Phase II Randomized Trial Evaluating Neoadjuvant Therapy With Neratinib and/or Trastuzumab Followed by Postoperative Trastuzumab in Women With Locally Advanced HER2-positive Breast Cancer

• Sponsor: NSABP Foundation Inc (Other)
• Overall Status: Completed
• CT.gov ID: NCT01008150
• Collaborator: Puma Biotechnology, Inc. (Industry)
• Enrollment: 141
• Locations: 42
• Arms: 4
• Duration (Months): 73.8
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

FB-7 is a Phase II, multi-center randomized study of neratinib in combination with weekly paclitaxel with or without trastuzumab followed by doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for women with HER2-positive locally advanced breast cancer. Patients in the control arm will receive neoadjuvant trastuzumab in combination with weekly paclitaxel followed by AC. The primary aim of the study is to determine the pathologic complete response (pCR) rate in breast and axillary nodes following the neoadjuvant therapy regimens. The secondary aims include determination of the pCR rate in breast only, clinical complete response (cCR) rate, two-year recurrence-free interval, two-year overall survival, toxicity of the neoadjuvant regimens, and exploration of molecular and genetic correlates of response.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Paclitaxel; Drug: Trastuzumab; Drug: Neratinib; Drug: Doxorubicin; Drug: Cyclophosphamide	Phase 2

Detailed Description

Sequential AC followed by a taxane initiated concurrently with trastuzumab has become a standard of care in the United States for operable HER2-positive breast cancer following initial surgery.

Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein, was developed to block HER2 signaling pathways and has been shown to substantially improve the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers.

However, some patients develop recurrence and succumb to the disease following trastuzumab-based adjuvant therapy. Evaluation of additional approaches that target this pathway have shown promising results in trastuzumab-resistant breast cancer.

Neratinib (HKI-272), an orally administered small molecule, is an irreversible inhibitor of pan ErbB receptor tyrosine kinases, which distinguishes this small molecule from lapatinib. Because of the high degree of homology between kinase domains of EGFR and HER2, neratinib inhibits both EGFR and HER2 function. Neratinib is designed to block kinase activity by binding to the ATP site of the enzymes. In BT474 cell lines, HKI-272 effectively repressed phosphorylation of MAPK and Akt signal transduction pathways, whereas trastuzumab failed to completely inhibit HER2 receptor phosphorylation or downstream signaling events. In tumor xenografts which overexpress HER2, neratinib has been observed to repress tumor growth in a dose-dependent manner.

A comparison of overall response rates with lapatinib and neratinib in comparable patients, albeit in separate Phase II studies, suggest favorable efficacy of neratinib as monotherapy in trastuzumab-refractory patients (response rate of 5.1% vs. 26%) and in trastuzumab-naïve patients (response rate of 24% vs. 56%). Taken together, the data support the rationale that a small molecule TKI may be more efficacious than trastuzumab in the neoadjuvant setting, and that neratinib may be more active than lapatinib.

The study started as a two-arm design with randomization to the control arm (Arm 1) and to the investigational arm (Arm 2) in a 1:2 ratio. With the addition of a second investigation arm, (Arm 3), the study becomes a three-arm design with a 1:1:1 allocation ratio (about equal numbers of patients randomized to Arms 1, 2, and 3). The sample size will be up to 126 patients with about 42 evaluable patients in each arm. Patients who enter the trial but are not treated for any reason will be replaced. Accrual is expected to occur over 18 months. Patients will be randomized to one of three neoadjuvant therapy regimens: Patients in Arm 1 will receive 4 cycles of paclitaxel 80 mg/m2 administered on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab will begin concurrently with paclitaxel and will be given weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC will be administered every 21 days for 4 cycles; Patients in Arm 2 will receive 4 cycles of paclitaxel 80 mg/m2 administered on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg will be taken orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Standard AC administered every 21 days for 4 cycles will be administered following paclitaxel/neratinib therapy; Patients in Arm 3 will receive 4 cycles of paclitaxel 80 mg/m2 administered Days 1, 8, and 15 of a 28 day cycle with trastuzumab, beginning concurrently with paclitaxel, given weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg will be taken orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Standard AC will be administered every 21 days for 4 cycles following paclitaxel/trastuzumab/neratinib therapy.

In all arms, clinical response will be assessed by palpation between the chemotherapy regimens and prior to surgery. Following recovery from surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) will be administered every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy). Patients will receive adjuvant radiation therapy and endocrine therapy as clinically indicated.

At the time of local IRB approval of amendment #6, submission of fresh tumor samples for FB-7 correlative science studies will be optional for all patients. For patients who agree, a core biopsy procedure to procure three fresh tumor samples will be performed before randomization (after the patient has signed the consent form and has been screened for eligibility). Submission of a tumor block from the diagnostic core biopsy sample and a tumor block from gross residual disease greater than or equal to 1.0 cm, if found in the surgical specimen, will be required. In addition, a blood sample collected after randomization (before the start of study therapy) will also be required for the correlative science studies.

Beginning with Amendment #8, Arm 1 and Arm 2 were closed to accrual in the US subsequent to FDA approval of pertuzumab when given in combination with trastuzumab for neoadjuvant therapy in breast cancer. Pertuzumab and trastuzumab are both targeted therapy drugs. US patients enrolled in the study will not be randomized but will be placed into the combined targeted therapy group, Arm 3 NR, only. Randomization and study therapy for patients entered via institutions outside of the US remains unchanged.

Study Design

• Study Type: Interventional
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens With Weekly Paclitaxel Plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide With Postoperative Trastuzumab in Women With Locally Advanced HER2-Positive Breast Cancer
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Nov 25, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1: paclitaxel + trastuzumab then A C 4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)	Drug: Paclitaxel; Other Names: Taxol ; Drug: Trastuzumab; Other Names: Herceptin ; Drug: Doxorubicin; Other Names: Adriamycin A ; Drug: Cyclophosphamide; Other Names: C
Experimental: Arm 2: paclitaxel + neratinib then A C 4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)	Drug: Paclitaxel; Other Names: Taxol ; Drug: Neratinib; Drug: Doxorubicin; Other Names: Adriamycin A ; Drug: Cyclophosphamide; Other Names: C
Experimental: Arm 3: paclitaxel + trastuzumab + neratinib then A C 4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)	Drug: Paclitaxel; Other Names: Taxol ; Drug: Trastuzumab; Other Names: Herceptin ; Drug: Neratinib; Drug: Doxorubicin; Other Names: Adriamycin A ; Drug: Cyclophosphamide; Other Names: C
Experimental: Arm 3 NR: paclitaxel+trastuzumab+neratinib Non-randomized: 4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)	Drug: Paclitaxel; Other Names: Taxol ; Drug: Trastuzumab; Other Names: Herceptin ; Drug: Neratinib; Drug: Doxorubicin; Other Names: Adriamycin A ; Drug: Cyclophosphamide; Other Names: C

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response in Breast and Axillary Lymph Nodes. [At time of surgery, approximately 7 months]

   Number of participants with no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes after neoadjuvant chemotherapy

Secondary Outcome Measures

1. Pathologic Complete Response in Breast. [At time of surgery, approximately 7 months]

   Number of participants with by no histologic evidence of invasive tumor cells in the surgical breast specimen.

2. Clinical Complete Response, as Measured by Physical Exam [At the completion of AC prior to surgery, approximately 7 months]

   Upon physical exam the number of participants with resolution of all target and non-target lesions identified at baseline and no new lesions or other signs of disease progression.

3. Recurrence-free Interval (RFI) [2 years]

   Number of participants with no events of inoperable progressive disease and local, regional and distant recurrence.

4. Overall Survival [24 months]

   Number of participants alive at 24 months.

5. Adverse Events Experienced by Participants as a Measure of Toxicity [Assessed through 2 years from randomization]

   Number of patients with at least one adverse event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer.

• Submission of a block from the diagnostic biopsy sample and from the surgical sample, if gross residual disease greater than or equal to 1.0 cm was removed at the time of surgery, is required for all patients

• Patients of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy and for at least 6 months after the last dose of study therapy.

• The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

• Patients must have the ability to swallow oral medication.

• The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or by limited incisional biopsy.

• Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. (Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.)

• Breast cancer must be determined to be HER2-positive prior to randomization. Assays using FISH or CISH require gene amplification. Assays using IHC require a strongly positive (3+) staining score.

• Clinical staging, based on the assessment by physical exam, must be American Joint Committee on Cancer (AJCC) stage IIB, IIIA, IIIB, or IIIC: cT2 and cN1; cT3 and cN0 or cN1; Any cT and cN2 or cN3; or cT4

• The patient must have a mass in the breast or axilla measuring greater than or equal to 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required.

• At the time of randomization, blood counts performed within 4 weeks prior to randomization must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1200/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL

• The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met: total bilirubin must be less than or equal to upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and aspartate aminotransferase (AST) and ALT must be less than or equal to 1.5 x ULN for the lab.

• Patients with alkaline phosphatase greater than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET, or PET-CT scan) performed within 4 weeks prior to randomization does not demonstrate metastatic disease and the requirements for adequate hepatic function are met.

• Patients with either unexplained skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does not demonstrate metastatic disease. Patients with suspicious findings on bone scan or PET scan are eligible if suspicious findings are determined to be benign by x-ray, MRI, or biopsy.

• Serum creatinine performed within 4 weeks prior to randomization must be less than or equal to 1.5 x ULN for the lab.

• The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or multiple gated acquisition(MUGA) scan performed within 90 days prior to randomization must be greater than or equal to 50% regardless of the facility's LLN.

Exclusion Criteria:

• fine-needle aspiration (FNA) alone to diagnose the primary breast cancer.

• Excisional biopsy or lumpectomy performed prior to randomization.

• Surgical axillary staging procedure prior to randomization. (Procedures that are permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for any patient, and 2) although not recommended, a pre-neoadjuvant therapy SN biopsy for patients with clinically negative axillary nodes.)

• Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.)

• History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiation therapy (RT). (Patients with a history of LCIS are eligible.)

• Contralateral invasive breast cancer at any time. (Patients with contralateral DCIS or lobular carcinoma in situ (LCIS) are eligible.)

• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.

• Known metastatic disease from any malignancy (solid tumor or hematologic).

• Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy.

• Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.

• Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.)

• Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization.

• Active hepatitis B or hepatitis C with abnormal liver function tests.

• Intrinsic lung disease resulting in dyspnea.

• Active infection or chronic infection requiring chronic suppressive antibiotics.

• Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.

• Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

• Sensory or motor neuropathy greater than or equal to grade 2, as defined by the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0.

• Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication.

• Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

• Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with hypertension that is well-controlled on medication are eligible.)

• Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen. This includes but is not confined to: Active cardiac disease: symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis. History of cardiac disease: myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; history of documented congestive heart failure (CHF); and documented cardiomyopathy.

• Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.

• Pregnancy or lactation at the time of randomization.

• The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.

• Use of any investigational agent within 4 weeks prior to randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Medical Center	Loma Linda	California	United States	92354
2	Kaiser Permanente-San Diego	San Diego	California	United States	92120
3	CCOP - Colorado Cancer Research Program, Inc.	Denver	Colorado	United States	80224
4	Hartford Hospital	Hartford	Connecticut	United States	06102
5	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
6	St. Luke's Mountain States Tumor Institute - Boise	Boise	Idaho	United States	83712
7	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
8	Edward Cancer Center	Naperville	Illinois	United States	60540
9	Edward Cancer Center Plainfield	Plainfield	Illinois	United States	60585
10	Yorkville Family Practice	Yorkville	Illinois	United States	60560
11	St. Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
12	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
13	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
14	University of Missouri-Ellis Fischel	Columbia	Missouri	United States	65203
15	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
16	University Hospital and Medical Center - SUNY Stony Brook	Stony Brook	New York	United States	11794
17	CCOP Carolinas HealthCare System	Charlotte	North Carolina	United States	28232-2861
18	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157
19	Case Western Reserve University/University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
20	CCOP - Dayton	Dayton	Ohio	United States	45409
21	CCOP - Dayton	Kettering	Ohio	United States	45429
22	Allegheny Cancer Center at Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
23	NSABP Foundation, Inc.	Pittsburgh	Pennsylvania	United States	15212
24	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15232-1305
25	York Hospital	York	Pennsylvania	United States	17403
26	Roper Hosp & Med Asso (Care Alliance Health)	Charleston	South Carolina	United States	29401
27	Spartanburg Regional Healthcare System	Spartanburg	South Carolina	United States	29303
28	MD Anderson Cancer Center	Houston	Texas	United States	77030
29	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298
30	West Virginia University Hospitals Inc.	Morgantown	West Virginia	United States	26506
31	University of Montreal Hospital Group	Montreal	Quebec	Canada	H2W 1T8
32	Montreal General Hospital	Montreal	Quebec	Canada	H3G 1A4
33	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
34	Azienda Ospedaliera Fatebenefratelli Milano	Milano		Italy	20121
35	MBCCOP - San Juan	San Juan		Puerto Rico	00927-5800
36	Galicia Hospital Universitario A Coruña	A Coruna	Galicia	Spain	15006
37	Madrid Quiron Madrid	Pozuelo de Alarcon	Madrid	Spain	28223
38	Cataluna Hospital del Mar	Barcelona		Spain	08003
39	Cataluna Hospital Quiron de Barcelona	Barcelona		Spain	08023
40	Extremadura Hospital San Pedro Alcantara	Caceres		Spain	10003
41	Cataluna Hospital Amau de Vilanova de Lleida	Lleida		Spain	25198
42	Valencia Institut Valencia de Oncologia	Valencia		Spain	46009

Sponsors and Collaborators

• NSABP Foundation Inc
• Puma Biotechnology, Inc.

Investigators

• Principal Investigator: Norman Wolmark, MD, NSABP Foundation Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NSABP Foundation Inc
• ClinicalTrials.gov Identifier: NCT01008150
• Other Study ID Numbers: NSABP FB-7
• First Posted: Nov 5, 2009
• Last Update Posted: Oct 25, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by NSABP Foundation Inc: breast cancer; neoadjuvant; neratinib; paclitaxel; trastuzumab; doxorubicin; cyclophosphamide
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Cyclophosphamide; Doxorubicin; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then AC
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Period Title: Overall Study
STARTED	43	43	43	12
COMPLETED	42	42	42	12
NOT COMPLETED	1	1	1	0

Baseline Characteristics

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C	Total
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	Total of all reporting groups
Overall Participants	42	42	42	12	138
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.1 (9.70)	53.7 (9.87)	50.9 (12.68)	48.7 (11.94)	51.6 (10.86)
Sex: Female, Male (Count of Participants)
Female	42 100%	42 100%	42 100%	12 100%	138 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 7.1%	7 16.7%	4 9.5%	1 8.3%	15 10.9%
Not Hispanic or Latino	38 90.5%	35 83.3%	38 90.5%	8 66.7%	119 86.2%
Unknown or Not Reported	1 2.4%	0 0%	0 0%	3 25%	4 2.9%
Race/Ethnicity, Customized (Count of Participants)
White	37 88.1%	34 81%	38 90.5%	7 58.3%	116 84.1%
Black or African American	3 7.1%	4 9.5%	3 7.1%	2 16.7%	12 8.7%
Asian	2 4.8%	3 7.1%	1 2.4%	2 16.7%	8 5.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 2.4%	0 0%	0 0%	1 0.7%
White/American Indian or Alaskan Native	0 0%	0 0%	0 0%	1 8.3%	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response in Breast and Axillary Lymph Nodes.
Description	Number of participants with no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes after neoadjuvant chemotherapy
Time Frame	At time of surgery, approximately 7 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratininb Then AC
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	42	42	42	12
Count of Participants [Participants]	16 38.1%	14 33.3%	21 50%	5 41.7%

2. Secondary Outcome

Title	Pathologic Complete Response in Breast.
Description	Number of participants with by no histologic evidence of invasive tumor cells in the surgical breast specimen.
Time Frame	At time of surgery, approximately 7 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	42	42	42	12
Count of Participants [Participants]	21 50%	16 38.1%	22 52.4%	6 50%

3. Secondary Outcome

Title	Clinical Complete Response, as Measured by Physical Exam
Description	Upon physical exam the number of participants with resolution of all target and non-target lesions identified at baseline and no new lesions or other signs of disease progression.
Time Frame	At the completion of AC prior to surgery, approximately 7 months

Outcome Measure Data

Analysis Population Description

Only patients with palpable disease at baseline are included in this outcome. Arm1-38 patients at baseline, 2 patients missing data. Arm 2-35 patients at baseline, 4 patients missing data. Arm 3-38 patients at baseline, 4 patients missing data. Arm 3 NR-10 patients at baseline, 1 patient missing data.

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	36	31	34	9
Count of Participants [Participants]	25 59.5%	25 59.5%	28 66.7%	6 50%

4. Secondary Outcome

Title	Recurrence-free Interval (RFI)
Description	Number of participants with no events of inoperable progressive disease and local, regional and distant recurrence.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	42	42	42	12
Count of Participants [Participants]	42 100%	39 92.9%	40 95.2%	12 100%

5. Secondary Outcome

Title	Overall Survival
Description	Number of participants alive at 24 months.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	42	42	42	12
Count of Participants [Participants]	42 100%	42 100%	42 100%	12 100%

6. Secondary Outcome

Title	Adverse Events Experienced by Participants as a Measure of Toxicity
Description	Number of patients with at least one adverse event.
Time Frame	Assessed through 2 years from randomization

Outcome Measure Data

Analysis Population Description

Refer to Adverse Events section for more details.

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C	Arm 2: Paclitaxel + Neratinib Then A C	Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C	Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then A C
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide	4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
Measure Participants	42	42	42	12
Count of Participants [Participants]	41 97.6%	42 100%	42 100%	12 100%

Adverse Events

Arm/Group Title	Arm 1: Paclitaxel + Trastuzumab Then A C		Arm 2: Paclitaxel + Neratinib Then A C		Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C		Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then AC
Arm/Group Description	4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Doxorubicin Cyclophosphamide		4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Neratinib Doxorubicin Cyclophosphamide		4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide		4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy) Paclitaxel Trastuzumab Neratinib Doxorubicin Cyclophosphamide
All Cause Mortality
	Arm 1: Paclitaxel + Trastuzumab Then A C		Arm 2: Paclitaxel + Neratinib Then A C		Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C		Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then AC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Paclitaxel + Trastuzumab Then A C		Arm 2: Paclitaxel + Neratinib Then A C		Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C		Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then AC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/42 (16.7%)		7/42 (16.7%)		10/42 (23.8%)		2/12 (16.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/42 (2.4%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Cardiac disorders
Left venrticular dysfunction	1/42 (2.4%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Cardiac valve disease	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Gastrointestinal disorders
Diarrhoea	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Abdominal pain	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Colitis	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Nausea	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Vomiting	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
General disorders
Pyrexia	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Influenza like illness	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Oedema peripheral	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Fatigue	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Hepatobiliary disorders
Cholecystitis	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Infections and infestations
Infection	1/42 (2.4%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Erysipelas	0/42 (0%)		1/42 (2.4%)		1/42 (2.4%)		0/12 (0%)
Cellulitis	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Neutropenic infection	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Osteomyelitis	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Bacteraemia	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Cystitis	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Device related infection	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Injury, poisoning and procedural complications
Radiation skin injury	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Metabolism and nutrition disorders
Hypokalaemia	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Hyponatraemia	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Nervous system disorders
Syncope	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Psychiatric disorders
Anxiety	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Depression	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/42 (2.4%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Vascular disorders
Embolism	2/42 (4.8%)		1/42 (2.4%)		1/42 (2.4%)		0/12 (0%)
Haematoma	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1: Paclitaxel + Trastuzumab Then A C		Arm 2: Paclitaxel + Neratinib Then A C		Arm 3: Paclitaxel + Trastuzumab + Neratinib Then A C		Arm 3 NR: Paclitaxel + Trastuzumab + Neratinib Then AC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/42 (97.6%)		42/42 (100%)		42/42 (100%)		12/12 (100%)
Blood and lymphatic system disorders
Neutropenia	13/42 (31%)		9/42 (21.4%)		8/42 (19%)		3/12 (25%)
Anaemia	9/42 (21.4%)		5/42 (11.9%)		8/42 (19%)		2/12 (16.7%)
Leukopenia	5/42 (11.9%)		6/42 (14.3%)		2/42 (4.8%)		0/12 (0%)
Lymphopenia	1/42 (2.4%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Cardiac disorders
Tachycardia	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Ear and labyrinth disorders
Tinnitus	2/42 (4.8%)		0/42 (0%)		1/42 (2.4%)		1/12 (8.3%)
Eye disorders
Vision blurred	3/42 (7.1%)		6/42 (14.3%)		1/42 (2.4%)		1/12 (8.3%)
Conjunctivitis	0/42 (0%)		3/42 (7.1%)		3/42 (7.1%)		0/12 (0%)
Dry eye	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Lacrimation increased	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Photopsia	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Diarrhoea	16/42 (38.1%)		42/42 (100%)		41/42 (97.6%)		12/12 (100%)
Nausea	12/42 (28.6%)		25/42 (59.5%)		20/42 (47.6%)		8/12 (66.7%)
Vomiting	7/42 (16.7%)		16/42 (38.1%)		13/42 (31%)		6/12 (50%)
Constipation	6/42 (14.3%)		12/42 (28.6%)		11/42 (26.2%)		7/12 (58.3%)
Dyspepsia	9/42 (21.4%)		13/42 (31%)		6/42 (14.3%)		2/12 (16.7%)
Stomatitis	2/42 (4.8%)		6/42 (14.3%)		7/42 (16.7%)		1/12 (8.3%)
Abdominal Pain	3/42 (7.1%)		3/42 (7.1%)		4/42 (9.5%)		3/12 (25%)
Haemorrhoids	1/42 (2.4%)		2/42 (4.8%)		4/42 (9.5%)		0/12 (0%)
Abdominal Pain Upper	3/42 (7.1%)		0/42 (0%)		3/42 (7.1%)		2/12 (16.7%)
Dry mouth	0/42 (0%)		3/42 (7.1%)		3/42 (7.1%)		1/12 (8.3%)
Abdominal distension	0/42 (0%)		3/42 (7.1%)		2/42 (4.8%)		2/12 (16.7%)
Oral pain	2/42 (4.8%)		1/42 (2.4%)		1/42 (2.4%)		1/12 (8.3%)
Dysphagia	0/42 (0%)		2/42 (4.8%)		2/42 (4.8%)		1/12 (8.3%)
Gastritis	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Flatulence	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Gastrooesophageal reflux disease	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Anorectal discomfort	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Oesophagitis	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Rectal haemorrhage	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
General disorders
Fatigue	18/42 (42.9%)		22/42 (52.4%)		18/42 (42.9%)		8/12 (66.7%)
Asthenia	9/42 (21.4%)		7/42 (16.7%)		10/42 (23.8%)		0/12 (0%)
Pain	4/42 (9.5%)		9/42 (21.4%)		5/42 (11.9%)		2/12 (16.7%)
Pyrexia	1/42 (2.4%)		6/42 (14.3%)		6/42 (14.3%)		3/12 (25%)
Oedema peripheral	2/42 (4.8%)		5/42 (11.9%)		3/42 (7.1%)		2/12 (16.7%)
Catheter site pain	1/42 (2.4%)		1/42 (2.4%)		1/42 (2.4%)		1/12 (8.3%)
Influenza like illness	1/42 (2.4%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Chest pain	0/42 (0%)		0/42 (0%)		3/42 (7.1%)		1/12 (8.3%)
Chills	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		1/12 (8.3%)
Early satiety	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Mucosal inflammation	7/42 (16.7%)		3/42 (7.1%)		8/42 (19%)		1/12 (8.3%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/42 (2.4%)		1/42 (2.4%)		0/42 (0%)		2/12 (16.7%)
Immune system disorders
Hypersensitivity	2/42 (4.8%)		5/42 (11.9%)		6/42 (14.3%)		1/12 (8.3%)
Drug hypersensitivity	1/42 (2.4%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Infections and infestations
Infection	5/42 (11.9%)		2/42 (4.8%)		2/42 (4.8%)		0/12 (0%)
Urinary tract infection	4/42 (9.5%)		3/42 (7.1%)		0/42 (0%)		0/12 (0%)
Nasopharyngitis	3/42 (7.1%)		2/42 (4.8%)		2/42 (4.8%)		1/12 (8.3%)
Influenza	2/42 (4.8%)		0/42 (0%)		3/42 (7.1%)		0/12 (0%)
Folliculitis	3/42 (7.1%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Sinusitis	2/42 (4.8%)		1/42 (2.4%)		1/42 (2.4%)		0/12 (0%)
Upper respiratory tract infection	2/42 (4.8%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Onychomycosis	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Localised infection	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		1/12 (8.3%)
Rhinitis	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Infusion related reaction	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	7/42 (16.7%)		16/42 (38.1%)		17/42 (40.5%)		7/12 (58.3%)
Aspartate aminotransferase increased	6/42 (14.3%)		13/42 (31%)		14/42 (33.3%)		7/12 (58.3%)
Neutraphil count	5/42 (11.9%)		6/42 (14.3%)		1/42 (2.4%)		0/12 (0%)
Weight decreased	2/42 (4.8%)		6/42 (14.3%)		4/42 (9.5%)		3/12 (25%)
White blood cell count	5/42 (11.9%)		4/42 (9.5%)		1/42 (2.4%)		1/12 (8.3%)
Haemoglobin	2/42 (4.8%)		5/42 (11.9%)		2/42 (4.8%)		2/12 (16.7%)
Alanine aminotransferase	2/42 (4.8%)		2/42 (4.8%)		3/42 (7.1%)		1/12 (8.3%)
Blood alkaline phosphatase increased	0/42 (0%)		2/42 (4.8%)		3/42 (7.1%)		0/12 (0%)
Blood creatinine increased	0/42 (0%)		1/42 (2.4%)		4/42 (9.5%)		0/12 (0%)
Gamma-glutamyltransferase increased	0/42 (0%)		1/42 (2.4%)		4/42 (9.5%)		0/12 (0%)
Neutrophil count decreased	2/42 (4.8%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Blood alkaline phosphatase	1/42 (2.4%)		2/42 (4.8%)		0/42 (0%)		2/12 (16.7%)
Ejection fraction decreased	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Blood bilirubin increased	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Metabolism and nutrition disorders
Decreased appetite	2/42 (4.8%)		11/42 (26.2%)		11/42 (26.2%)		2/12 (16.7%)
Hyperglycaemia	4/42 (9.5%)		8/42 (19%)		3/42 (7.1%)		0/12 (0%)
Hypokalaemia	1/42 (2.4%)		7/42 (16.7%)		6/42 (14.3%)		6/12 (50%)
Hyponatraemia	1/42 (2.4%)		6/42 (14.3%)		4/42 (9.5%)		1/12 (8.3%)
Hypocalcaemia	1/42 (2.4%)		5/42 (11.9%)		4/42 (9.5%)		0/12 (0%)
Dehyrdration	2/42 (4.8%)		3/42 (7.1%)		1/42 (2.4%)		1/12 (8.3%)
Hypomagnesaemia	0/42 (0%)		1/42 (2.4%)		3/42 (7.1%)		0/12 (0%)
Hypernatraemia	2/42 (4.8%)		1/42 (2.4%)		0/42 (0%)		0/12 (0%)
Hypoalbuminaemia	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Hypoproteinaemia	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Hyperkalaemia	0/42 (0%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/42 (14.3%)		2/42 (4.8%)		3/42 (7.1%)		0/12 (0%)
Myalgia	4/42 (9.5%)		3/42 (7.1%)		2/42 (4.8%)		1/12 (8.3%)
Musculoskeletal pain	5/42 (11.9%)		0/42 (0%)		3/42 (7.1%)		0/12 (0%)
Back pain	0/42 (0%)		3/42 (7.1%)		4/42 (9.5%)		0/12 (0%)
Muscular weakness	1/42 (2.4%)		3/42 (7.1%)		1/42 (2.4%)		0/12 (0%)
Neck pain	2/42 (4.8%)		1/42 (2.4%)		1/42 (2.4%)		0/12 (0%)
Bone pain	3/42 (7.1%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Pain in extremity	1/42 (2.4%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Musculoskeletal chest pain	1/42 (2.4%)		1/42 (2.4%)		0/42 (0%)		1/12 (8.3%)
Flank pain	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Muscle tightness	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Pain in jaw	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Nervous system disorders
Headache	10/42 (23.8%)		7/42 (16.7%)		7/42 (16.7%)		4/12 (33.3%)
Peripheral sensory neuropathy	8/42 (19%)		8/42 (19%)		4/42 (9.5%)		3/12 (25%)
Dysgeusia	3/42 (7.1%)		8/42 (19%)		7/42 (16.7%)		3/12 (25%)
Dizziness	4/42 (9.5%)		5/42 (11.9%)		6/42 (14.3%)		4/12 (33.3%)
Neurapathy peripheral	6/42 (14.3%)		5/42 (11.9%)		3/42 (7.1%)		0/12 (0%)
Paraesthesia	4/42 (9.5%)		4/42 (9.5%)		5/42 (11.9%)		1/12 (8.3%)
Neurotoxicity	2/42 (4.8%)		1/42 (2.4%)		3/42 (7.1%)		0/12 (0%)
Hypoaesthesia	0/42 (0%)		1/42 (2.4%)		4/42 (9.5%)		1/12 (8.3%)
Restless leg syndrome	2/42 (4.8%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Cranial nerve disorder	0/42 (0%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Dyskinesia	1/42 (2.4%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Psychiatric disorders
Insomnia	8/42 (19%)		6/42 (14.3%)		3/42 (7.1%)		3/12 (25%)
Anxiety	4/42 (9.5%)		5/42 (11.9%)		4/42 (9.5%)		0/12 (0%)
Mood altered	2/42 (4.8%)		4/42 (9.5%)		1/42 (2.4%)		0/12 (0%)
Depression	1/42 (2.4%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Depressed mood	0/42 (0%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Renal and urinary disorders
Dysuria	2/42 (4.8%)		4/42 (9.5%)		1/42 (2.4%)		0/12 (0%)
Reproductive system and breast disorders
Breast pain	3/42 (7.1%)		3/42 (7.1%)		2/42 (4.8%)		0/12 (0%)
Vaginal inflammation	1/42 (2.4%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Pelvic pain	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	8/42 (19%)		8/42 (19%)		7/42 (16.7%)		1/12 (8.3%)
Cough	8/42 (19%)		4/42 (9.5%)		6/42 (14.3%)		0/12 (0%)
Dyspnoea	6/42 (14.3%)		4/42 (9.5%)		2/42 (4.8%)		0/12 (0%)
Rhinorrhoea	3/42 (7.1%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Oropharyngeal pain	0/42 (0%)		1/42 (2.4%)		3/42 (7.1%)		0/12 (0%)
Dyspnoea exertional	2/42 (4.8%)		0/42 (0%)		2/42 (4.8%)		0/12 (0%)
Dysphonia	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Rhinitis allergic	0/42 (0%)		1/42 (2.4%)		2/42 (4.8%)		0/12 (0%)
Productive Cough	2/42 (4.8%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Atelectasis	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	20/42 (47.6%)		22/42 (52.4%)		15/42 (35.7%)		6/12 (50%)
Rash	9/42 (21.4%)		9/42 (21.4%)		6/42 (14.3%)		4/12 (33.3%)
Pruritus	5/42 (11.9%)		4/42 (9.5%)		2/42 (4.8%)		1/12 (8.3%)
Acne	4/42 (9.5%)		4/42 (9.5%)		1/42 (2.4%)		0/12 (0%)
Nail disorder	3/42 (7.1%)		1/42 (2.4%)		3/42 (7.1%)		0/12 (0%)
Dry skin	0/42 (0%)		4/42 (9.5%)		2/42 (4.8%)		3/12 (25%)
Dermatitis aceniform	0/42 (0%)		3/42 (7.1%)		2/42 (4.8%)		1/12 (8.3%)
Erythema	0/42 (0%)		2/42 (4.8%)		2/42 (4.8%)		1/12 (8.3%)
Palmar-plantar erythrodysaesthesia syndrome	1/42 (2.4%)		2/42 (4.8%)		0/42 (0%)		0/12 (0%)
Exfoliative rash	0/42 (0%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Skin fissures	0/42 (0%)		1/42 (2.4%)		2/42 (4.8%)		0/12 (0%)
Palmar erythema	2/42 (4.8%)		0/42 (0%)		0/42 (0%)		0/12 (0%)
Skin disorder	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		1/12 (8.3%)
Rash generalised	0/42 (0%)		0/42 (0%)		0/42 (0%)		1/12 (8.3%)
Skin hyperpigmentation	0/42 (0%)		0/42 (0%)		1/42 (2.4%)		1/12 (8.3%)
Vascular disorders
Hypertension	7/42 (16.7%)		8/42 (19%)		2/42 (4.8%)		0/12 (0%)
Embolism	0/42 (0%)		4/42 (9.5%)		1/42 (2.4%)		1/12 (8.3%)
Flushing	1/42 (2.4%)		2/42 (4.8%)		1/42 (2.4%)		0/12 (0%)
Hypotension	0/42 (0%)		1/42 (2.4%)		0/42 (0%)		1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.