narcotics, systematic 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 event (Appendix. I) 
1.1.1.a.2. 
Non-skin or nail-related toxicities, any grade 3 or 4 toxicity with the following 
exceptions: 
• 
Panitumumab only be withheld for symptomatic hypomagnesemia and/or hypocalcemia 
that persist despite aggressive magnesium and/or calcium replacement. 
• 
Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that 
persists despite of maximum supportive care. 
• 
Panitumumab will only be withheld for grade ≥ 3 anemia or grade 4 thrombocytopenia 
that cannot be managed by blood transfusions or cytokine therapy. 
b. 
Criteria for re-treatment with panitumumab 
1.1.1.b.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 patient 
has recovered to the point to which symptomatic skin- or nail-related toxicity is 
considered tolerable; or systemic steroids are no longer required; or IV antibiotic or IV 
antifungal treatment is no longer required. 
1.1.1.b.2. 
Non-skin- or nail-related toxicities:  
• 
Panitumumab administration may recommence once the adverse event has improved 
to ≤ grade 1 or returned to baseline. 
 
 

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Fig 6. Algorithm of toxicity based dose modification of Panitumumab. 
 
 
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
 

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6.5.2    Paclitaxel 
 
 
• 
Pre-medication: If paclitaxel is being given then prior to commencing chemotherapy give 
paclitaxel hypersensitivity prophylaxis, including H1/H2 antagonists and corticosteroids, as per 
MD Anderson standards. Immediately prior to chemotherapy give anti-emetics as per local 
standards; this may include oral or intravenous 5HT3 antagonists. 
• 
Paclitaxel should be given prior to carboplatin. 
• 
Caution: Subjects who had a mild or moderate hypersensitivity reaction despite 
prophylactic medication have been successfully re-challenged, but careful attention to 
prophylaxis and bedside monitoring of vital signs is recommended. Adequate clinical 
supervision, in accordance to institutional policy, must be present and appropriate 
intervention must be readily available to diagnose and treat hypersensitivity reactions. The 
following are recommendations for management of hypersensitivity reactions: 
• 
Mild Symptoms: Complete study therapy. Supervise at bedside. No treatment required. 
• 
Moderate Symptoms: Stop paclitaxel infusion. Consider oral or IV diphenhydramine and 
oral or IV dexamethasone. Resume paclitaxel infusion at the discretion of the treating 
physician following the recovery of symptoms. If paclitaxel is resumed, start at a low rate, 
(e.g., 20 ml/hour for 15 minutes) then increase as tolerated to a full dose rate until infusion 
is complete. If symptoms recur, stop paclitaxel infusion and do not re- challenge further with 
paclitaxel. Patient may continue on study at the discretion of treating MD with only 
Panitumumab and Carboplatin, but may not be re-challenged with paclitaxel. 
• 
Severe, Life-Threatening Symptoms: Stop paclitaxel infusion. Give IV diphenhydramine and 
IV dexamethasone as above. Add epinephrine or bronchodilators if indicated. Patient may 
continue on study at the discretion of treating MD with only Panitumumab and Carboplatin, 
but may not be re- challenged with paclitaxel. 
 
6.5.3 Carboplatin 
 
Dosing: Use normally available stock in keeping with the standard local practice. There are no 
special drug accountability arrangements for carboplatin. Reconstitute carboplatin AUC 4 
(calculated dose) or AUC4 (GFR measured), in 250ml of 5% dextrose according to local 
standard practice. 
Allergic reactions to carboplatin are not a dose limiting toxicity and should be managed 
according to standard local practice. Patients may be re-challenged with increased prophylactic 
medications and/or slowing of infusion rates at the discretion of the treating physician. If it 
becomes necessary to discontinue carboplatin due to hypersensitivity then patients will continue 
treatment with paclitaxel and Trial Drug. The carboplatin dose should be calculated according to 
the Calvert formula as follows 
• Carboplatin dose = Target AUC X (GFR + 25) 
 
For the purpose of this protocol the GFR is considered equivalent to the creatinine clearance. 
The exact dose of carboplatin therefore depends on the GFR and the method of calculating 
the GFR will also affect the carboplatin dose. The GFR can be calculated using a variety of 
different formulae and should be calculated as per local practice. 
If the estimated serum creatinine clearance is <50 ml/minute, then a formal measurement of the 
GFR is required, using either a 24 hour urine collection or an isotopic clearance. If the isotopic 
clearance is measured then the value uncorrected for body surface area (BSA) should be used 
in dose calculations. 
 

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The target AUC for carboplatin depends on the method of GFR assessment. Where the 
carboplatin dose is based on a GFR measured by isotopic clearance, or a 24hour creatinine 
clearance (urine collection), the target AUC is one unit lower than that based on the estimated 
GFR. This is summarized in Table 3. 
 
Table 3: Target AUC Depending on GFR Calculation Method 
Estimated GFR 
Measured GFR 
Cockcroft-Gault/Jellife/W right 
Isotopic/24hr Urine 
AUC 4 
AUC 4 
Dose capping of carboplatin may be carried out according to standard MD Anderson practice. 
 
 
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. 
If the toxicities are deemed to be associated with paclitaxel or carboplatin, two levels of dose 
reductions are permitted. Table 4a provides guideline for reducing the dose of paclitaxel and 
carboplatin. 
GFR Limitations for carboplatin dosing: Isotopic GFR is inaccurate in patients with significant 
effusions, ascites or edema as the isotope distributes into third space fluid collections.    
Patients who have had complicated or prolonged post-operative recovery and who have been 
maintained on prolonged IV fluids with poor nutrition will have a falsely low serum creatinine.  
Formulae, such as the Cockcroft-Gault formula, are inaccurate at the extremes of age and weight. 
The calculated GFR may be falsely high in obese young women and falsely low in thin, elderly 
women. 
It is assumed that clinicians entering patients into this protocol will be aware of these issues 
and the clinical judgment of an experienced clinician should be applied to the calculation of the 
carboplatin dose. 
Table 4a. Paclitaxel and carboplatin de-escalation schedule 
Dose level 
Paclitaxel dose (mg/m2) 
Carboplatin dose (AUC) 
 
Starting dose 
80 
4 
 
Level -1 
60 
Modified GFR to reduce 
the dose per physician’s 
discretion 
 
 
Level -2 
Hold 
Modified GFR to reduce the 
dose per physician’s discretion 
 
 
Off study* 
Off study* 
 
* If paclitaxel and/or carboplatin continue to cause chemotherapy-related toxicities at dose 
level-2, patient will be removed from the study. 
  
Depending on the extent of toxicity, dose reduction may be needed for only one drug (paclitaxel or 
carboplatin) or for both drugs. If the investigator is unsure of which type of reduction is needed, 
both drugs should be reduced. If the toxicity level indicates that only one drug should be reduced, 
the other drug should be remain at its original dose level. If the potentially dangerous toxicities are 
observed, the investigator and sponsor should be discuss the options for dose reductions. 
Doses that have been reduced as a results of toxicity must not be re-escalated back to the starting 
level. 
Treatment may be delayed no more than 4 weeks to allow recovery from toxicities. 
If the toxicities are associated with paclitaxel and carboplatin, a maximum of two dose reductions 
will be allowed per patient.  

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Patients who are age 65 years old or older will have the risk of carboplatin-associated toxicity 
calculated by the CARG score (Table 4c) (http://www.mycarg.org/Chemo_Toxicity_Calculator).37 
We highly recommended that patients who have an intermediate (6 to 9 points; 52%) or high (10 to 
19 points; 83%) CARG risk score consider dose modification of carboplatin (see Table 4b).   
         
 
             
 Table 4b. Carboplatin de-escalation schedule for 65 years old or older 
CARG score 
Carboplatin (AUC) 
 Low risk (0 to 5 points) 
4 
 Intermediate risk (6-9 points) 
Modify per physician’s discretion 
 High risk (10-19 points) 
Modify per physician’s discretion 
    
 
Table 4c. CARG score37(J Clin Oncol. 2011 Sep 1;29(25):3457-65, Table 5.) 
(http://www.mycarg.org/Chemo_Toxicity_Calculator) 
 
 
NOTE:  All toxicities should be graded according to the NCI Common Toxicity Criteria 
(version 4.0) 
 
All dose modifications must be recorded in the data capture system. 
 
 
 
Risk factor 
Score 
Age≥72 
2 
Cancer type GI or GU 
2 
Chemotherapy dosing, standard dose  
2 
No. of chemotherapy drugs, polychemotherapy 
2 
Hemoglobin<10g/dl (female) 
3 
Creatinine clearance (Jelliffe, ideal weight)<34 ml/min 
3 
Hearing, fair or worse 
2 
No. of falls in last 6 months, 1 or more 
3 
IADL: taking medications, with some help/unable 
1 
MOS: Walking 1 block, somewhat limited/limited a lot 
2 
MOS: Decreased social activity because of physical/emotional 
health, limited at least sometimes 
1 
Abbreviations: GU, genitourinary; IADL, instrumental activities of daily living; MOS, Medical 
Outcome Study 

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7 
Reporting of Adverse Events 
 
7.1 Assessment of Safety 
Safety assessments will consist of monitoring and reporting AEs and SAEs per protocol. This 
includes all events of death, and any study-specific issue of concern 
 
7.2 Adverse Events 
• 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP) or other protocol imposed 
intervention, regardless of attribution. 
• 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
• 
All adverse events will be recorded in the patient’s electronic medical record, electronic 
database, and/or the AE log. The PI or designee will be responsible for determining attributions 
for each AE. The PI will be responsible for the sign off of all AE logs.  
 
 
 
7.3 Serious Adverse Events (SAE) Reporting 
 
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). 

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• 
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. 
 
• 
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 MD Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. 
• 
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 in accordance with the timeframes and 
procedures outlined in “The University of Texas MD Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse Events 
for Drugs and Devices”. This may include the development of a secondary malignancy. 
• 
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 supporter’s guidelines, and Institutional Review Board policy. 
 
The principal investigator has the obligation to report all serious adverse events to the FDA 
and IRB. 
 
7.3.1 
The PI and the research team is responsible for compliance with expedited reporting 
requirements for serious and unexpected and related adverse events (SUSARs) to 
Amgen Global Safety at 1-888-814-8653.  
 
Please see most recent version of the IB for a sample form for reporting of these events.  
MDACC SAE form will be used for the reporting of these events. 
 
 

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Table 5. 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious Adverse 
Reaction (SUSARs) 
Sent to Amgen at time of regulatory 
submission 
Serious Adverse Events (SAEs) 
Individual reports batched to Amgen 
every 90 days 
Pregnancy/Lactation 
Within 10 days of investigator awareness 
All SAEs and AEs 
Fatal AEs 
AEs 
leading 
to 
panitumumab 
discontinuation 
Related SAEs and AEs 
End-of-study summary tabulations 
The PI will notify Amgen of protocol amendments and follow institutional procedures to 
obtain necessary IRB approvals.  
 
 
8.0 Supportive Care 
 
All supportive measures consistent with optimal patient care should be given throughout the study. 
Exceptions include the use of erythropoietin to treat therapy-induced anemia. Investigators who 
choose to use myeloid growth factors should administer either GCSF or pegylated GCSF 
beginning on either day 2 or 3 of each cycle. The use of growth factor support should follow ASCO 
guidelines. 
 
9.1 Duration of Therapy 
 
Patients will receive protocol therapy unless: 
 
 
Patient experiences unacceptable drug toxicity. 
 
Patient withdraws consent. 
 
Patient has progression of disease as defined in section 6.0. 
 
The patient completes the required 4 cycles of therapy. 
 
Pregnancy 
 
10.0 Duration of Follow-up 
 
For this protocol, all patients, including those who discontinue protocol therapy early, will be 
followed until 1 month after surgical resection of the tumor.  Date of last follow up clinic visit 
should be within 30 days (+/- 10 days) of surgical resection. Investigators will also collect data on 
recurrence for 2 years after surgical resection of the tumor. Should a patient withdraw consent, 

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then the patient will be removed from study at that time and no further data will be collected. 
 
11.0 Protection of human subjects 
 
All current FDA, NCI, state federal and institutional regulations concerning informed consent will be 
followed. 
 
In order to protect confidential patient information, all study participants will be assigned a study ID 
number. Specimens will be assigned a separate specimen ID number. All study information will be 
stored on password-protected computer files.  Only authorized study personnel will have access to 
these files. 

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12.1 Scheduled evaluations 
 
12.2 Pretreatment Evaluation 
 
 
Medical history and physical examination including weight and performance status. 
 
 
Laboratory studies: CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, magnesium, albumin, alkaline phosphatase, total bilirubin, 
SGOT [AST], SGPT [ALT], serum or urine pregnancy test (WOCBP). 
 
 
Radiologic evaluation of measurable disease within 4 weeks of starting treatment. 
 
 
Patient must sign IRB-approved informed consent prior to any study-specific procedures 
unless such procedures are part of the standard of care. 
 
12.3 Evaluation During Study 
 
 
Physical examination (including vital signs, weight, performance status): on day 1 of (or 
up to 3 days prior to) each treatment cycle. 
 
 
CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, magnesium, albumin, alkaline phosphatase, total bilirubin, SGOT 
[AST], SGPT [ALT] within 48 hours prior to starting each cycle of therapy. 
 
 
Patients will undergo repeat imaging (mammogram, ultrasound and/or MRI, as clinically 
indicated) of the involved breast and axillary nodal basin as standard of care prior to 
surgical resection (after 4 cycles of therapy) or at the time of clinically suspected disease 
progression. 
 
13.1 Measurement of Effect 
 
13.2 Pathologic response 
The RCB is a continuous variable derived from the primary tumor dimensions, cellularity of the 
tumor bed, and axillary nodal burden. RCB can be divided into four classes (RCB-0 to RCB-III) 
and will be collected as part of the study. 
RCB-0 (pCR), Minimal RCB (RCB-I), Moderate RCB (RCB-II), and Extensive RCB (RCB-III).  
The following parameters are required from pathologic examination in order to calculate 
Residual Cancer Burden (RCB) after neoadjuvant treatment: 
 
The largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor bed if 
multicentric disease) 
 
Submission of the entire largest cross-sectional area of the residual tumor bed for histologic 
mapping, with specific identification of those slides in the pathology report (e.g. "the largest cross-
sectional area of primary tumor bed was submitted in cassettes A5 - A9") 
 
If the residual tumor is large (i.e. largest diameter > 5 cm), then at least 5 representative 
cassettes from the largest cross-sectional area are sufficient, but should be identified in the original 
pathology report (e.g. "representative sections from the largest cross- sectional area of primary 

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tumor bed were submitted in cassettes A5 - A9") 
 
Histologic assessment of the percentage of the tumor bed area that contains carcinoma 
(all carcinoma, i.e. invasive and in situ), select one of the following: 
 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 
To assess cellularity it is helpful to scan across the sections of tumor bed 
and then estimate the average cellularity from the different microscopic fields. 
 
When estimating percentage cancer cellularity in any microscopic field, compare the involved 
area with obvious standards, e.g. more or less than half, one quarter, one fifth, one tenth, one 
twentieth, etc. 
 
Expect there to be variable cellularity within the cross section of any tumor bed, but estimate 
the overall cellularity from the average of the estimates in different microscopic fields of the tumor 
bed. 
 
e.g. if cellularity in different fields of the tumor bed were estimated as 20%, 10%, 
20%, 0%, 20%, 30%, then an average estimate of overall cellularity would be 20%. 
 
Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, select 
one of the following: 
 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 
 
The number of positive (metastatic) lymph nodes 
 
The largest diameter (mm) of the largest nodal metastasis 
 
The RBC can be accessed online: www.m danderson.org/breastcancer_RBC 
 
 
13.3 Radiographic Imaging 
 
• 
Radiographic criteria of response will be based on the on regional ultrasound examination 
(decrease in size of the primary tumor and/or fatty replacement in regional lymph nodes) 
 
• 
A decrease in size of the product of the two largest dimensions should =/> 50% will be 
considered a partial response. 
 
• 
Complete disappearance of the primary tumor by physical exam and or ultrasound and 
normalization of the lymph nodes by ultrasound will be considered a complete clinical 
response. 
 
• 
Progression of disease will be defined as 30% increase in the size of the primary tumor 
and/or lymph nodes on physical exam and/or ultrasound. 
 
 
 
14.0 Correlative Studies 
 
All molecular correlative studies will involve molecular profiling data generated through biopsy of 
the primary breast tumor and profiled within the existing BMO molecular triaging protocol that is 
currently IRB approved (MDACC 2014-0185).For Patients who were previously not consented to 
protocol 2014-0185, we will attempt to retrieve archival tissue from the initial diagnostic biopsy if 
available, to conduct additional correlative studies. Potential biomarkers of response will be 
correlated with pathologic response to PaCT using appropriate statistical analyses for the 
biomarker of interest (see rationale section). 

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Peripheral Blood  
These samples will be used to perform correlative studies aimed at identifying predictive markers 
and to enhance the understanding of EGFR inhibition in the neoadjuvant setting.  
 

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15.0 Statistical Considerations 
Over view 
This is a non-randomized open label phase II study. Counting pCR (RCB-0) or RCB-I as 
response, a two-stage Gehan-type design will be employed with 14 patients in the first stage. If at 
least one patient responds, 33 more patients will be added for a total of 47 patients. This design 
has a 49% chance of terminating after the first stage if the true response rate is 0 .05, 23% 
chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If 
accrual continues to the second stage and a total of 47 patients are enrolled, the 95% 
confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. 
 
The proportion of patients with pCR (RCB-0) or RCB-I as the response rate along with an 
appropriate 95% confidence interval will be estimated, as well as the proportion of patients in the 
remaining RCB categories with confidence intervals as well. We will estimate the PFS distribution 
using the Kaplan-Meier method from the date of enrollment onto this study until the date of 
progression or death without evidence of progression. Patients alive and disease-free at the latest 
clinical evaluation will be censored at the date of that evaluation. We will also estimate the OS 
distribution in a similar fashion. 
 
 
16.0 Secondary Objectives and Correlative Studies: 
 
Potential biomarkers of response will be correlated with pathologic response to this treatment 
using appropriate statistical analyses for the biomarker of interest. 
A secondary objective of this study is to also estimate the PFS distribution. PFS is defined as the 
time from enrollment to progression of disease (> 20% increase in tumor size as defined in 
Section 10.1) or death whichever comes first. 
We  will estimate the proportion of patients with pCR (RCB-0) or RCB-I as the response rate along 
with an appropriate 95% confidence interval. We will estimate the proportion of patients in the 
remaining RCB categories with confidence intervals as well. We will estimate the PFS distribution 
using the Kaplan-Meier method from the date of enrollment onto this study until the date of 
progression or death without evidence of progression. Patients alive and disease-free at the latest 
clinical evaluation will be censored at the date of that evaluation. 
Early drop outs (i.e., patients not getting to surgery) should be counted as treatment failures 
(i.e., non-responders with RCB > 1). 
If no RCB-0 or -1 response has been observed prior to enrolling the 15th patient, enrollment will 
stop until all of the 14 patients in the first stage are evaluable and resume only if a response has 
been documented. 
Comparison will be made to patients from the parent study (2014 -0185) who received taxane- 
based therapy using matched propensity score methods for toxicity, pathologic response (RCB) 
and PFS. 
Recent findings by Yau et al. (2019) indicated that TNBC patients with RCB-I have a slightly 
worse event free survival than patients with PCR (26). Therefore as a secondary objective, we 
will determine pCR (RBC-0) alone as a response rate. Currently, 5 patients enrolled on this study 
have had a pCR. If these numbers hold and we end with 5/37 (13.5%) patients with pCR, then 
the exact 95% confidence interval around this number will be barely below 5%, which will be 
inconclusive. If we increase by 10 patients to a total of 47, then if we have 7/47 patients with a 
pCR, the exact 95% CI will have a lower bound of 6.2%, which will provide the conclusive 
evidence we need to move forward with the analysis. 

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17.0 Inclusion of Minorities 
 
The study will be available to all eligible patients regardless of race, or ethnic origin. There is no 
information currently available regarding differential effects of this regimen in subsets defined by 
race or ethnicity. 

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32 
 
18.0 Study Calendar 
 
The Study Calendar summarizes the study procedures to be performed at each visit. Due to scheduling, these visits can 
occur +/- 3 days from the required time point. It may be necessary to perform these procedures at unscheduled time 
points if deemed clinically necessary by the investigator. 
 
 
STUDY W EEK 
 
Window 
Period 
Cycle 1 Cycle 2 Cycle 3 Cycle 4 
 
Post 
Treatment 
STUDY DAY 
-28 to 0 1 week 
1 8 15 1 8 15 1 8 15 1 8 15 
 
Surgical 
Resection 
 
Follow Up 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Physical a 
X 
 
X 
X 
X 
X 
 
Xf 
 
Vitals Signs, W eight a 
X 
 
X 
X 
X 
X 
 
 
 Performance Status a 
X 
 
X 
X 
X 
X 
 
 
Baseline Symptoms 
 /Toxicities 
 
X 
 
X 
X 
X 
X 
 
 
 
CBC 
 
X 
 
X X X X X X X X X X X X  
 
Chemistries 
Chem 12 and LFTs b 
 
X 
 
X 
X 
X 
X 
 
 
Pregnancy Test (Serum 
or urine) 
 
X 
 
 
 
 
Radiographic 
Evaluation c 
X 
 
 
X 
 
 
Correlative Studies d 
X 
X 
X  
X 
 
Panitumumab 
 
 
X 
X X X X X X X X X X X X 
 
 
Carboplatin 
 
 
X 
X 
X 
X 
 
 
Paclitaxel 
 
 
X X X X X X X X X X X X 
 
 
 
a. 
Physical examination (including vital signs, weight, performance status): on day 1 of (or up to 3 days prior to) each 
treatment cycle 
b. 
CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, albumin, alkaline phosphatase, 
total bilirubin, SGOT [AST], SGPT [ALT] within 48 hours prior to starting each cycle of therapy 
c. 
Patients will undergo repeat imaging (mammogram, ultrasound and/or MRI, as clinically indicated) of the involved breast and 
axillary nodal basin as standard of care prior to surgical resection (after 4 cycles of therapy) or at the time of clinically 
suspected disease progression. 
d. 
Correlative Study samples will be collected at: Baseline, 1 week (+/- 1 day) after the first dose of Panitumumab, mid-
treatment and before surgery.  
f. 
Patient tracking by the study team will take place per standard of care adjuvant measures for PFS analysis.  This will be 
completed by way of a physical examination every 3-4 months. 

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19.1 References : 
 
1. 
Lehmann BD, Bauer JA, Chen X, et al: Identification of human triple-negative 
breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 
121:2750-67, 2011 
2. 
Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast 
cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414 -22, 2007 
3. 
Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy and 
long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-81, 2008 
4. 
von Minckwitz G, Kummel S, Vogel P, et al: Neoadjuvant vinorelbine- 
capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast 
cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst 100:542 -51, 2008 
5. 
Houssami N, Macaskill P, von Minckwitz G, et al: Meta-analysis of the 
association of breast cancer subtype and pathologic complete response to neoadjuvant 
chemotherapy. Eur J Cancer 48:3342-54, 2012 
6. 
Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al: Characterization of a 
naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and 
stem cell characteristics. Cancer Res 69:4116-24, 2009 
7. 
Lehmann BD, Pietenpol JA: Identification and use of biomarkers in treatment 
strategies for triple-negative breast cancer subtypes. J Pathol 232:142-50, 2014 
8. 
Prat A, Adamo B, Cheang MC, et al: Molecular characterization of basal-like and 
non-basal-like triple-negative breast cancer. Oncologist 18:123-33, 2013 
9. 
Hatzis C, Pusztai L, Valero V, et al: A genomic predictor of response and survival 
following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA 305:1873 -81, 
2011 
10. 
Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast 
tumours. Nature 406:747-52, 2000 
11. 
Prat A, Parker JS, Karginova O, et al: Phenotypic and molecular characterization 
of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68, 2010 
12. 
Arun B, Bayraktar S, Liu DD, et al: Response to neoadjuvant systemic therapy 
for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J 
Clin Oncol 29:3739-46, 2011 
13. 
Masuda H, Baggerly KA, Wang Y, et al: Differential response to neoadjuvant 
chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res 
19:5533-40, 2013 
14. 
Corkery B, Crown J, Clynes M, et al: Epidermal growth factor receptor as a 
potential therapeutic target in triple-negative breast cancer. Ann Oncol 20:862-7, 2009 
15. 
Zhang D, LaFortune TA, Krishnamurthy S, et al: Epidermal growth factor receptor 
tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in 
inflammatory breast cancer. Clin Cancer Res 15:6639-48, 2009 
16. 
Cabioglu N, Gong Y, Islam R, et al: Expression of growth factor and chemokine 
receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol 18:1021 -9, 2007 
17. 
Lee CH, Wu YT, Hsieh HC, et al: Epidermal growth factor/heat shock protein 27 
pathway regulates vasculogenic mimicry activity of breast cancer stem/progenitor cells. Biochimie 
104:117-26, 2014 
18. 
Zheng Z, Shao N, W eng H, et al: Correlation between epidermal growth factor 
receptor and tumor stem cell markers CD44/CD24 and their relationship with prognosis in breast 
invasive ductal carcinoma. Med Oncol 32:275, 2015 
19. 
Sun B, Zhang S, Zhang D, et al: Identification of metastasis-related proteins and 
their clinical relevance to triple-negative human breast cancer. Clin Cancer Res 14:7050 -9, 2008 
20. 
Masuda H, Zhang D, Bartholomeusz C, et al: Role of epidermal growth factor 
receptor in breast cancer. Breast Cancer Res Treat 136:331-45, 2012 

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21. 
Costa DB, Halmos B, Kumar A, et al: BIM mediates EGFR tyrosine kinase 
inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4:1669 - 
79; discussion 1680, 2007 
22. 
Zhang D, Pal A, Bornmann W, et al: Activity of lapatinib is independent of EGFR 
expression level in HER2-overexpressing breast cancer cells. Mol Cancer Ther 7:1846, 2008 
23. 
Lee MJ, Ye AS, Gardino AK, et al: Sequential application of anticancer drugs 
enhances cell death by rewiring apoptotic signaling networks. Cell 149:780 -94, 2012 
24. 
Mueller KL, Yang ZQ, Haddad R, et al: EGFR/Met association regulates EGFR 
TKI resistance in breast cancer. J Mol Signal 5:8, 2010 
25. 
Nabholtz JM, Abrial C, Mouret-Reynier MA, et al: Multicentric neoadjuvant phase 
II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable 
triple-negative breast cancer: identification of biologically defined signatures predicting treatment 
impact. Ann Oncol 25:1570-7, 2014 
 
26. 
Yau C, Van der Noordaa M, Wei J, et al: Residual cancer burden after neoadjuvant 
therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis. SABCS 
December 2019. Publication number: GS5-01 
 

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Appendix I.  Dermatology/Skin/Nail Assessment (from CTCAE version 4.0 
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) 
Target lesions 
covering <10% 
BSA and not 
associated with 
skin tenderness 
Target lesions 
covering 10 - 
30% BSA and 
associated with 
skin tenderness 
Target lesions 
covering >30% 
BSA and 
associated with oral 
or 
genital erosions 
Target lesions 
covering >30% 
BSA; associated 
with fluid or 
electrolyte 
abnormalities; 
ICU 
care or burn unit 
indicated 
Pruritis/itching 
(Pruritis) 
Mild or localized; 
topical 
intervention 
indicated 
Intense or 
widespread; 
intermittent; skin 
changes from 
scratching (e.g., 
edema, 
papulation, 
excoriations, 
lichenification, 
oozing/crusts); 
oral intervention 
indicated; 
limiting 
instrumental 
ADL 
Intense or 
widespread; 
constant; limiting 
self care ADL 
or sleep; oral 
corticosteroid or 
immunosuppressive 
therapy 
indicated 
___ 
Rash: 
acne/acneiform 
(Acne) 
Papules and/or 
pustules 
covering <10% 
BSA, which may 
or may not be 
associated with 
symptoms of 
pruritus or 
tenderness 
Papules and/or 
pustules 
covering 10 - 
30% BSA, which 
may or may not 
be associated 
with symptoms 
of pruritus or 
tenderness; 
associated with 
psychosocial 
impact; limiting 
instrumental 
ADL 
Papules and/or 
pustules 
covering >30% 
BSA, which may 
or may not be 
associated with 
symptoms of 
pruritus or 
tenderness; limiting 
self care 
ADL; associated 
with local 
superinfection with 
oral 
antibiotics indicated 
Papules and/or 
pustules 
covering any % 
BSA, which 
may or may not 
be associated 
with symptoms 
of pruritus or 
tenderness and 
are associated 
with extensive 
superinfection 
with IV 
antibiotics 
indicated; 
lifethreatening 
consequences 
Rash maculo-
papular 
Macules/papules 
covering 
Macules/papules 
covering 10 - 
Macules/papules 
covering 
___ 

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<10% BSA with 
or without 
symptoms (e.g., 
pruritus, 
burning, 
tightness) 
30% BSA with or 
without 
symptoms (e.g., 
pruritus, 
burning, 
tightness); 
limiting 
instrumental 
ADL 
>30% BSA with or 
without 
associated 
symptoms; limiting 
self care ADL 
Skin ulceration 
Combined area 
of ulcers <1 cm; 
nonblanchable 
erythema of 
intact skin with 
associated 
warmth or edema 
Combined area 
of ulcers 1 - 2 
cm; partial 
thickness skin 
loss 
involving skin or 
subcutaneous 
fat 
Combined area of 
ulcers >2 cm; 
full-thickness skin 
loss involving 
damage to or 
necrosis of 
subcutaneous 
tissue that may 
extend down to 
fascia 
Any size ulcer 
with extensive 
destruction, 
tissue necrosis, 
or 
damage to 
muscle, bone, or 
supporting 
structures with 
or 
without full 
thickness skin 
loss 
*Desquamation is defined as sloughing of skin and does not apply to dry flaking skin. 

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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.  

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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 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.