Paclitaxel + Trastuzumab + Pertuzumab as Pre-Op for Infla... | NCT01796197

Paclitaxel + Trastuzumab + Pertuzumab as Pre-Op for Infla... | NCT01796197 | Trialant

Description Module

Brief Summary

This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. In this study, paclitaxel and trastuzumab are being combined with pertuzumab which is "investigational" for the preoperative treatment of inflammatory breast cancer. Trastuzumab is given for a total of 12 months for the treatment of HER2 positive breast cancer. This study also adds pertuzumab to trastuzumab so that both drugs are given for a total of 12 months; this combination is also "investigational".

"Investigational" means that pertuzumab is being studied. It also means that although the FDA has approved pertuzumab for preoperative use to treat breast cancer, it has not been thoroughly studied in combination with paclitaxel and trastuzumab for preoperative treatment of inflammatory breast cancer. It has been FDA approved for specific use in advanced breast cancer that is HER2 positive.

Pertuzumab is an antibody, which is a protein that attacks a foreign substance is the body. Pertuzumab blocks the function of the HER2 protein like trastuzumab does. However, pertuzumab binds to a different part of the HER2 receptor and stops cancer cells from growing. This drug has been used in the treatment of advanced breast cancer that is HER2 positive, and has been combined with trastuzumab and chemotherapy in those studies. Information from those other research studies suggests that pertuzumab may help to kill the cancer cells in the breast and enable you to undergo a mastectomy. The addition of pertuzumab may also help reduce the chance of cancer recurrence.

In this research study, we are combining pertuzumab with paclitaxel and trastuzumab as preoperative therapy and will determine the response of the cancer remaining in the breast at the time of mastectomy. In addition, we are combining trastuzumab with pertuzumab for a total of 12 months and we are looking to see whether the combination reduces the chance that the cancer will return.

Another goal of this research study is to determine whether we can develop a way to identify tumors that will respond well to this study treatment. We will do research tests on your tumor tissue before, during and after study treatment. These tests may help doctors understand how the study treatment may work to treat your type of breast cancer. In the future, these tests may help us find ways to help match patients with the drugs most likely to work against their specific tumors before treatment begins.

Detailed Description

If you agree to take part in this study we will ask you to undergo some screening tests and procedures to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. The screening process will include the following: a medical history, performance status, physical examination, scans and x-rays, blood samples, blood pregnancy test, electrocardiogram, echocardiogram. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria you will not be able to participate in this research study.

Before beginning study treatment you will undergo a tumor biopsy and have photographs of your tumor taken to assess the response of your tumor to the study treatment.

On the first day of study treatment (Week 1, Day 1) with trastuzumab and pertuzumab, you will receive an intravenous infusion of trastuzumab over about 90 minutes, followed by a 60 minutes observation period. If the trastuzumab infusion is tolerated, you will receive the rest of your study treatment, the pertuzumab. This will also be given as an intravenous infusion over about 60 minutes with you being observed for a further 60 minutes. Thus, the total duration of infusion and observation periods for the first dose of study treatment (Week 1, Day 1) is about 5 hours. If the drugs are well tolerated at Week 1, the duration of the infusion with trastuzumab and pertuzumab may be shortened for subsequent doses.

Prior to starting Week 2, you will undergo a second research biopsy of your breast. The biopsy will be performed either prior to Week 2, Day 8 or on the same day. You will then receive an infusion of trastuzumab and begin chemotherapy. If the infusion of trastuzumab was tolerated on Week 1, Day 1, then the infusion time is reduced to about 30 minutes. You will then be pre-medicated with drugs to reduce the chance of having a sensitivity reaction to paclitaxel. This takes approximately 30 minutes. The paclitaxel is give by intravenous infusion over about 60 minutes. If you tolerate the paclitaxel infusions, then the pre-medication can be changed by your doctor.

The pertuzumab is given every 3 weeks beginning on Week 1 and continues until paclitaxel administration is complete. Trastuzumab is given weekly beginning on Week 1 and continues until paclitaxel administration is complete. Paclitaxel is given weekly for a total of 16 doses beginning on Week 2. After completing 16 doses of paclitaxel, trastuzumab and pertuzumab may be continued every 3 weeks until surgery.

Study treatment visits will occur at regular intervals during the period of study treatment, beginning on Week 1. During these study treatment visits the following will be done: physical exam, performance status, blood samples, heart function tests.

After completing 16 doses of paclitaxel in combination with pertuzumab and trastuzumab, you will undergo surgery for removal of your breast cancer. This will occur approximately 4-5 weeks after your last paclitaxel infusion. Prior to surgery, you will have the following assessments: a repeat breast MRI, PET scan (if necessary), physical exam, vital signs, performance status, blood tests, tumor tissue tests.

Approximately 4-5 weeks after surgery, when you are well-healed, you will have two options for treatment (at your physician's discretion):

Option 1: Doxorubicin and cyclophosphamide (AC), every 2-3 weeks x 4 cycles. This is standard chemotherapy for IBC. Followed by trastuzumab and pertuzumab every 3 weeks to complete 12 months of HER2-directed therapy.

Option 2: Continue trastuzumab and pertuzumab every 3 weeks to complete 12 months of HER2-directed therapy.

Doxorubicin is given by vein over about 5-10 minutes. This is followed by cyclophosphamide by vein given about 30 minutes. Anti-nausea medicine is given first under the direction of your doctor.

Approximately 4-5 weeks after finishing the AC treatment if you pursue Option 1 (or 4-5 weeks after surgery if you pursue Option 2), you will receive radiation therapy to the mastectomy site and the surrounding lymph nodes. This will be given daily, Monday through Friday for approximately 6-7 weeks. This will be administered as standard of care for IBC.

Approximately 3-4 weeks following the completion of AC if you pursue Option 1 (or 3-4 weeks after surgery if you pursue Option 2), you will begin maintenance therapy with trastuzumab and pertuzumab. As with Week 1, Day 1, you will receive an intravenous infusion of trastuzumab over about 90 minutes followed by a 60 minute observation period. If the trastuzumab infusion is tolerated, you will receive the rest of your study treatment, the pertuzumab. This will also be given as an intravenous infusion over about 60 minutes with your being observed for a further 60 minutes. Thus, the total duration of infusion and observation periods for the first day of maintenance study treatment is about 5 hours. If the study drugs are well tolerated, the duration of the infusion with trastuzumab and pertuzumab may be shortened for subsequent doses. Both trastuzumab and pertuzumab will be given every 3 weeks to complete a 12 month duration of HER2-directed therapy. Every 9 weeks (every third dose of trastuzumab and pertuzumab) you will undergo the same procedure as taht described above in Study Treatment visits.

About one month after your last dose of study treatment, you will be asked to return to the clinic. At this visit tests will be done to check your physical condition and to check that you have recovered from any side effects of study treatment. During this visit the following will be done: physical exam, vital signs, performance status and blood tests.

You will be asked to attend regular follow up visits to check if you are experiencing any long term side effects and to check taht the cancer has not come back. We plan to follow participants for up to 13 years after the start of teh study. During these visits the following will be done: physical exam and questions about your health/medications you have taken (every 3 months for the first year, every 6 months for the next 4 years, yearly until the end of study follow up); blood draws (every 6 months for the first 4 years, yearly after that); mammograms will be performed annually, other scans may be performed as needed.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Treatment Arm	Experimental	Run in: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1 Week 1) Pre-Op: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8 Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above, add Pertuzumab 420 mg IV x 3 weeks. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued x 3 weeks until surgery Modified Radical Mastectomy Post-Op: Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV x 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg x 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation to the chest wall / regional lymph nodes and endocrine therapy by standard of care.	Drug: Trastuzumab Drug: Pertuzumab Drug: Paclitaxel Drug: Doxorubicin Drug: Cyclophosphamide Procedure: Mastectomy Radiation: Radiation Therapy

Name	Type	Description	Arm Group Labels	Other Names
Trastuzumab	Drug		Treatment Arm
Pertuzumab

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentages of Participants With Pathologic Complete Response	Pathologic complete response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR.	18 weeks
Residual Cancer Burden Rate	Residual cancer burden is calculated an then categorized based on the methods described in the following: Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28): 4414-22. This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. These parameters are combined in a formula that outputs a RCB index. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III. The previous categories are in order of increasing severity of RCB.	18 Weeks

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Congestive Heart Failure	Number of participants with clinically significant congestive heart failure (CHF) as determined by established medical practices.	1 year and 8 months
Median Disease Free Survival

Contacts/Locations Module

Name	Affiliation	Role
Filipa Lynce, MD	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Brigham and Women's Hospital		Boston	Massachusetts	02215	United States
Dana-Farber Cancer Institute

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
35923923	Derived	Pernas S, Guerriero JL, Naumenko S, Goel S, Regan MM, Hu J, Harrison BT, Lynce F, Lin NU, Partridge A, Morikawa A, Hutchinson J, Mittendorf EA, Sokolov A, Overmoyer B. Early on-treatment transcriptional profiling as a tool for improving pathological response prediction in HER2-positive inflammatory breast cancer. Ther Adv Med Oncol. 2022 Jul 30;14:17588359221113269. doi: 10.1177/17588359221113269. eCollection 2022.

Arm/Group Information

ID	Title	Description
FG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00023 subjects
COMPLETED		FG00021 subjects
NOT COMPLETED		FG0002 subjects

Type	Comment	Reasons
Lost to Follow-up		FG0001 subjects
Lack of Efficacy		FG0001 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentages of Participants With Pathologic Complete Response

Pathologic complete response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR.

Subjects evaluable for response. Participants are not being evaluated based on their post-operative treatment option. Two options are provided to the participants in order to best treat them based on the nature of their disease

Posted

Number

90% Confidence Interval

percentage of participants

18 weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Treatment Arm	Pre-op phase: Trastuzumab: IV 4mg/kg/first dose, then IV 2mg/kg weekly. Pertuzumab: IV 840mg/first dose, then IV 420mg every 3 weeks Paclitaxel: IV 80mg/m2 weekly x 16 doses Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery. Surgery: Modified Radical Mastectomy Post-Operative Treatment: Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy All patients should also complete radiation therapy.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anemia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Beth Overmoyer, MD, FACP	Dana-Farber Cancer Institute	617.632.3800		beth_overmoyer@dfci.harvard.edu

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Apr 23, 2021	May 24, 2021	Prot_SAP_000.pdf

Condition Browse Module

ID	Term
D001943	Breast Neoplasms

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases

Intervention Browse Module

ID	Term
D000068878	Trastuzumab
C485206	pertuzumab
D017239	Paclitaxel
D004317	Doxorubicin
D003520	Cyclophosphamide
D008408	Mastectomy
D011878	Radiotherapy

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000
Asian	BG0001
Native Hawaiian or Other Pacific Islander	BG0000
Black or African American	BG0001
White	BG00019
More than one race	BG0001
Unknown or Not Reported	BG0001

Breast Cancer Stage

IIIB:

Tumor may be any size and has spread to the chest wall and/or skin of the breast and caused swelling or an ulcer and may have spread to >10 axillary lymph nodes or spread to lymph nodes near breastbone.

IIIC:

May be no sign of cancer in the breast or, tumor may be any size and may have spread to the chest wall and/or the skin of the breast and 10 or more axillary lymph nodes or lymph nodes above or below the collarbone or spread to axillary lymph nodes or to lymph nodes near the breastbone

IV:

Spready beyond the breast and nearby lymph nodes.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
IIIB	BG00016
IIIC	BG0006
IV	BG0001

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000	Null Hypothesis: pCR rate is less than or equal to 15% Alternative Hypothesis: pCR rate is greater than or equal to 40% Hypothesized False Positive Rate (alpha) : 3.9% Hypothesized False Negative Rate (1-beta) : 9.9%	Two stage design, exact method				Pathelogic Complete Response Rate	40			2-Sided						Decision Rule: If the percentage of participants experiencing pathologic complete response (pCR) is ≤ 15% then the preoperative regimen is considered minimally effective. If the proportion of pCR ≥ 40% then the regimen is worthy of further study.		Superiority

Primary

Residual Cancer Burden Rate

Residual cancer burden is calculated an then categorized based on the methods described in the following: Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28): 4414-22.

This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. These parameters are combined in a formula that outputs a RCB index. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III. The previous categories are in order of increasing severity of RCB.

Posted

Number

90% Confidence Interval

percentage of participants

18 Weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00021

Title

Denominators

Categories

RCB-0

Title	Measurements
	OG00048(29 to 67)

RCB-I

Title	Measurements
	OG00033(17 to 54)

RCB-II

Secondary

Number of Participants With Congestive Heart Failure

Number of participants with clinically significant congestive heart failure (CHF) as determined by established medical practices.

Participants evaluable for adverse events. Participants are not being evaluated based on their post-operative treatment option. Two options are provided to the participants in order to best treat them based on the nature of their disease.

Posted

Count of Participants

Participants

1 year and 8 months

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00023

Title

Denominators

Categories

Title	Measurements
	OG0000

Secondary

Median Disease Free Survival

Disease-free survival (DFS) is defined for the participants who undergo surgery, as the duration of time from surgery until ipsilateral local-regional, contralateral or distant invasive recurrence or death from any cause; in the absence of an event, DFS will be censored at the date last know alive and free from recurrence.

Posted

Median

95% Confidence Interval

months

63 months

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00021

Title

Denominators

Categories

Title	Measurements
	OG000NA(NA to NA)Less than 50% recurrence at the time of data extraction, so median DFS not reached. It is not possible to calculate the lower limit of the confidence interval.

Secondary

Median Time to Treatment Failure

Time to treatment failure (TTF) will be defined among all participants, as the duration of time from treatment initiation to a DFS event or progressive disease during preoperative therapy or treatment disease that is not surgically resectable; in the absence of an event, TTF will be censored at the date last know alive and free from recurrence or progression.

Subjects evaluable for response. Two options are provided to the participants in order to best treat them based on the nature of their disease.

Posted

Median

95% Confidence Interval

months

63 months

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00021

Title

Denominators

Categories

Title	Measurements
	OG000NA(NA to NA)Less than 50% recurrence at the time of data extraction, so median TTF not reached. Participants are not being evaluated based on their post-operative treatment option. It is not possible to calculate the lower limit of the confidence interval.

Secondary

Median Overall Survival

Overall survival (OS) will be defined among all participants, as the duration of time from treatment initiation to death from any cause, or is censored at date last known alive. Post-surgery OS will be defined among the participants who undergo surgery, as the duration of time from treatment initiation to death from any cause, or is censored at date last known alive.

Subjects evaluable for response. Two options are provided to the participants in order to best treat them based on the nature of their disease.

Posted

Median

95% Confidence Interval

months

63 months

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00021

Title

Denominators

Categories

Title	Measurements
	OG000NA(NA to NA)Less than 50% recurrence at the time of data extraction, so median OS not reached. Participants are not being evaluated based on their post-operative treatment option. It is not possible to calculate the lower limit of the confidence interval.

Secondary

Pathological Complete Response Rate by Intrinsic Subtype

Participants' pCR was tabulated according to the intrinsic subtype and the association of intrinsic subtype (Estrogen receptor 2 - enriched vs. other) with pCR was assessed using Fisher's exact test.

No samples collected since very few patients had residual disease and sample size would be too small for any meaningful analysis.

Posted

18 Weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG0000

Secondary

Residual Disease Rate by Intrinsic Subtype

Residual Disease Rate is the percentage of participants who do not achieve Pathologic complete response (pCR) by the end of preoperative treatment. pCR is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Residual disease within the breast at time of mastectomy was assessed by microarray analysis. Residual disease rate was reported by intrinsic subtype identified using day 1 RNAseq analysis.

No samples collected since very few patients had residual disease and sample size would be too small for any meaningful analysis.

Posted

18 Weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG0000

Secondary

Predictive Accuracy Rate of Pre-Treatment Versus On-Treatment Tumor Biopsy RNA Sequencing Profiles

Tumor RNA expression from pre-treatment (Day 1) and on-treatment (Day 8) biopsies were evaluated to see if the expression profiles had predictive accuracy of pCR. pCR is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR. The biopsies were analyzed by differential expression analysis using standard procedures in R package, limma. A predictive Random Forest model was trained using leave-pair-out-cross-validation with the 80 genes most associated with pCR and/or non-pCR. This model gives an accuracy rate, which indicates the percentage of time that the gene profile predicts pCR or non-pCR for both the pre-treatment and on-treatment profiles. An increase in accuracy for the on-treatment profile would indicate an adaptive response within the tumor associated with resistance to HER2 directed therapies.

Subjects evaluable for response. Two options are provided to the participants in order to best treat them based on the nature of their disease.

Posted

Number

percent accuracy

18 Weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG00021

Title

Denominators

Categories

Day 1 Biopsy

Title	Measurements
	OG00050

Day 8 Biopsy

Title	Measurements
	OG00090

Secondary

Residual Cancer Burden Rate by ctDNA Profile Change

Biopsy/blood will be collected on day 1 and day 8 of therapy for analysis of circulating biomarkers, including ctDNA.

Associations between change in ctDNA during therapy and residual cancer burden at the time of definitive surgery will be evaluated.

Data was not collected due to a lack of clinical research funding.

Posted

18 weeks

ID	Title	Description
OG000	Treatment Arm	Run in phase: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1, Week 1) Pre-op phase: Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8, Week 2) x 16 doses. Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above and add Pertuzumab 420 mg IV every 3 weeks during 16 doses of paclitaxel administration. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued every 3 weeks until surgery Modified Radical Mastectomy Post-Operative Treatment (Two Options): Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV every 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg every 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation therapy to the chest wall and regional lymph nodes and endocrine therapy administered to participants by standard of care.

Units	Counts
Participants	OG0000