A Phase II Study of Breast Cancer Treatment Using Weekly Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting
Phase: PHASE2
Conditions: Breast Cancer, HER2-negative Breast Cancer, HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Sponsor: University of California, Irvine

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Created by RMehta   10/02/14  Neoadjuvant 
 
 
A Phase II Study of Breast Cancer Treatment Using Weekly Carboplatin+Nab-paclitaxel, 
plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting 
 
SCHEMA ........................................................................................................................... 2 
1.0 
OBJECTIVES ....................................................................................................... 3 
2.0 
BACKGROUND ................................................................................................... 3 
3.0 
DRUG INFORMATION ...................................................................................... 5 
4.0 
STAGING CRITERIA…………………………………………………………..9 
5.0 
ELIGIBILITY CRITERIA .................................................................................. 9 
6.0 
TREATMENT PLAN ......................................................................................... 10 
7.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS . 12 
8.0       STUDY CALENDAR………………………………………………………..…14  
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .......... 15 
10.0 
STATISTICAL CONSIDERATIONS .............................................................. 16 
11.0 
ETHICAL AND REGULATORY CONSIDERATIONS ............................... 18 
12.0 
BIBLIOGRAPHY ............................................................................................... 24 
 
 
 
 
LEAD INVESTIGATOR: 
 
Rita Mehta, M.D. 
 
OTHER INVESTIGATORS: 
Division of Hematology/Oncology (714) 456-5153 
Jason Zell, D.O.; M.P.H.; M.S. 
Richard Huynh, M.D. 
Chaitali S. Nangia, M.D. 
James Ward, M.D. 
Leslie Klein, M.D. 
Min-Ying Su, Ph.D., Department of Radiological Sciences, (949) 824-6001, 824-4925 
Shadfar Bahri, M.D., Department of Radiological Sciences, (949) 824-6001, 824-5479 
Jeon-Hor Chen, M.D., Department of Radiological Sciences, (949) 824-6001, 824-9327 
Hon Yu, Ph.D., Department of Radiological Sciences, (949) 824-6001, 824-5479 
David Hsiang, M.D., Department of Surgical Oncology, (714) 456-8030 
Karen Lane, M.D., Department of Surgical Oncology, (714) 456-8030 
Joseph Wu, M.D., Brain Imaging Center, (949) 824-7867 
 
 
STATISTICIAN 
Christine E. McLaren, M.D. 

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Created by RMehta   10/02/14  Neoadjuvant 
 
 
AGENTS: 
Nab-paclitaxel (Abraxane®)(ABI 007) 
Carboplatin (Paraplatin®) (NSC 241240) 
Bevacizumab-Avastin 
Trastuzumab-Herceptin 
 
 
Please refer all questions regarding chemotherapy treatment or dose modifications to Dr. 
Rita Mehta at 714-456-2239, pager 714-506-6174. 
 
 
 
 
SCHEMA 
UCI 07-61 
 
 
Invasive Breast Cancer 
                                            1cm and or lymph node positive 
Neoadjuvant chemo 
 
 
 
Nab-paclitaxel-Abraxane weekly 12 doses 
Carboplatin weekly 12 doses  
 
 
                                                                     
                                                                       Plus 
 
 
 
 
                                 Her2Neu - 
 
                            Her2Neu+  
 
 
 
 
Bevacizumab-Avastin                                 Trastuzumab-Herceptin 
                    Every other week-5 doses                                    Weekly 12 doses          
 
 
 

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1.0 OBJECTIVES 
There are two study components, 1) to evaluate the treatment response and toxicity of the 
protocol, and 2) to investigate the role of Magnetic Resonance Imaging (MRI) to monitor and 
predict the final pathological response. 
 
Objectives for treatment study component: 
1.1  To estimate 2 year progression-free survival in patients with breast cancer more than 1 cm 
and/or lymph node positive breast cancer treated with weekly Carboplatin/Nab-Paclitaxel 
(with trastuzumab in patients with HER2+ disease, and with bevacizumab in HER2-).  
 
1.2  To measure clinical response rates in patients treated in the neoadjuvant setting. 
 
1.3  To measure the microscopic pathological response rate of this regimen in patients treated in 
the neoadjuvant setting. 
 
1.4  To measure the toxicity and delivered dose intensity of this regimen. 
 
1.5  To assess the association between microscopic pathologic complete response and    clinical 
complete response at the primary tumor site in these patients. 
 
1.6 To measure the outcome of patients treated with doxorubicin and cyclophosphamide with 
patients not treated with doxorubicin and cyclophosphamide.  
 
Objectives for MRI response monitoring study component: 
1.7 Develop quantitative analysis methods to obtain pre-treatment tumor characteristic 
morphological, enhancement kinetic, and Choline metabolic parameters in breast cancer. 
Select an optimal set of features using the logistic regression analysis and the Artificial 
Neural Network (ANN) to predict pathologic complete remission (pCR) in HER-2 positive 
and negative arm. 
 
1.8 Investigate whether the early response patterns, analyzed using the percent tumor size 
changes, or changes in other lesion characteristic parameters, can be used to predict 
pathologic complete remission (pCR) in HER-2 positive and negative arm. 
 
1.9 Investigate whether combining the pre-treatment tumor characteristic parameters, and the 
early response pattern during the treatment course, can achieve a higher AUC (area under 
the ROC curve) in prediction of pCR than those based on pre-treatment MRI characteristics 
or tumor response patterns alone. 
 
 
2.0 BACKGROUND 
The aim of neoadjuvant systemic therapy is to reduce the tumor volume in patients before 
surgical resection, thus reducing the surgical field.  More recently, neoadjuvant therapy has been 
studied as a way of testing the relevance of biological markers in predicting disease outcome, 
monitoring treatment response, and thereby directing alternative effective therapy in patients 
with poor response the first line therapy.  

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The largest trial (1523 patients) run by the NSABP found no differences in disease-free and 
overall survival in patients treated with neoadjuvant versus adjuvant treatment (1). These trials 
were done in the era when the pathologic complete responses were typically in the range of 10-
15% with non-targeted and non-biologic treatment putting majority of patients at risk of delaying 
one of the most effective therapy (surgery) needlessly. 
 
But the use of neoadjuvant systemic treatment has been spurred by the use of ever increasing 
effective targeted systemic therapy with higher pathologic complete response, and accumulating 
knowledge of complete pathologic response as a surrogate marker of improved overall survival.  
Therefore, induction of clinical or pathologic Complete Response should be one of the primary 
goals of neoadjuvant therapy because patients with no evidence of tumor cells in breast and 
lymph nodes after treatment may have a longer disease-free and overall survival (1-3), and by 
extrapolation, patients with complete clinical response should similarly have a longer disease-
free survival than patients not achieving this response. 
Use of anthracycline has been standard in the treatment of breast cancer for over 40 
years.  Unfortunately, the use of anthracyclines is being questioned as the result of 2 trials 
(Slamon et al, Jones et al.) have shown diminished therapeutic rational for the use of 
anthracycline when compared to taxane based non anthracyline regimens.  Therefore, while the 
use or non-use of anthracyline in breast cancer is being hotly contested, use of anthracycline is 
optional off study. However, the data will be analyzed for the whole group of patients enrolled, 
and subset analysis will be performed based on use or non-use of anthracycline.  
Rationale for the use of Taxane/carboplatin: 
Incorporation of taxanes on a 3 weekly schedule has resulted in statistically higher pathological 
CR (2, 3).  Recently, weekly paclitaxel regimens have reported increased pathological responses 
compared to 3 weekly taxane regimens (4).  Carboplatin has also emerged as an effective agent 
in the treatment of metastatic breast cancer (5). Moreover, the combination of carboplatin and 
paclitaxel has been found to be additive or synergistic both in three-weekly regimens and weekly 
regimens.   Furthermore, the weekly regimens of these drugs have been found to have 
significantly improved tolerability over three weekly regimens (6). Albumin bound paclitaxel has 
been found to have a better therapeutic ratio compared to parent paclitaxel. We plan to 
administer nab-paclitaxel and carboplatin weekly for a total of 12 doses. 
 
Rationale for the use of nab-paclitaxel: 
Abraxane (ABI 007) was approved by the U.S. Food and Drug Administration (FDA) in 2004.  
Abraxane is a new formulation of paclitaxel that is bound with albumin and delivers high 
concentrations of this active ingredient to cancer cells with less toxicity.  Gradishar et al reported 
on a large trial with metastatic breast cancer that was treated with either abraxane or paclitaxel.  
Some patients received prior chemotherapy regimens with progression of disease, while others 
received no previous chemotherapy.  Patients who received abraxane demonstrated almost 
double the response rate compared to paclitaxel, as well as improvement in duration of survival 
of 65 weeks compared to 55 weeks in favor of abraxane.  The subgroup of patients who received 
prior chemotherapy regimens had better response rates when treated with abraxane compared to 
paclitaxel with average survival time of 56 weeks compared to 46 weeks in favor of abraxane.  It 
was concluded that the treatment of metastatic breast cancer with abraxane demonstrates 
improved therapeutic ratio compared to paclitaxel (7).   
 
The rationale for use of Trastuzumab: 

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The use of trastuzumab which targets breast cancer with amplified HER2 has demonstrated 
improved pathologic response, disease-free and overall survival compared to patients not 
receiving trastuzumab with or without AC, with or without paclitaxel, with or without 
carboplatin (8-16).  
 
At the San Antonio Breast Cancer Conference on December 8, 2004, we presented the sequential 
use of doxorubicin and cyclophosphamide (AC) followed by paclitaxel, carboplatin, and 
trastuzumab (TCH) in patients with Her-2 positive breast cancer.  A pathological complete 
remission (pCR) was seen in 7 of 8 patients.  All patients received 2-4 cycles of AC followed by 
4 cycles of 3 weekly TCH regimens.  Only 1 of 8 patients had a 3mm residual invasive 
carcinoma in the biopsy scan.  Moreover, 7 of 7 patients with palpable lymph nodes 
demonstrated no residual cancer after this neoadjuvant regimen (17).  A confirmatory phase II 
trial using TC [(+H in Her-2 positive, + Bevacizumab (B)] in patients following in vivo response 
adjusted AC showed a high pathologic remission for the whole group of breast cancer patients 
with strikingly high rates in Her-2 positive breast cancer subset (18).  As we found that TC± 
Bevacizumab, or strikingly TCH reverses anthracycline resistance, the patients may have 
improved therapeutic ratio without anthracyclines, as anthracyclines are historically associated 
with cardiac toxicity and leukemia risk. Therefore, we will compare the outcome of patients 
treated with nabTCH/nab-TCB with or without anthracyclines exposure, adjusted for various 
prognostic factors.  Patients showing progression will be taken off the study. 
 
The rationale for use of bevacizumab: 
In metastatic breast cancer, the administration of bevacizumab to capecitabine has shown a 
significant increase in response rates.  The combination arm of bevacizumab plus capecitabine 
demonstrated a response rate of 19.8% compared to 9.1% in the capecitabine arm alone (17).  
However, prolonged free survival or overall survival was comparable in both treatment arms.  A 
randomized controlled, multicenter trial enrolled 878 patients who had not received previous 
chemotherapy for non-small cell lung cancer, and compared standard chemotherapy with 
paclitaxel and carboplatin with or without bevacizumab.  The bevacizumab-based regimen was 
associated with improved survival compared to paclitaxel and carboplatin alone (18). A multi-
center study enrolled 722 women with previously untreated metastatic breast cancer and 
randomized the patients to receive adjuvant paclitaxel with or without bevacizumab.  The trial 
excluded women who had her-2/neu positive breast cancer unless they received trastuzumab 
previously or were unable to receive this medication.  The analysis revealed a doubling of 
progression-free survival with the addition of bevacizumab to chemotherapy compared to 
chemotherapy alone.  These findings were presented at ASCO 2006 (19). 
 
3.0 DRUG INFORMATION 
 
3.1 
Albumin-stabilized nanoparticle formulation of paclitaxel. (Abraxane) (Nab-paclitaxel) 
(ABI 007) 
  
a.  DESCRIPTION 
Abraxane is an albumin-bound nanoparticle of paclitaxel.  It is solvent free and therefore does 
not contain cremophor or Tween 80.  The active agent of abraxane is paclitaxel.  Solvent-based 
taxanes affect optimal delivery of the drug to tumor.  Abraxane is prepared by the 
homogenization of paclitaxel to albumin.  Paclitaxel is a natural product derived from Taxus 
media demonstrating antitumor activity in many cancers that is bound to human serum albumin 
at a concentration of 3%-4% similar to albumin concentration in blood. 

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Molecular Weight:  853.9  
Empiric Formula: C47H51NO14 
Description:  White to yellow sterile, lyophilized powder 
Mechanism of Action: A solvent-free taxane that is thought to accumulate in tumors and 
therefore have increased antitumor activity via albumin-mediated receptor transport.  Nab-PC 
can cross the endothelial wall and then bind to albumin-mediated receptors, such as gp-60 
receptors in tumor blood vessel walls.  This will allow endocytosis of albumin-bound paclitaxel 
into the tumor cells by a process called receptor-mediated transcytosis via gb-60 receptors.  This 
allows paclitaxel to penetrate tumor cells and inhibit tumor cell synthesis by binding to 
microtubules. 
 
b.  TOXICITY  
The major toxicities include alopecia, which is often reversible, sensory neuropathy (dose-
limited), and hematological toxicity (mild and not cumulative).  Superficial keratopathy has been 
documented but this is a reversible and dose related/dependent phenomenon.  Other toxicities 
include mucositis, arthralgias, myalgias, nausea, vomiting.  Abraxane may cause bradycardia and 
hypotension during administration, but these side effects usually do not require treatment.  No 
reported hypersensitivity reactions seen with this drug.  Abraxane may cause irritation at the 
injection site. Reactions include: erythema, swelling, discomfort, or ulceration. These reactions 
are usually cause by extravasation of the drug into the surrounding tissue. 
 
Pregnancy and Lactation:  Abraxane may cause fetal harm when administered to a pregnant 
woman.  Since the active agent of abraxane is paclitaxel and paclitaxel has been shown to be 
embryo- and fetotoxic in rats and rabbits and to decrease fertility in rats, women should avoid 
becoming pregnant while on this medication.  In these studies, paclitaxel was shown to result in 
abortions, decreased corpora lutea, a decrease in implantations and live fetuses, and increased 
reabsorption and embryo-fetal deaths. Studies have also shown paclitaxel to be present in the 
breast milk of animals and therefore women should avoid breastfeeding when taking this 
medication.  No information is available on the excretion of this drug in human milk.   
 
c.  PHARMACOLOGY 
Formulation:  Each mL of the reconstituted formulation will contain 5mg/mL paclitaxel.  Each 
vial contains 100mg of abraxane in an individualized carton. 
Solution Preparation:  Abraxane is reconstituted by injecting 2mL of 0.9% Sodium Chloride 
Injection, USP over a minute onto the wall of the vial.  Direct injection of 0.9% Sodium Chloride 
onto the solution will result in foaming. After the injection is complete, the vial must sit for a 
minimum of five minutes to allow the lyophilized power to wet and then must be swirled to 
allow for complete resolution of the powder. Each bag/bottle should be prepared immediately 
before administration. 
Administration of Nab-paclitaxel:  Nab-paclitaxel, at the appropriate dose, will be given as a 
continuous IV infusion over 30 minutes as specified in the protocol, diluted in 0.9% Sodium 
Chloride Injection, USP.  Nothing else is to be infused through the line where paclitaxel is being 
administered.  Premedication to prevent hypersensitivity reactions is not required prior to the 
administration of abraxane. 
Storage and Stability:  The intact vials of abraxane should be stored between 20-25°C.  
Unopened vials are stable until the expiration date and in the original bag to protect it from 
bright light.  Reconstituted abraxane should be used immediately, but may be refrigerated at 2 
degrees Celsius to 8 degrees Celsius for a maximum of eight hours.   
Supplier:  Commercially available 

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3.2 
Carboplatin (Paraplatin®) (NSC 241240) 
 
a. DESCRIPTION 
Carboplatin (CBDCA) is a platinum compound related to cisplatin. Carboplatin is formed by 
replacing the chloride leaving groups of cisplatin with 1, 1-cyclobutanedicarboxylato ligand, 
which increases the stability of the leaving groups. On a molar basis, carboplatin is 45 times less 
cytotoxic than cisplatin. Carboplatin has a more favorable adverse effect profile than cisplatin, 
which has led to the investigation of the replacement of cisplatin with carboplatin in many 
regimens. 
 
b.  TOXICOLOGY 
Adverse effects include myelosuppression, nausea, vomiting, peripheral neuropathy, ototoxicity, 
hepatic toxicity, electrolyte imbalance, hypomagnesemia, hypocalcemia, and allergic reaction. 
 
c.  PHARMACOLOGY 
Formulation: Paraplatin® is supplied as a sterile lyophilized powder available in single-dose vial 
containing 50 mg, 150 mg and 450 mg of carboplatin for administration by intravenous infusion. 
Each vial contains equal parts by weight of carboplatin and mannitol. 
Preparation: Immediately before use, the content of each vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP, 
according to the following schedule:  Vial strength Diluent volume (50 mg 5 ml/150 mg 15 
ml/450mg 45 ml)  These dilutions all produce a carboplatin concentration of 10mg/ml.  When 
prepared as directed, Paraplatin® solutions are stable for 8hours at room temperature, since no 
antibacterial preservative is contained in the formulation it is recommended that Paraplatin® 
solutions be discarded 8 hours after dilution.  
      NOTE: Aluminum reacts with Paraplatin® causing precipitate formation and loss of potency, 
therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must not be used for the preparation or administration of Paraplatin®. 
Storage: Unopened vials of Paraplatin® are stable for the life indicated on the package when 
stored at controlled room temperature and protected from light. 
Supplier: Commercially available.  
 
3.3   Trastuzumab 
 
a.   DESCRIPTION 
Trastuzumab is an anti-Her2/c-erbB2 monoclonal antibody. 
 
b.   TOXICOLOGY  
Adverse effects include bronchospasm, dyspnea, pulmonary infiltrates, pleural effusions, cough, 
rhinitis, and sinusitis.  Nephrotic syndrome has been reported in some patients.  Hypersensitivity 
reactions have resulted after administration.  Other infusion-related events include fever, chills, 
hypotension, headaches, and dizziness.  Rash, nausea, vomiting, myelosuppression, and 
hypoprothrombinemia.  Cardiac toxicity has been associated with administration including 
ventricular dysfunction, congestive heart failure, and peripheral edema.  Other adverse effects 
include asthenia, insomnia, abdominal pain, and diarrhea. 
 

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c.   PHARMACOLOGY 
Kinetics.  The half-life of trastuzumab is 6 days. 
Formulation:  Trastuzumab is available in 440mg vials in lipophilized powder.  It is 
stored in 30mL vial in bacteriostatic water for injection of 1.1% benzyl alcohol. 
Storage and Stability: Vials of Herceptin are stable at 2 to degrees Celsius.  Reconstituted 
vials of Herceptin with bacteriostatic water for injection containing 1.1% benzyl 
alcohol as a preservative can be kept for 28 days stored at 2-8 degrees Celsius. 
Administration:  Trastuzumab, at the appropriate dose, will be administered intravenously 
with the loading dose over 90 minutes and monitored for 60 minutes post-
administration.  Maintenance doses will be administered over 30 minute infusions if 
the loading dose is tolerated. 
Supplier: Commercially available. 
 
3.4    Bevacizumab (Avastin) 
 
a.   DESCRIPTION   
Bevacizumab is a recombinant human/murine monoclonal antibody to the vascular 
endothelial growth factor receptor. 
 
b.   TOXICOLOGY   
Adverse effects include nausea, vomiting, diarrhea, anorexia, asthenia, abdominal pain, 
headache, deep vein thrombosis, hypertension, and constipation.  Thrombocytopenia is 
commonly seen.  Other side effects include proteinuria, nephritic syndrome, congestive 
heart failure, gastrointestinal perforations, dyspnea, epistaxis, severe hemorrhage, wound 
healing complications.  Skin toxicities include exfoliative dermatitis, skin ulcers, dry 
skin, and nail changes.  The effect of this drug on pregnancy and lactation remain largely 
unknown and therefore not recommended during pregnancy or breastfeeding.   
 
Congestive heart failure was reported in 22/1032 patients who received avastin.  CHF 
occurred in 6/44 patients who received avastin with concurrent anthracycline and 13/299 
patients who received prior anthracyclines and/or left chest wall irradiation.  The safety 
of continuation or resumption of avastin in patients with cardiac dysfunction has not been 
studied. 
 
c.   PHARMACOLOGY: 
Kinetics: The pharmacokinetics of bevacizumab are linear after doses of 0.3 mg/kg or 
greater (Anon, 2002).  The estimated elimination half-life of bevacizumab was 20 
days (range 11 to 50 days) in a pharmacokinetic population analysis of 491 patients 
receiving 1 to 20 mg/kg weekly, every 2 weeks, or every 3 weeks (Prod Info 
Avastin(TM), 2004). 
Storage and Stability: Bevacizumab contains no preservatives and stored in vials 
protected by light.  It must be kept under refrigeration conditions at 2 to 8 degrees 
Celsius.  The product cannot be freeze or shaken.  Diluted solutions of bevacizumab 
may be stored up to a maximum of eight hours under refrigeration conditions at 2 to 8 
degrees Celsius. 
Administration:  The calculated dose of bevacizumab in 100mL of 0.9% sodium chloride 
Injection to be given over 60-90 minutes. 
Supplier: Commercially available. 
 

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4.0 STAGING:  
This study will utilize the American Joint Committee on Cancer (AJCC) staging system which 
provides a strategy for grouping patients with respect to prognosis. The AJCC has designated 
staging by TNM classification (22).  The researchers will also review tumor size, lymph node 
status, estrogen-receptor and progesterone-receptor levels in the tumor tissue, menopausal status, 
and the general health of the patient.  
   
5.0 ELIGIBILITY CRITERIA 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  Use the spaces provided to confirm a patient’s eligibility.  
 
Patient Number: ______________________ 
 
Patient’s Initials: ______________________ 
 
____ 5.1 
Patients must be women with a histologically confirmed diagnosis of breast 
cancer that is more than 1 cm and or lymph node positive.   
Inflammatory breast cancer? (circle) Yes   No 
 
 
 
____ 5.2 
Physical examination, and scans needed for tumor assessment must be performed 
within 90 days prior to registration. 
Date of physical examination ___________________ 
Date of mammogram __________________________ 
Date of breast Ultrasound_______________________ 
Date of MRI breast____________________________ 
 
____ 5.3 
Patients with the clinical diagnosis of congestive heart failure or angina pectoris 
are NOT eligible.    
 
____ 5.4 
Patients must have a serum creatinine and bilirubin within normal limits, and an 
SGOT or SGPT ≤ 2x the institutional upper limit of normal.  These tests must 
have been performed within 90 days prior to registration. 
 
 
Serum creatinine _______ IULN ________ Date Obtained ___________ 
 
 
Bilirubin ____________    IULN_________ Date Obtained ___________ 
 
 
SGOT/SGPT (circle one) _______ IULN _________ Date ____________ 
 
____ 5.5 
Patients must have an ANC of ≥ 1,500/μl and a platelet count of ≥ 100,000/μl.  
These tests must have been performed within 90 days prior to registration. 
 
 
ANC____________ Platelets __________ Date Obtained _____________ 
 
____ 5.6 
Patients must have a performance status of 0-2 by Zubrod criteria (see section 
10.2) 
 
 

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____ 5.7 
Pregnant or nursing women may not participate due to the possibility of fetal 
harm or of harm to nursing infants from this treatment regimen.  Women of 
reproductive potential may not participate unless they have agreed to use an 
effective contraceptive method. 
 
Pregnancy test required for women of childbearing potential. 
 
____ 5.8 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0.  Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  This allows for efficient patient 
scheduling without exceeding the guidelines.  If Day 28 or 42 falls on a weekend 
or holiday, the limit may be extended to the next working day. 
 
____ 5.9 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines. 
 
6.0 TREATMENT PLAN 
 
For treatment or dose modification related questions, please contact Dr. Rita Mehta at 714-456-
3800/2239 or pager 714-506-6174. 
6.1  Good Medical Practice  
The pre-study tests should be obtained within 90 days prior to registration in accordance with 
good medical practice.  Results of these tests do not determine eligibility and minor 
deviations would be acceptable if they do not impact on patient safety in the clinical 
judgment of the treating physician.  
 
All patients will be followed in the clinic every month, where they routinely will be 
examined for clinical response and toxicity evaluations like swelling of extremities, shortness 
of breath.  Routine lab work and procedures such as urinalysis, CBC and Comprehensive 
Metabolic Panel are outlined in the Study Calendar.    
 
It is recommended that the following tests be done to evaluate for metastatic disease and test 
to evaluate heart function: 
a. CT scan of abdomen and chest and/or CT/PET fusion. 
b. Bone scan if indicated. 
c. All patients preferably should have a MUGA or echocardiogram scan performed 
prior to registration. 
6.2 MRI Response Monitoring Study 
If the subject also agrees to participate in the MRI response monitoring study, she will come 
to Center for Functional Onco-Imaging at Irvine campus for 4-5 MRI studies, one baseline 
before treatment, and 3-4 during the course of therapy before surgery. The study will be 
performed on the 3T scanner. After subject arrives at the center, she will fill out a medical 
questionnaire for the investigators to determine whether there are any contradictions for 
participating in this study. If not, the subject will be prepared for the study, including 
changing of clothes, and set-up of an IV line. Then the subject will be placed into the MRI 
scanner at a prone (facing down) position. The bilateral breasts will be positioned into a bra-
shaped MR coil. After collecting some pre-contrast images, the MR contrast agent, 
Gadolinium (Omniscan® 287mg/ml Injections, 1 cc/10 lb body weight), will be injected 

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through the IV line. The imaging time for the entire protocol will last approximately one 
hour. The study time including preparation is approximately 1.5 hours. 
 
The MRI schedule is summarized in the table below. The baseline study will be done before 
treatment. The first follow-up (F/U-1) is after week-4 chemo infusion. If the subject showing 
greater than 10% tumor size shrinkage, she will receive second follow-up (F/U-2) at week-12 
after completing this protocol. If the tumor in F/U-1 is showing less than 10% reduction, the 
F/U-2 will be done after week-8 chemo infusion, and F/U-3 done at week-12 after 
completing this protocol. After completing the 12 weeks treatment the doctors may decide to 
give the subject additional chemotherapy using standard of care protocol, then she will 
receive another F/U after completing all treatment before surgery.  
 
 
 
Week-4 
 
 
Week-8 
Week-12 
if 
given 
more 
therapy 
 
 
 
 
 
<10% size  
  F/U-2  
  F/U-3  
   F/U-4 
Baseline 
F/U-1  
 reduction 
MRI 
MRI 
 
 
 
 
 
 
 
>10% size 
 
 
  F/U-2  
   F/U-3 
 
 
 
 
  reduction 

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6.3 Treatment: Weekly Carboplatin/Nab-Paclitaxel, (and Trastuzumab in HER2+ BC, 
Bevacizumab in HER2- BC).  
 
Agent 
Dose 
Route 
Days Interval 
Nab-paclitaxel*** 
90 mg/m2 
IV over 30 min.    
1 
weekly 12 doses 
Carboplatin 
AUC 2 
IV over 60 min. 
1 
weekly 12 doses 
 
Trastuzumab (for 
HER2+) 
4mg/kg induction, 
followed by weekly 
2mg/kg 
IV-induction over 
90 min., then 
weekly over 30-60 
min.                
1 
weekly 12 doses          
 
Bevacizumab (for 
HER2-) 
            
10mg/Kg    
IV over 90 or 60 or 
30 min.  
1 
Every other week for 5 
doses 
   
*** Nab-paclitaxel must be administered prior to Carboplatin 
 
1. Dosing of Carboplatin-The dose of Carboplatin will be calculated to reach a target area 
under the curve (AUC) of concentration x time according to the Calvert formula using an 
estimated glomerular filtration rate (GFR) from the Cockcroft & Goult formula. 
 
GFR+ 0.85 [(140-age) x Ideal Body Weight (Kg)] 
               72 x Serum Creatinine   
Carboplatin Dose = Target AUC x (GFR + 25) 
GFR will be capped at 125 
 
2. BSA will be capped at 2.2m2 for Nab-paclitaxel dosing. 
 
3. Actual body weight will be used for Trastuzumab and Bevacizumab dosing. 
 
4. Suggested pre-medications 
a. Antiemetic-Zofran 16 mg IV or PO 
b. Diphenhydramine 25mg PO or IV 
c. Acetaminophen 650mg PO prior to Trastuzumab 
d. Dexamethasone 10mg IVPB 
 
6.4 Response Assessment 
Patients will have the primary disease site evaluated after every 4 weeks at minimum 
physical examination documentation, and any clinically indicated x-rays and scans for tumor 
measurement every 4 weeks (see sections 8, Study Calendar). 
 
6.5 Surgery 
Post-chemotherapy surgery for patients with a response or stable disease must take place no 
sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab 
to allow for normalization of blood counts.   
 

Page 13 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
Patients who progress will be removed from protocol treatment.  Patients who have 
unresectable disease at the completion of chemotherapy will be taken off the study. Further 
treatment (radiation or additional chemotherapy) is allowed and will be per the treating 
physician’s discretion.  
 
6.6 Criteria for Removal from Protocol Treatment: 
a. Progression of disease (as defined in Section 10.3). 
b. Delay of treatment for more than 3 weeks for hematologic toxicity or more than 2 
weeks for other toxicity. 
c. Unacceptable toxicity. 
d. Completion of planned treatment. 
e. The patient may withdraw from the study at any time for any reason. 
f.  Unresectability of the breast cancer  
 
6.7 All patients will be followed for five years or until death, whichever occurs first. 
 
7 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
7.1 This study will utilize the CTC (NCI Common Toxicity Criteria) Version 3.0 for toxicity 
and Adverse Event reporting.  A copy of the CTC Version 3.0 can be downloaded from 
the CTEP home page (http://ctep.cancer.gov). 
 
7.2 Dose Modifications for Nab-paclitaxel/carboplatin – Chemo will be on hold if the 
following criteria are not met.   
 
a. Hematologic:  If ANC < 1,000 or platelets < 75,000, therapy will be withheld until 
ANC ≥1,000 or platelets ≥75,000. 
Remaining doses will be treated according to the physician judgment (i.e. dose 
reduction and/or use of Colon Stimulating Growth Factors). 
  
b. Hepatic:  Patients with Grade 4 hepatic toxicity will have nab- paclitaxel/carboplatin 
treatment held until toxicity recovers to ≤ Grade 2. 
 
c. Stomatitis:  If Grade 3 or 4 stomatitis occurs, hold  carboplatin/paclitaxel until 
recover to Grade ≤ 1, and then resume at 25% dose reduction for this and subsequent 
cycles.   
 
d. Peripheral neuropathy (nab-paclitaxel only):  Patients who experience ≥ Grade 3 
peripheral neuropathy should have their nab-paclitaxel dose held for one week.  If the 
peripheral neuropathy has improved by the next week, resume at full dose.  If the 
peripheral neuropathy is not improved, hold dose another week then resume with a 
reduction of 25% for this and subsequent cycles. 
 
e. Proteinuria (Bevacizumab) Hold if Spot Urine Protein/Creatinine is greater than 3.5.  
 
f. HTN (Bevacizumab): Patients will be treated with antihypertensive medicines at the 
physicians’ discretion.  Hold if BP> 150/90. 
 

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Created by RMehta   10/02/14  Neoadjuvant 
 
g. g . Other (for both carboplatin and nab-paclitaxel):  If toxicities are ≤ Grade 2, 
manage symptomatically, if possible, and treat without dose reduction.  If toxicities 
are > Grade 2, treatment should be withheld (except for anemia) until recover to ≤ 
Grade 1 (or baseline, if baseline was > Grade 1). 
 
h. All held doses will be made up at the end of the treatment.  Bevacizumab and 
Trastuzumab are given even if chemotherapy is held.   
 
i. For treatment or dose modification related questions, please contact Dr. Rita Mehta at 
714-456-2239 or pager 714-506-6174. 
 
j. Unexpected or fatal toxicities (included suspected reactions) must be reported to the 
IRB.  The procedure for reporting adverse reactions is outlined in Section 11.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Created by RMehta   10/02/14    Neoadjuvant      Page 15 of 32 
8 
STUDY CALENDAR “A Phase II Study of Breast Cancer Treatment Using Weekly Carboplatin/Nab-Paclitaxel, Plus Trastuzumab (HER2+) or 
Bevacizumab (HER2-) in the Neoadjuvant Setting”. 
REQUIRED STUDIES 
Pre-
Study 1 
Wk
1 
Wk
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk  
9 
Wk 
10 
Wk 
11 
Wk 
12 
F/U9 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & Physical Exam 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessment2 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Toxicity Notation 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
CBC, platelets, differential 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Comprehensive Metabolic Panel 3 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Spot Urine Protein, Spot urine 
Creatinine (Avastin patients only. 
Week prior to scheduled Avastin) 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X-RAYS AND SCANS8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Breast mammogram, breast 
ultrasound, for disease assessment 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
MRI breast  
X 
 
 
 
X6 
 
 
 
X6 
 
 
 
 
X 
PET/CT 
X5 
 
 
 
 
 
X 
 
 
 
 
 
 
X5 
Bone scan 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT (See Section 6.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nab-paclitaxel-Abraxane 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Carboplatin 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Trastuzumab/Herceptin (HER2+) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bevacizumab/Avastin (HER2-) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
                                                 
1 Pre-entry exams and procedures must be performed within 90 days prior to registration.   
2 A detailed description of the primary tumor, including results of physical exam or results of imaging studies. 
3 Comprehensive Metabolic Panel to include: Serum Creatinine, Bilirubin, SGOT or SGPT. 
4 MUGA or echocardiogram is encouraged prestudy and at the completion of chemotherapy.  MUGA or echocardiogram will be obtained prestudy for patients with hypertension or age > 60 years. 
5 These tests are encouraged prestudy, week 6, and post study. 
6 See protocol section 6.2. 
7 If clinically indicated. 
8 Suggested week scheduling listed for x-rays and scans 
9 Pre-surgery 

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Created by RMehta   10/02/14    Neoadjuvant      Page 16 of 32 
 
9 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
9.1 Definitions 
 
a. Inflammatory Disease:  Erythema AND peau d’orange involving 1/3 or more of 
the breast with a histological diagnosis of breast cancer.  The findings of focal 
dermal lymphatic involvement on histology does not constitute inflammatory 
breast cancer. 
 
b. Microscopic path CR (pCR):  No evidence of microscopic invasive tumor at the 
primary tumor site in the surgical specimen. 
 
c. Clinical CR: Normal breast on physical exam.  No mass, no thickening, no 
erythema, no peau d’orange. 
 
d. Progression of disease: A new lesion or a greater than or equal to 25% increase 
in the product of the largest perpendicular diameters of any one lesion on clinical 
exam or by U/S or MRI 
 
e. Performance Status:  Patients will be graded according to the Zubrod 
performance status scale. 
 
POINT 
 
DESCRIPTION 
 
 
 
 
 
 
 
 
0 
Full active, able to carry on all pre-disease performance 
without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or secondary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out 
any work activities; up and about more than 50% of waking 
hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
9.2 Time to Progression:  From date of registration to date of first documentation of 
progressive disease defined as: clear increase in disease sites present at registration, or 
development of new sites of disease.   

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Created by RMehta   10/02/14  Neoadjuvant 
 
 
9.3 Survival:  From date of registration to date of death. 
 
9.4 Breast Cancer Specific Survival: From date of registration to date of death from breast 
cancer. Patient who die of other causes will be censored at the time of last contact. 
 
10 STATISTICAL CONSIDERATIONS 
 
The primary endpoint will be the 2-year progression free survival with the nab-TCB/Nab-TCH 
regimen in the adjuvant setting. Secondary endpoints will be clinical complete response, 
pathologic complete response rates, and the toxicity of the combinations in HER2 positive and 
HER2 negative breast cancer will be secondary endpoints. 
 
This is a non-randomized study with two treatment arms. Clinical and demographic 
characteristics of the patients in each treatment arm will be described including frequency counts 
for categorical variables and mean, median and standard deviation for continuous variables.  
Transformations will be considered for continuous variables that are not normally distributed. 
Progression-free survival and the proportion of patients with pathologic complete response 
(pCR) and clinical complete response will be determined. Two-year progression free survival 
will analyzed using the Kaplan-Meier method for the full cohort of patients and for each 
treatment group. In addition, treatment groups will be compared with regard to the estimated 
censoring distribution due to early treatment termination using the Kaplan-Meier method. Cox 
proportional-hazards analysis will be used to derive the hazard ratio and 95% confidence interval 
between the two treatment arms, adjusted for clinical and demographic variables. The ninety-five 
percent confidence interval (CI) for each proportion will be computed. Let p1=proportion of 
Her2- patients treated with Carboplatin+Nab-paclitaxel plus Bevacizumab who achieve pCr and 
let p2=proportion Her2+ patients treated with Carboplatin+Nab-paclitaxel plus Trastuzumab who 
achieve pCr. The two-sample test of binomial proportions will be applied to the null hypothesis 
that p1= p2. Exploratory analyses will include application of log-binomial regression to assess the 
rates of pathologic and clinical complete response for the two treatment groups, adjusted for 
clinical and demographic measures and interaction terms.  Because different treatments are given 
to subgroups of Her2- and Her2+ patients, it will not be possible to estimate the independent 
effect of treatment on response outcomes. The frequency of toxicities will be recorded.  
 
Patients will be invited to participate in an MRI study, funded by NCI CA 127927, entitled “Prediction 
of Neoadjuvant Chemo Pathological Response Using MRI Markers”. The objective is to investigate the 
role of MRI in monitoring and predicting the final pathological response. Three aims are proposed.  The 
power analysis was performed for these aims. 
 
Aim 1:  Develop quantitative analysis methods to obtain pre-treatment tumor characteristic 
morphological, enhancement kinetic, and Choline metabolic parameters in breast cancer. 
Select an optimal set of features using the logistic regression analysis and the Artificial 
Neural Network (ANN) to predict pathologic complete remission (pCR) in HER-2 
positive and negative arm. 

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Created by RMehta   10/02/14  Neoadjuvant 
 
Aim 2: Investigate whether the early response patterns, analyzed using the percent tumor size 
changes, or changes in other lesion characteristic parameters, can be used to predict 
pathologic complete remission (pCR) in HER-2 positive and negative arm. 
Aim 3: Investigate whether combining the pre-treatment tumor characteristic parameters, and 
the early response pattern during the treatment course, can achieve a higher AUC (area 
under the ROC curve) in prediction of pCR than those based on pre-treatment MRI 
characteristics or tumor response patterns alone. 
 
The role of MRI in monitoring and predicting the final pathological response will be 
investigated. In brief, artificial neural network (ANN) analysis will be applied to differentiate 
between pCR and non-pCR subjects with jackknife leave-one-out cross validation. After the 
selection, ANN models will be built to test the discriminative ability of morphologic/texture, 
kinetic, and combined features. Since patient age and tumor grade are likely confounding factors, 
they will be included in the input parameters. The receiver operating characteristic (ROC) curve 
of the classifier will be recorded. The area under the ROC curve (AUC) will used to evaluate 
classification performance. For comparison to results by ANN, statistical methods for variable 
reduction and logistic regression modeling also will be applied to avoid including correlated 
predictors and overfitting. Transformations will be considered for variables that exhibit 
departures from normality. The objective is to find parameters in pre-treatment biomarker data 
category to differentiate between pCR and non-pCR. A final set of parameters that can achieve 
the highest accuracy in differentiating between pCR and non-pCR within each treatment arm will 
be identified. The area under the ROC curve achieved by using each data category alone and 
combined will be compared to test the hypothesis that combining all 3 data categories can 
achieve a higher accuracy in prediction of pCR than using either set of data alone. Models 
selected by ANN and by logistic regression will be compared with regard to sensitivity, 
specificity, positive and negative predictive value, and AUC. 
 
10.1 Sample Size Considerations  
Eligible patients will be patients who do not have metastatic disease at presentation. 
 
Many times patients sign consent before all studies are complete given we have to submit to 
insurance in parallel, so as not to prolong pretreatment time. This means some patients have 
metastatic disease found either by scans or later on biopsy. These patients are not eligible. 
 
Eligible patients will be patients who received all protocol drugs and complete at least one cycle. 
Many patients sign consent, but the drugs get denied by insurance, these patients will not be 
eligible for study. 
 
Some patients choose alternative Rx after signing consent these patients will not be eligible 
 
Since it is difficult to recruit patients who meet the criteria for neoadjuvant chemotherapy, the 
total subject number is limited. According to the previous recruitment rate, we expect that we 
will be able to enroll 120 patients during 4.5 years, 48 positive HER-2 patients and 72 negative 
HER-2 patients.  
 
Power analyses for evaluation of progression-free survival and pCr 

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Created by RMehta   10/02/14  Neoadjuvant 
 
The first study component is to evaluate progression-free survival and the response of patients 
receiving Carboplatin+Na-paclitaxel, plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in 
the neoadjuvant setting. Sample size calculations were performed to assess the power of a one-
sample test for survival probability assuming an exponential distribution (Lawless, J. Statistical 
Models and Methods for Lifetime Data, John Wiley and Sons, 1982). The computer program 
provided by the Southwest Oncology Group for one arm survival sample size was utilized, 
http://www.swogstat.org/stat/public/one_survival.htm. An 85% progression-free survival on a 
similar patient population in the adjuvant setting has been reported with use of AC-based 
regimen. Empirically, a disease-free survival of approximately 78% would be unacceptable. As 
shown in the table, assuming an accrual of 48 months, a follow-up time of 36 month, the two-
sided test of significance with an alternative survival probability of 0.85 has 95% power to detect 
a difference from the null survival rate of 0.76. 
 
Null survival probability 
Alternative survival probability 
Power 
0.76 
0.85 
0.95 
0.77 
0.85 
0.91 
0.78 
0.85 
0.82 
0.79 
0.85 
0.71 
 
Based on previous results, it is expected that 75% of patients in the positive HER-2 arm will 
achieve pCR (i.e. 36 pCR and 12 non-pCR), compared to 42% of patients in the negative HER-2 
arm (30 pCR and 42 non-pCR). Response rates will be compared between the two treatment 
groups using a 2-sided test of proportions. Let p1=proportion of Her2- patients treated with 
Carboplatin+Nab-paclitaxel plus Bevacizumab who achieve pCr and let p2=proportion Her2+ 
patients treated with Carboplatin+Nab-paclitaxel plus Trastuzumab who achieve pCr. We will 
test the null hypothesis that p1=p2 versus the alternative that p1≠p2. Based on previous results, we 
expect the ratio of Her2- to Her2+ to be 1.5, and that 75% of patients in the Her2+ arm will 
achieve pCR (i.e. 36 pCR and 12 non-pCR), compared to 42% of patients in the Her2- arm (30 
pCR and 42 non-pCR). PASS was used for sample size calculations. Under these assumptions, at 
a 5% significance level there is 96% power to detect a difference of 0.33 between the proportions 
of patients in the two treatment groups achieving pCR. 
 
The 2nd study component is to investigate the role of Magnetic Resonance Imaging (MRI) to 
monitor and predict the final pathological response. 
 
Power analysis for Aim-1, predicting pCR using the pre-treatment lesion MRI characteristics  
In a previous study we performed logistic regression modeling to find optimal parameters for 
predicting response to AC treatment based on pre-treatment MRI morphological and kinetics 
parameters. For analysis of data from 33 patients, 17 responders and 16 non-responders, the area 
under the ROC curve was 0.76 using one morphologic predictor, roughness, compared to 0.84 
using one LAWS’ texture feature. The AUC for the predictive model including both parameters 
was 0.91. To address AIM-1, power calculations were performed for comparison of an 
hypothesized area under a receiver operating characteristic (ROC) curve to a null value of 0.50. 
Calculations were based on a 1-sided asymptotic z-test with significance level of 0.05 using the 
macro ROCPOWER.SAS (SAS 9.1 SAS, Cary, NC). The table 1 gives the power to compare an 
alternative AUC of 0.75 for various proportions of patients achieving pathologic complete 

Page 20 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
remission, i.e. pCR is the “event”. Based on our preliminary results, an alternative AUC of 0.75 
is achievable with only one predictor in the model.  
 
For example, with the expected enrollment of 48 positive HER-2 patients, of whom 36 of 48 
achieve pathologic complete remission, the power for a 1-tailed test is 0.88 for comparing an 
AUC of 0.75 to the null of 0.50. Higher power is achieved as the proportion of patients achieving 
pCR approaches 50% of the total enrolled with positive HER-2. Similarly, the expected 
enrollment of 72 negative HER-2 patients, of whom 30 of 72 achieve pathologic complete 
remission, the power is 0.99 to compare an improved AUC of 0.75, to a null AUC of 0.50 
 
Table 1: power analysis for comparison of an hypothesized area under ROC to a null value of 0.50 
 
 
 
Power analysis for Aim-3, improved pCR prediction by adding tumor size response 
patterns to the pre-treatment lesion MRI characteristics: 
To address aim 3, power calculations were performed for comparison of the area under 
paired ROC curves assuming an average correlation between the two AUCs of 0.80. Power 
calculations were based on asymptotic 1-tailed z-tests with significance level of 0.05 using the 
macro ROCPOWER.SAS (SAS 9.1 SAS, Cary, NC). The table 2 gives the power to compare the 
AUC for paired ROCs for various proportions of patients achieving pathologic complete 
remission. For example, with the expected enrollment of 48 positive HER-2 patients, of whom 
36 of 48 achieve pathologic complete remission, the power for a 2-sided test is 0.83 to detect a 
significant difference in AUCs, assuming an AUC of 0.75 compared to that of 0.90. Similarly, 
the expected enrollment of 72 negative HER-2 patients, of whom 30 of 72 achieve pathologic 
complete remission, the power is 0.97 to detect a significant difference in AUCs assuming an 
AUC of 0.9 compared to an AUC of 0.75. 
 
Table 2: power calculations for comparison of the area under paired ROC curves between 
two AUCs of 0.80 
 

Page 21 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
 
 
 
11.0  ETHICAL AND REGULATORY CONSIDERATIONS 
 
11.1 The following must be observed to comply with Food and Drug Administration 
regulations for the conduct and monitoring of clinical investigations; they also represent 
sound research practice: 
 
a. Informed Consent. The principles of informed consent are described by Federal 
Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and 
the Office for Protection from Research Risk Reports: Protection of Human Subjects 
(Code of Federal Regulations 45 CFR 46).  They must be followed to comply with FDA 
regulations for the conduct and monitoring of clinical investigations. 
 
b. Institutional Review  This study must be approved by an appropriate institutional 
review committee as defined by Federal Regulatory Guidelines (Ref. Federal Register 
Vol. 46, No. 17, January 27, 1981, part 56) and the Office for Protection of Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). 
 
11.2  Adverse events will be reported according to the following guidelines from the 
UCIrvine Office of Research Human Research Protections Program 
(http://www.rgs.uci.edu/ora/rp/hrpp/adverseexperiences.htm). 
Researcher Responsibility to Report Adverse 
Events/Unanticipated Problems Involving Risk to 
Participants or Others/Protocol Violations 

Page 22 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
Federal regulations require that UCI have written procedures for ensuring prompt reporting 
of unanticipated problems involving risk to subjects or others to the IRB, appropriate UCI 
officials, the funding agency or study sponsors, and federal department or agency heads 
including the Office of Human Research Protections (OHRP), the Food and Drug 
Administration (FDA), when applicable. Per UCI IRB policy the following events or problems 
must be reported to the UCI IRB within the specified timeframe via the electronic Adverse 
Events/Unanticipated Problems (AE/UP) reporting process. 
The IRB will review the AE/UP report in a timely manner and determine whether the 
reported event is an unanticipated problem involving risk to participants or others 
(hereinafter referred to as unanticipated problems). Unanticipated problems will be reported 
to the appropriate entities per UCI IRB policy. 
Reportable Events/Problems 
Report any event/problem listed below to the IRB within the specified 
timeframe  
1 
Any unexpected, internal adverse events or external adverse events that occur 
anytime during the conduct of the research study or during the follow-up 
period after the research, which in the opinion of the UCI Investigator includes 
the following components: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the IRB-approved 
documents, such as the protocol and informed consent document; and 
(b) the characteristics of the subject population being studied;  
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or problem may have been caused by the procedures 
involved in the research); and  
3. Suggests that the research places subjects at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.  
Report within 10 working days of the researcher becoming aware of the event. 
2 
Any internal, serious adverse event that is,  
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the IRB-approved 
documents, such as the protocol and informed consent document; and 
(b) the characteristics of the subject population being studied; and  
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or problem may have been caused by the procedures 
involved in the research).  
Report within 5 working days of the researcher becoming aware of the event. 
3 Any external adverse event that occurs anytime during the conduct of the 
research study or during the follow-up period after the research, which in the 

Page 23 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
opinion of the UCI Investigator: 
1. changes the study’s risk/benefit profile; and/or  
2. necessitates submission of an e-MOD request to revise the IRB-
approved consent document(s) and/or the IRB-approved protocol.  
Report within 10 working days of the researcher becoming aware of the event. 
4 
An event/problem that affects the safety and welfare of subjects and requires 
prompt reporting to the sponsor.  
Report within 10 working days of the researcher becoming aware of the event. 
5 
Any permanent or temporary hold on some or all research activities. 
Report within 10 working days of the researcher becoming aware of the event. 
6 
Early termination of the study due to a change in the risk/benefit profile. 
Report within 10 working days of the researcher becoming aware of the event. 
7 
Any change in FDA safety labeling or withdrawal from marketing of a drug, 
device, or biologic used in an IRB approved research study due to adverse 
events or unanticipated problems. 
Report within 10 working days of the researcher becoming aware of the event. 
8 
Protocol Violations 
Report within 5 working days of the researcher becoming aware of the event. 
9 
Any change to the IRB-approved protocol conducted without prior IRB 
approval to eliminate an apparent immediate hazard to a research subject. 
Report within 5 working days of the researcher becoming aware of the event. 
10 
Any publication in the literature, any safety monitoring reports, interim 
results, or other reports that indicates an unexpected change to the 
risk/benefit profile of the research. 
Report within 10 working days of the researcher becoming aware of the event. 
11 
Any breach in confidentiality that caused harm or places subjects or others at 
a greater risk of harm (including physical, psychological, economic, or social 
harm). 
Report within 10 working days of the researcher becoming aware of the event. 
12 
Any complaint by a subject that indicates an unexpected risk or which cannot 
be resolved by the UCI Investigator. 
Report within 10 working days of the researcher becoming aware of the event. 
13 Other event/problem that involved subjects or others and which in the opinion 

Page 24 of 32 
Created by RMehta   10/02/14  Neoadjuvant 
 
of the UCI Investigator includes the following three components: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the IRB-approved 
documents, such as the protocol and informed consent document; and 
(b) the characteristics of the subject population being studied;  
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and  
3. Suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.  
Report within 5 working days of the researcher becoming aware of the event. 
The IRB will accept other reports when Investigators are unsure whether the 
event/problem should be reported.  
NOTE: 
1. When changes to the IRB-approved documents (e.g., protocol narrative, informed 
consent form) are necessary, the Researcher must submit an electronic Modification 
(e-MOD) Request. Please reference the e-AE/UP number when submitting the 
e-MOD request.  
2. Reasonable judgment must be used when determining what constitutes a reportable 
event, experience, or problem. Researchers must consider the psychological, 
emotional, economic and social harms, not merely physical harms. When in doubt, it 
is best to err on the side of reporting the event or contacting the HRP staff for 
guidance.  
3. A follow-up report is required to be submitted via the e-AE/UP process if the AE is 
not resolved as expected or if the AE results in a chronic condition or death.  
Adverse Events 
Adverse events are untoward or undesirable experiences associated with research, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, 
or disease, temporally associated with the subject’s participation in the research, whether or 
not considered related to the subject’s participation in the research. 
Adverse events may be the result of: 
• 
the interventions and interactions used in the research,  
• 
the collection of identifiable private information in the research,  
• 
an underlying disease, disorder, or condition of the subject, and/or  
• 
other circumstances unrelated to the research.  
Most adverse events are not reportable to the IRB. The majority of adverse events 
that occur in the context of research are expected: (1) the known toxicities and side effects 

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Created by RMehta   10/02/14  Neoadjuvant 
 
of the research procedures; (2) the expected natural progression of the subjects’ underlying 
diseases, disorders, and conditions; and (3) subjects’ predisposing risk factor profiles for 
adverse events. 
UNEXPECTED ADVERSE EVENT: Any adverse event occurring in one or more 
subjects in a research protocol, the nature, severity, or frequency of which is not 
consistent with either:  
• 
the known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the IRB-approved documents 
(e.g., applicable investigator brochure, current protocol narrative, current 
informed consent document), and (b) other relevant sources of information, 
such as product labeling and package inserts; or  
• 
the expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the adverse event and the subject’s 
predisposing risk factor profile for the adverse event.  
Unexpected adverse events as defined above are reportable to the IRB via the e-AE/UP 
process if in the opinion of the UCI Researcher, the event is related to the research 
procedures. That is, if the event could at least possibly be caused by the research activities, 
and suggests that the research places the subjects at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
See the List of Reportable Events/Problems. 
SERIOUS ADVERSE EVENT: is any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria: 
• 
results in death, #  
• 
is life-threatening situation,  
• 
requires inpatient hospitalization or prolongation of existing hospitalization,  
• 
results in persistent or significant disability/incapacity,  
• 
results in a congenital anomaly/birth defect,  
• 
any other adverse events based upon the Researcher’s medical judgment, that 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition.  
Serious adverse events as defined above are reportable to the IRB via the e-AE/UP process 
if in the opinion of the UCI Researcher, the event is “unexpected” and “related” to the 
research procedures. See the list of Reportable Events/Problems. Note the following 
exception: 
# Clinical Investigations exception: All internal, serious adverse events resulting in death 
that, in the judgment of the UCI Investigator, appear unrelated to the research procedures 
must still be reported to the IRB via the Internal Unrelated SAE Summary Log at the time of 
Continuing Review. 

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Protocol Violations 
PROTOCOL VIOLATION: Accidental or unintentional change to, or non-compliance 
with the IRB approved protocol without prior sponsor and IRB approval. Violations 
generally increase risk or decrease benefit, affects the subject's rights, safety, or 
welfare, or the integrity of the data.  
Protocol Violations are reportable events and must be submitted to the IRB via the 
e-AE/UP reporting process within 5 working days of the researcher becoming 
aware of the event. See the list of Reportable Events/Problems. 
Examples of protocol violations: 
1. Failure to obtain valid informed consent (e.g., obtained verbal consent when IRB 
requires signed informed consent)  
2. Loss of laptop computer that contained identifiable, private information about 
subjects  
3. Accidental distribution of incorrect study medication  
Protocol Deviations 
PROTOCOL DEVIATION: Accidental or unintentional changes to, or non-compliance 
with the research protocol that does not increase risk or decrease benefit or; does 
not have a significant effect on the subject's rights, safety or welfare; and/or on 
the integrity of the data. Deviations may result from the action of the subject, 
researcher, or research staff.  
A deviation may be due to the research subject’s non-adherence, or an unintentional 
change to or non-compliance with the research protocol on the part of a researcher. 
Examples of a deviation include:  
1. A rescheduled study visit  
2. Failure to collect an ancillary self-report questionnaire  
3. Subject’s refusal to complete scheduled research activities  
Deviations are NOT reportable to the IRB. Investigators may report deviations to the 
Human Research Protections (HRP) staff by submitting the Tracking Log for Non-reportable 
Events. The HRP staff will confirm that the event does not qualify as a reportable event and 
send an acknowledgment to the researcher. If the event/problem is determined to be 
reportable, the Lead Researcher will be required to submit an e-AE/UP report. 
It is the responsibility of the Lead Researcher to ensure that all research staff involved in 
the conduct of the research follows the IRB-approved research protocol. When modifications 
are necessary, an e-MOD request should be submitted to the IRB for review and approval 
prior to implementation of the changes.  

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Safety Reports/External Adverse Events 
Safety Report (SR) alerts are issued by the FDA or the study sponsor to inform all 
researchers using the same pharmacological compound about serious adverse events or 
reactions that have occurred in patients/subjects. These events, considered external 
adverse events, may occur on the same clinical investigation being conducted by a UCI 
investigator, or more often these SR events occur on different clinical investigation using 
the same pharmacological compound as the UCI investigator.  
It is the UCI Investigator’s responsibility to ensure that each external adverse event is 
reviewed to determine whether the event is reportable to the IRB. External adverse events 
should be submitted to the IRB within the 10 working day timeframe if in the opinion of the 
UCI researcher the event is: [See 1 and 3 on the List of Reportable Events or Problems] 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the IRB-approved documents; and (b) the 
characteristics of the subject population being studied;  
• 
At least possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or problem may have been caused 
by the procedures involved in the research); and  
• 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
OR the event: 
• 
changes the study’s risk/benefit profile; and/or  
• 
necessitates submission of an e-MOD request to revise the IRB-approved consent 
document(s) and/or the IRB-approved protocol.  
Safety Reports that do not meet the 10 working day reporting timeframe are NOT 
reportable to the IRB. The researcher should initial and date the Safety Report and file 
with research documentation.  
Reporting Methods and Timeframes 
The following are types of events/problems require reporting to the IRB. If the 
event/problem does not fit the categories, the event is not reportable to the IRB; however 
may be reportable to the sponsor. Please notify the IRB within the specified reporting 
timeframe, followed by follow-up reports, as required.  
Type of Event/Problem 
Reporting 
Timeframe 
Reporting 
Method 
Any 
• 
internal, serious adverse event,  
5 working days 
e-AE/UP report 

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• 
protocol violation,  
• 
change to the protocol without prior IRB 
approval to eliminate an apparent 
immediate hazard to a research subject 
[see # 9]  
• 
other event/problem involving subjects 
or others tht is unexpected, related or 
possibly related to the research, and 
caused harm to others or places others 
at a greater risk of harm as a result of 
the research [see # 13]  
Any other event/problem described in the 
list of Reportable Events/ Problems 
10 working days 
e-AE/UP report 
Any external adverse event described in 
the list of Reportable Events/ Problems 
(e.g., Safety Report) 
1. 10 working 
days if event 
constitutes a 
reportable 
event [see # 1 
and 3 on the 
list]  
2. If not on list, 
reporting NOT 
required  
1. e-AE/UP 
report  
2. none  
Any protocol deviation 
1. Reporting NOT 
required  
2. Researchers 
may report 
deviation to 
HRP staff  
1. none  
2. Tracking 
Log for 
Non-
reportable 
Events  
Any 
internal, 
unrelated 
death 
as 
determined 
by 
UCI 
Investigator 
[REQUIRED 
FOR 
CLINICAL 
INVESTIGATIONS ONLY] 
At time of Continuing 
Review 
Internal Unrelated 
SAE Summary Log 
Important Notes when completing e-AE/UP report: 
1. In order to maintain the subject's privacy, please do not include any names 
and/or other personal identifiers in the report and remember to remove all 
identifiable, private information from any supporting documentation you provide the 
IRB.  
2. If the event/problem requires submission of an e-MOD request, please remember to 
submit a highlighted or underlined version of the revised document(s).  

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3. If an internal event/problem is unresolved at the time of initial reporting, a follow-up 
report is required to be submitted via the e-AE/UP process if the AE is not resolved 
as expected or if the AE results in a chronic condition or death.  
Reporting DSMB Interim Reports to the IRB 
The Lead Researcher is expected to review any Data and Safety Monitoring interim report 
and determine whether the report indicates a change in the risk/benefit profile. If the report 
indicates a change in the risk/benefit profile, an e-AE/UP report should be submitted [see 
#10 on the list of Reportable Events/Problems] to the IRB along with an e-MOD request. Be 
sure to reference the e-AE/UP number when submitting the e-MOD request. If there is no 
change in the risk/benefit profile, the DSMB report should be submitted along with the 
Summary Log, if applicable, at the time of continuing review.  
IRB Actions Regarding Unanticipated Problems Involving 
Risk to Participants or Others 
The IRB will review e-AE/UP reports in a timely manner and determine whether the reported 
event represents an unanticipated problem involving risk to participants or others. The IRB 
may take the following actions: 
• 
Accept the report with no changes;  
• 
Accept the report with changes to the risk/benefit ratio, the protocol, or the informed 
consent documents (submission of e-MOD Request required);  
• 
Request re-consenting of participants or require notification to current and past 
participants of the changes (the changes must be reviewed by the IRB prior to 
notification);  
• 
Request further information from the researcher or DSMB;  
• 
Increase the frequency of continuing review;  
• 
Impose additional monitoring requirements;  
• 
Require additional training of the researcher and research team;  
• 
Require notification of researchers at other sites; or  
• 
Request “Administrative Hold” pending receipt of further information.  
The IRB will report any unanticipated problems involving risk to participants or others to the 
Lead Researcher, appropriate UCI officials, the funding agency or study sponsor, if 
applicable, the Office of Human Research Protections, and other applicable regulatory 
authorities. 
IRB Authority to Suspend or Terminate Approval 
The IRB also has the authority to suspend or terminate approval of research that has been 
associated with unexpected serious harm to participants. When an IRB Committee takes 
such action, it is required to provide a statement of reason for the action and to promptly 
report this action to the Lead Researcher, Department Chair or School Dean, and other UCI 
officials, the funding agency or study sponsor, if applicable, the Office of Human Research 
Protections, and possibly other regulatory authorities.  

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Serious Adverse Event Reporting Requirements for Human 
Gene Transfer Research 
Lead Researchers of human gene transfer (a.k.a. "gene therapy") protocols have extra 
adverse event reporting responsibilities. In addition to submitting AE/UP reports to the UCI 
IRB, they also must complete and submit the NIH Office of Biotechnology Activities' (OBA) 
Serious Adverse Event report form when a subject on a gene transfer protocol experiences a 
hospitalization or a death. If the gene transfer study is supported by an external sponsor, 
this reporting should be coordinated with the sponsor.  
Failure to report gene transfer SAEs to the federal oversight bodies (FDA, NIH-OBA) may 
result in sanctions for the individual researcher and for the institution. For more information 
regarding the additional AE reporting responsibilities for human gene transfer research, 
please contact a UCI biomedical IRB Administrator.  
Serious Adverse Events or Unanticipated Problems Involving 
Risk to Participants or Others Related to a Humanitarian Use 
Device (HUD) 
Whenever the physician or health care provider receives or otherwise becomes aware of 
information, from any source, that reasonably suggests that a HUD has or may have caused 
or contributed to the death or serious injury of a patient, the physician or health care 
provider must report such findings to the FDA and the IRB as soon as possible, but no later 
than 5 working days after the physician first learns of the event/problem. This reporting is 
in addition to, not a substitute for, FDA and/or manufacturer reporting requirements in 
accordance with 21 CFR 803.30.  
The physician or health care provider must promptly report any FDA action regarding the 
death or serious injury to the patient to the IRB.  
11.2  Sponsorship: An NIH/NCI R01 CA127927 grant has been submitted for the data 
management of this trial.  If funding is obtained, sponsors’ adverse event report 
guidelines will also be followed.   
 
11.3  Early Termination:  Patients may be discontinued from participating in the study prior 
to completion of study requirement for any of the following reasons: 
1. The patient has a clinically significant adverse event as determined by the Principal 
Investigator. 
2. The patient requests to be withdrawn from the study. 
3. The patient fails to comply with the requirements for study evaluations and visits.  
4. Other conditions for which, in the investigator’s opinion, it is in the patient’s best 
interest to be withdrawn from the study. Patient did not meet the eligibility 
requirements. 
 
 
 

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12. BIBLIOGRAPHY 
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