T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02326974
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 164
• Locations: 4
• Arm: 1
• Anticipated Duration (Months): 156
• Patients Per Site: 41
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This research study is studying a combination of drugs as a possible treatment for breast cancer that has tested positive for a protein called HER2.

The names of the study interventions involved in this study are:

• Trastuzumab emtansine (also called T-DM1)

• Pertuzumab

Condition or Disease	Intervention/Treatment	Phase
HER-2 Positive Breast Cancer; Breast Cancer; Stage II Breast Cancer; Stage III Breast Cancer	Drug: T-DM1; Drug: Pertuzumab; Procedure: Excision of tumor/mastectomy	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for pre-operative use in breast cancer but it has been approved for other uses in breast cancer. The FDA has approved pertuzumab as a pre-operative treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 164 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Impact of HER2 Heterogeneity on the Treatment of Early-stage HER2-positive Breast Cancer: a Phase II Study of T-DM1 in Combination With Pertuzumab in the Preoperative Setting
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Jun 1, 2018
• Anticipated Study Completion Date: Jan 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: T-DM1 and Pertuzumab T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.	Drug: T-DM1; Neoadjuvant treatment is for a total of 18 weeks.; Other Names: Kadcyla ; Drug: Pertuzumab; Neoadjuvant treatment is for a total of 18 weeks.; Other Names: Perjeta ; Procedure: Excision of tumor/mastectomy; Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.

Outcome Measures

Primary Outcome Measures

1. Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous [Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.]

   The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Rate of Pathologic Complete Response (pCR) [Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.]

   The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB).

2. Hormone Receptor (HR) Status by HER2 Amplification Status [Day 0 (baseline/at study entry)]

   HR status classified by estrogen receptor (ER) and/or progesterone receptor (ER) positive versus ER negative and PR negative determined by immunohistochemical methods according to the local institution's standard protocol.

3. Median Disease-Free Survival [Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.]

   Disease-free survival (DFS) based on the Kaplan-Meier method is defined as the duration of time from study entry to the occurrence of the first of the following events: local/regional recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. In situ cancer is not included as DFS event. Participants alive without an event are censored at date of last disease assessment.

4. Median Overall Survival [Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.]

   Overall survival (OS) based on Kaplan-Meier methods is defined as the interval from the date of registration to death from any cause. Patients are censored at date last known alive.

5. Clinical Response Rate (Complete Response) [Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.]

   Clinical response rate was defined as the percentage of participants achieving complete response (CR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions

6. Clinical Response Rate (Partial Response) [Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.]

   Clinical response rate was defined as the percentage of participants achieving partial response (PR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD.

7. Number of Participants With a Dose Reduction [Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.]

   Number of participants with ever having dose reduction on neoadjuvant therapy up to surgery.

8. Treatment-Emergent Fatigue Rate [Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment.]

   Treatment-emergent fatigue rate is the percentage of participants who experienced grade 1-2 fatigue based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as reported on the adverse event case report form. CTCAE severity scale ranges from 0 (none) to 5 (death): Grade 1=mild and Grade 2=moderate.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have HER2-positive Stage II or III histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or imaging is required.

• HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH positive based on one of the three following criteria:

• Single-probe average HER2 copy number≥6.0 signals/cell OR

• Dual-probe HER2/CEP17 <2.0 with an average HER2 copy number ≥6.0 signals/cell OR

• Dual-probe HER2/CEP17 ratio ≥2.0

• ER/PR determination is required.

• Bilateral breast cancers are allowed if both cancers are HER2-positive.

• Patients with multifocal or multicentric disease are eligible as long as one area meets eligibility criteria.

• Breast imaging should include the ipsilateral axilla. For subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject's physicians. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes.

• Men and women (with any menopausal status) ≥ 18 years of age

• ECOG performance status 0 or 1

• Required laboratory values:

• ANC ≥1500/mm3

• Hemoglobin ≥ 9 g/dl

• Platelets ≥100,000/mm3

• Serum creatinine < 1.5 X ULN (institutional)

• Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range.

• AST and ALT ≤ 1.5x ULN (institutional)

• Alkaline phosphatase ≤1.5x ULN (institutional)

• Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing.

• Only for patients who test positive for hep B/C virus: PTT/INR < ULN (institutional)

• Left ventricular ejection fraction (LVEF) ≥ 55%

• Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.

• Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment.

• Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1.

• Excessive alcohol intake should be avoided (occasional use is permitted).

• Patients with a history of ipsilateral DCIS are eligible.

• Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy.

• Willing and able to sign informed consent.

• Willing to provide tissue for research purposes.

Exclusion Criteria:

• Pregnant or nursing women due to the teratogenic potential of the study drugs.

• Active, unresolved infection.

• Receipt of intravenous antibiotics for infection within 7 days prior to enrollment.

• Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis.

• Uncontrolled hypertension (systolic >180 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication.

• Significant symptoms (Grade ≥2) peripheral neuropathy.

• Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes.

• Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Tennessee Oncology/Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
4	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Genentech, Inc.

Investigators

• Principal Investigator: Otto Metzger, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 28, 2017

More Information

Publications

None provided.

• Responsible Party: Otto Metzger, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02326974
• Other Study ID Numbers: 14-409
• First Posted: Dec 30, 2014
• Last Update Posted: Mar 8, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Breast Neoplasms; Pertuzumab

Study Results

Participant Flow

Recruitment Details	Patients were enrolled from January 2015 to January 2018.

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Period Title: Overall Study
STARTED	164
Treated	163
COMPLETED	157
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Overall Participants	163
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	131 80.4%
>=65 years	32 19.6%
Sex: Female, Male (Count of Participants)
Female	163 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 0.6%
Not Hispanic or Latino	147 90.2%
Unknown or Not Reported	15 9.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	10 6.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 4.3%
White	139 85.3%
More than one race	1 0.6%
Unknown or Not Reported	6 3.7%
Region of Enrollment (participants) [Number]
United States	163 100%
Hormone Receptor Status (Count of Participants)
ER+ and/or PR+	112 68.7%
ER- and PR-	41 25.2%
HER2 Amplification Status (Count of Participants)
Heterogenous	16 9.8%
Non-Heterogenous	141 86.5%
Missing	6 3.7%
Clinical Stage (Count of Participants)
Stage 1	1 0.6%
Stage 2	138 84.7%
Stage 3	24 14.7%
HER-2 results by IHC (central confirmation) (Count of Participants)
2+	40 24.5%
3+	121 74.2%
Unknown	2 1.2%
Histologic Grade (Count of Participants)
Grade 1	3 1.8%
Grade 2	56 34.4%
Grade 3	103 63.2%
Missing	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous
Description	The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.

Outcome Measure Data

Analysis Population Description

Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).

Arm/Group Title	Heterogeneous HER2 Amplification Status	Non-Heterogeneous HER2 Amplification Status
Arm/Group Description	T-DM1 and Pertuzumab T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	16	141
Number (95% Confidence Interval) [percentage of participants]	0 0%	54.6 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heterogeneous HER2 Amplification Status, Non-Heterogeneous HER2 Amplification Status
	Comments	By estimating that the overall pCR with T-DM1 plus pertuzumab would be approximately 40%, and 20% of the population classified as heterogeneous, the study would have 80% power with 136 evaluable patients to detect a difference in pCR of 44.9% in the non-heterogenous versus 20.3% in the heterogenous subgroup. The study had a 90% power to detect difference in pCR of 43.4% in the non-heterogenous versus 8.8% in the heterogenous subgroup if the observed prevalence of HER2 heterogeneity was 10%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mantel Haenszel
	Comments

2. Secondary Outcome

Title	Rate of Pathologic Complete Response (pCR)
Description	The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB).
Time Frame	Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.

Outcome Measure Data

Analysis Population Description

Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	157
Number (95% Confidence Interval) [percentage of participants]	49.0 30.1%

3. Secondary Outcome

Title	Hormone Receptor (HR) Status by HER2 Amplification Status
Description	HR status classified by estrogen receptor (ER) and/or progesterone receptor (ER) positive versus ER negative and PR negative determined by immunohistochemical methods according to the local institution's standard protocol.
Time Frame	Day 0 (baseline/at study entry)

Outcome Measure Data

Analysis Population Description

Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).

Arm/Group Title	Heterogeneous HER2 Amplification Status	Non-Heterogeneous HER2 Amplification Status
Arm/Group Description	T-DM1 and Pertuzumab T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.	T-DM1 and Pertuzumab T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	16	141
HR-positive	13 8%	96 NaN
HR-negative	3 1.8%	45 NaN

4. Secondary Outcome

Title	Median Disease-Free Survival
Description	Disease-free survival (DFS) based on the Kaplan-Meier method is defined as the duration of time from study entry to the occurrence of the first of the following events: local/regional recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. In situ cancer is not included as DFS event. Participants alive without an event are censored at date of last disease assessment.
Time Frame	Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Median Overall Survival
Description	Overall survival (OS) based on Kaplan-Meier methods is defined as the interval from the date of registration to death from any cause. Patients are censored at date last known alive.
Time Frame	Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Clinical Response Rate (Complete Response)
Description	Clinical response rate was defined as the percentage of participants achieving complete response (CR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions
Time Frame	Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy. T-DM1: Neoadjuvant treatment is for a total of 18 weeks. Pertuzumab: Neoadjuvant treatment is for a total of 18 weeks. Excision of tumor/mastectomy: Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.
Measure Participants	163
Count of Participants [Participants]	62 38%

7. Secondary Outcome

Title	Clinical Response Rate (Partial Response)
Description	Clinical response rate was defined as the percentage of participants achieving partial response (PR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD.
Time Frame	Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	163
Count of Participants [Participants]	69 42.3%

8. Secondary Outcome

Title	Number of Participants With a Dose Reduction
Description	Number of participants with ever having dose reduction on neoadjuvant therapy up to surgery.
Time Frame	Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.

Outcome Measure Data

Analysis Population Description

Patients treated with at least one dose of T-DM1 and Pertuzumab.

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	163
Count of Participants [Participants]	18 11%

9. Secondary Outcome

Title	Treatment-Emergent Fatigue Rate
Description	Treatment-emergent fatigue rate is the percentage of participants who experienced grade 1-2 fatigue based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as reported on the adverse event case report form. CTCAE severity scale ranges from 0 (none) to 5 (death): Grade 1=mild and Grade 2=moderate.
Time Frame	Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment.

Outcome Measure Data

Analysis Population Description

Patients treated with at least one dose of T-DM1 and Pertuzumab.

Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.
Measure Participants	163
Number (95% Confidence Interval) [percentage of participants]	76.1 46.7%

Adverse Events

Time Frame	Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment.
Adverse Event Reporting Description	Serious adverse events (AEs) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. Maximum grade toxicity by type for a patient over time was calculated. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	T-DM1 and Pertuzumab
Arm/Group Description	T-DM1 via IV every 3 weeks for 6 doses and Pertuzumab loading dose via IV on Cycle 1 Day 1 followed by maintenance dose via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor T-DM1: Participants will receive Trastuzumab emtansine (T-DM1) by IV every 3 weeks for 6 doses; for a total of 18 weeks of treatment. Pertuzumab: Participants will receive a loading dose of pertuzumab by IV on Cycle 1 Day 1 followed by maintenance dose of pertuzumab by IV every 3 weeks for a total of 6 doses; for a total of 18 weeks of treatment. Excision of tumor/mastectomy: Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.
All Cause Mortality
	T-DM1 and Pertuzumab
	Affected / at Risk (%)	# Events
Total	0/163 (0%)
Serious Adverse Events
	T-DM1 and Pertuzumab
	Affected / at Risk (%)	# Events
Total	11/163 (6.7%)
Blood and lymphatic system disorders
Anemia	1/163 (0.6%)
Gastrointestinal disorders
Diarrhea	4/163 (2.5%)
General disorders
Fatigue	1/163 (0.6%)
Investigations
Platelet count decreased	2/163 (1.2%)
Metabolism and nutrition disorders
Hypokalemia	2/163 (1.2%)
Hyponatremia	1/163 (0.6%)
Other (Not Including Serious) Adverse Events
	T-DM1 and Pertuzumab
	Affected / at Risk (%)	# Events
Total	162/163 (99.4%)
Blood and lymphatic system disorders
Anemia	27/163 (16.6%)
Blood and lymphatic system disorders - Other, specify	2/163 (1.2%)
Cardiac disorders
Mitral valve disease	3/163 (1.8%)
Palpitations	5/163 (3.1%)
Sinus tachycardia	1/163 (0.6%)
Cardiac disorders - Other, specify	1/163 (0.6%)
Ear and labyrinth disorders
Ear pain	3/163 (1.8%)
Middle ear inflammation	1/163 (0.6%)
Tinnitus	2/163 (1.2%)
Vertigo	2/163 (1.2%)
Endocrine disorders
Hypothyroidism	1/163 (0.6%)
Gastrointestinal disorders
Diarrhea	2/163 (1.2%)
Dry mouth	2/163 (1.2%)
Nausea	3/163 (1.8%)
General disorders
Chills	2/163 (1.2%)
Edema limbs	2/163 (1.2%)
Fatigue	81/163 (49.7%)
Fever	3/163 (1.8%)
Flu like symptoms	4/163 (2.5%)
Infusion related reaction	3/163 (1.8%)
Non-cardiac chest pain	1/163 (0.6%)
Investigations
Alanine aminotransferase increased	2/163 (1.2%)
Skin and subcutaneous tissue disorders
Alopecia	1/163 (0.6%)
Dry skin	3/163 (1.8%)
Pruritus	1/163 (0.6%)
Rash acneiform	3/163 (1.8%)
Urticaria	1/163 (0.6%)
Skin and subcutaneous tissue disorders - Other, specify	1/163 (0.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.