A Study Of PF-05280014 Or Trastuzumab Plus Taxotere® And Carboplatin In HER2 Positive Breast Cancer In The Neoadjuvant Setting (REFLECTIONS B327-04)

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02187744
• Collaborator: (none)
• Enrollment: 226
• Locations: 52
• Arms: 2
• Actual Duration (Months): 17.5
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The current study will compare PK, efficacy, safety, and immunogenicity of PF-05280014 (Trastuzumab-Pfizer) in combination with Taxotere® and Carboplatin (Paraplatin) versus Herceptin® (Trastuzumab-EU) approved in the EU in combination with Taxotere® and Carboplatin (Paraplatin) in patients with operable HER2 positive, breast cancer in the neoadjuvant setting. The hypothesis to be tested in this study is the percentage of patients with steady state Cycle 5 Ctrough (Cycle 6 pre-dose) >20 µg/mL of trastuzumab-Pfizer is similar to EU-approved trastuzumab, using a margin of -12.5%.

Condition or Disease	Intervention/Treatment	Phase
Early Breast Cancer	Biological: PF-05280014; Drug: Taxotere®; Drug: Paraplatin®; Biological: Trastuzumab-EU; Drug: Taxotere®; Drug: Paraplatin®	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 226 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A RANDOMIZED, DOUBLE-BLIND PHARMACOKINETIC STUDY OF PF-05280014 PLUS TAXOTERE (REGISTERED) AND CARBOPLATIN VERSUS HERCEPTIN (REGISTERED) PLUS TAXOTERE (REGISTERED) AND CARBOPLATIN FOR THE NEOADJUVANT TREATMENT OF PATIENTS WITH OPERABLE HER2-POSITIVE BREAST CANCER
• Actual Study Start Date: Sep 23, 2014
• Actual Primary Completion Date: Mar 9, 2016
• Actual Study Completion Date: Mar 9, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PF-05280014	Biological: PF-05280014; Concentrate for solution for infusion, sterile vial 150 mg, Day 1 Cycle 1 will be a loading dose of 8 mg/kg infused over 90 minutes. Subsequent infusions will follow every 3 weeks (i.e., cycled every 21 days) with a dose of 6 mg/kg administered over 30 to 90 minutes depending on tolerability, maximum of 6 cycles.; Drug: Taxotere®; Injection concentrate single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL), each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80, The starting dose of Taxotere® (docetaxel) will be 75 mg/m2 administered intravenously over 60 minutes every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.; Other Names: docetaxel ; Drug: Paraplatin®; Lyophilized powder, single-dose vials containing 50 mg, 150 mg, and 450 mg of Carboplatin for administration by intravenous infusion (each vial contains equal parts by weight of Carboplatin and mannitol), starting dose 6 AUC, over 15 minutes or longer every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.; Other Names: carboplatin
Active Comparator: Herceptin®	Biological: Trastuzumab-EU; Concentrate for solution for infusion, sterile vial 150 mg, Day 1 Cycle 1 will be a loading dose of 8 mg/kg infused over 90 minutes. Subsequent infusions will follow every 3 weeks (i.e., cycled every 21 days) with a dose of 6 mg/kg administered over 30 to 90 minutes depending on tolerability, maximum 6 cycles.; Drug: Taxotere®; Injection concentrate single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL), each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80, The starting dose of Taxotere® (docetaxel) will be 75 mg/m2 administered intravenously over 60 minutes every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.; Other Names: docetaxel ; Drug: Paraplatin®; Lyophilized powder, single-dose vials containing 50 mg, 150 mg, and 450 mg of Carboplatin for administration by intravenous infusion (each vial contains equal parts by weight of Carboplatin and mannitol), starting dose 6 AUC, over 15 minutes or longer every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.; Other Names: carboplatin

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5. [Cycle 5]

   The percentage of participants with Cycle 5 Ctrough (Cycle 6 pre-dose) >20 μg/mL in each treatment group, the denominator being the number of participants in the per protocol population for each treatment group.

Secondary Outcome Measures

1. Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. [Cycles 1 through 6]

   Samples of blood were taken pre-dose on Cycles 1, 2, 4, 5, and 6, and at 1 hour post dose on Cycles 1 and 5 for pharmacokinetic evaluation.

2. Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes. [Cycle 6/End of treatment]

   Following surgery after treatment completion, tumors were assessed as Complete Pathological Response, Partial Pathological Response, or No Pathological Response.

3. Objective Response Rate (ORR) Defined as the Percentage of Participants Having Complete or Partial Response at End of Treatment, Based on Radiographic Assessments of the Tumor. [Cycle 6/End of treatment]

   ORR was defined as Complete Response (CR), Partial Response (PR), Stable (SD), Progressive Disease (PD) or Indeterminate (IND). ORR was the percentage of participants who had CR or PR at Cycle 6/End of treatment.

4. Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. [Cycles 1 through 6]

   The number of participants with positive (titer >=1.00) pre-dose ADA samples, participants counted towards the total if for at least one sample, the ADA was positive.

5. Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. [Cycles 1 through 6]

   The number of participants with positive (NAb response >=1.48) pre-dose NAb samples, participants counted towards the total if for at least one sample, the NAb was positive.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed HER2 overexpressing invasive breast cancer.

• Plan for definitive surgical resection of breast tumor (i.e., lumpectomy or mastectomy, and sentinel node (SN) biopsy or axillary lymph node dissection (ALND).

• Plan for neoadjuvant chemotherapy.

• Measurable disease in the breast after diagnostic biopsy, defined as longest diameter ≥ 2.0 cm.

Exclusion Criteria:

• Bilateral breast cancer.

• Inflammatory breast cancer.

• Presence of known distant metastases.

• Received prior treatment, including chemotherapy, endocrine therapy, biologic therapy, radiation or surgery with the exception of diagnostic biopsy for primary breast cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Compassionate Cancer Care Medical Group, Inc.	Fountain Valley	California	United States	92708
2	Millennium Oncology (Imaging Facility)	Kingwood	Texas	United States	77339
3	Millennium Oncology (Imaging Facility)	Shenandoah	Texas	United States	77380
4	Millennium Oncology	Shenandoah	Texas	United States	77384
5	SI 'Republican Research and Practice Centre of Oncology and Medical Radiology n.a. N.N. Alexandrov'	Lesnoy	Minsk Region	Belarus	223040
6	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
7	Bacs-Kiskun Megyei Korhaz	Kecskemet	Bacs-kiskun	Hungary	6000
8	Semmelweis Egyetem Altalanos Orvostudomanyi Kar-I. sz. Belgyogyaszati Klinika Onkologiai Reszleg	Budapest		Hungary	1083
9	Szent Imre Egyetemi Oktato Korhaz	Budapest		Hungary	1115
10	Uzsoki Utcai Korhaz, Onkoradiologia, Sugarterapia Fovarosi Onkoradiologiai Kozpont	Budapest		Hungary	1145
11	Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktatokorhaz,	Miskolc		Hungary	3526
12	Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz - Rendelointezet	Szolnok		Hungary	5000
13	Division of Medical Senology	Milano	MI	Italy	20141
14	Divisione di Oncologia Medica B	Roma	RM	Italy	00144
15	IRCCS Istituto Nazionale Tumori Regina Elena (IRE)	Roma	RM	Italy	00144
16	Dept. of Surgery	Roma	RM	Italy	00168
17	Szpitale Wojewodzkie w Gdyni Sp. z o.o., Oddzial Onkoligii i Radioterapii	Gdynia		Poland	81-519
18	Oddzial Chorob Rozrostowych	Lodz		Poland	93-513
19	SPZOZ MSW z Warminsko-Mazurskim Centrum Onkologii w Olsztynie	Olsztyn		Poland	10-228
20	State Budgetary Healthcare Institution "Leningrad Regional Oncological Dispensary"	Kuzmolovo	Leningrad Region	Russian Federation	188663
21	"State Budgetary Healthcare Institution ""Republican Clinical Oncological Dispensary of the Ministry	Ufa	Republic Bashkortost	Russian Federation	450054
22	Regional Budgetary Healthcare Institution "Kursk regional clinical oncological Dispensary"	Kislino Settlement	Ryshkovskiy Village Council	Russian Federation	305524
23	"State Budgetary Healthcare Institution of Stavropol Region ""Pyatigorsk Oncological Dispensary"""	Pyatigorsk	Stavropol Region	Russian Federation	357502
24	State Budgetary Healthcare Institution "Volgograd Regional Oncological Dispensary #3"	Volzhskiy	Volgograd Region	Russian Federation	404130
25	SBHI "Regional Oncology Dispensary"	Irkutsk		Russian Federation	664035
26	Regional Budgetary Healthcare Institution	Kursk		Russian Federation	305035
27	FSBI "Russian Oncology Scientific center n.a. N. N. Blokhin" RAMS	Moscow		Russian Federation	115478
28	State Budgetary Institution Of Healthcare	Moscow		Russian Federation	129301
29	SBHI of NNR "Clinical diagnostic center"	Nizhniy Novgorod		Russian Federation	603006
30	State Budgetary Healthcare Institution of NNR "Nizhniy Novgorod Regional Oncological Dispensary"	Nizhniy Novgorod		Russian Federation	603081
31	Budgetary Institution of healthcare of Omsk region "Clinical oncological dispensary"	Omsk		Russian Federation	644046
32	State Budgetary Educational Institution of Higher Professional Education "North-Western State	Saint-Petersburg		Russian Federation	195067
33	Saint-Peterbsurg Clinical Oncological dispensary of Moscow district	Saint-Petersburg		Russian Federation	196247
34	Saint-Petersburg State Budgetary Healthcare Institution "Oncological Dispensary of Moscow District"	Saint-Petersburg		Russian Federation	196247
35	LLC RAMSAY Diagnostic RUS	Saint-Petersburg		Russian Federation	197046
36	"Federal State Institution ""Scientific Research Institute of Oncology n.a. N.N.Petrov""	Saint-Petersburg		Russian Federation	197758
37	Saint-Petersburg State Budgetary Institution of healthcare "City Clinical Oncological Dispensary"	Saint-Petersburg		Russian Federation	198255
38	SRBHI "Regional Clinical Oncology Dispensary"	Velikiy Novgorod		Russian Federation	173023
39	Institute For Oncology And Radiology Of Serbia	Belgrade		Serbia	11000
40	Onkologicky ustav sv. Alzbety, s.r.o.	Bratislava		Slovakia	812 50
41	Narodny Onkologicky ustav	Bratislava		Slovakia	833 10
42	Vychodoslovensky onkologicky ustav, a.s.	Kosice		Slovakia	04191
43	Municipal Healthcare Institution 'Chernihiv Regional Oncology Dispensary', Mamology Department	Chernihiv		Ukraine	14029
44	MI 'City Dnipropetrovsk Multi-field Clin. Hospital #4 of DRC', Dep.-nt of Chemotherapy;	Dnipropetrovsk		Ukraine	49102
45	SI "Institute of Medical Radiology n.a.S.P. Hrygoriev of National Academy	Kharkiv		Ukraine	61024
46	Munincipal Healthcare Institution"Kharkiv Regional Clinical Oncologic Center	Kharkiv		Ukraine	61070
47	Khmelnytskyi Regional Oncologic Dispensary	Khmelnytskyi		Ukraine	29009
48	MI 'Kryvyi Rih Oncology Dispensary of Dnipropetrovsk Regional Council'	Kryvyi Rih		Ukraine	50048
49	Lviv State Oncologic Regional Treatment and Diagnostic Center	Lviv		Ukraine	79031
50	Municipal Institution 'Odesa Regional Clinical Hospital', Mamology Center	Odesa		Ukraine	65025
51	Regional Municipal Institution "Sumy Regional Clinical Oncology Dispensary", Thoracic Department	Sumy		Ukraine	40005
52	Vinnytsia Regional Oncology Clinical Dispensary, Chemotherapy Department	Vinnytsia		Ukraine	21029

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02187744
• Other Study ID Numbers: B3271004; REFLECTIONS B327-04; 2013-004679-11; REFLECTIONS (B327-04)
• First Posted: Jul 11, 2014
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Pfizer: Biosimilars; Non-inferiority; Neoadjuvant Setting; Early Breast Cancer; PK; Phase 3; Trastuzumab; Herceptin; HER2 Positive
• Additional relevant MeSH terms: Breast Neoplasms; Carboplatin; Docetaxel; Trastuzumab

Study Results

Participant Flow

Pre-assignment Detail	A single participant was randomized but not treated; this participant was included in the ITT population, but not in the Participant Flow, Per Protocol, or Safety populations.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin area under the concentration versus time curve (AUC) 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Period Title: Study
STARTED	113	112
COMPLETED	109	106
NOT COMPLETED	4	6
Period Title: Study
STARTED	113	112
COMPLETED	109	107
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	PF-05280014	Trastuzumab-EU	Total
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Total of all reporting groups
Overall Participants	114	112	226
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.0 (11.9)	51.2 (12.7)	52.6 (12.3)
Sex/Gender, Customized (Number) [Number]
Female	114 100%	112 100%	226 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5.
Description	The percentage of participants with Cycle 5 Ctrough (Cycle 6 pre-dose) >20 μg/mL in each treatment group, the denominator being the number of participants in the per protocol population for each treatment group.
Time Frame	Cycle 5

Outcome Measure Data

Analysis Population Description

All participants who were HER2+ and randomized into the study; and who had received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	101	89
Number (95% Confidence Interval) [Percentage of participants]	92.1 80.8%	93.3 83.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The hypothesis to be tested in this study is the percentage of participants with steady state (Cycle 5) Ctrough >20 μg/mL of PF-05280014 is non-inferior to trastuzumab-EU using a margin of -12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -8.02 to 6.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.70
	Estimation Comments	Stratified analysis was based on the normal approximation to the binomial distribution, adjusting for the randomization strata of primary tumor size, estrogen receptor status and by progesterone receptor status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The hypothesis to be tested in this study is the percentage of participants with steady state (Cycle 5) Ctrough >20 μg/mL of PF-05280014 is non-inferior to trastuzumab-EU using a margin of -12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -8.59 to 6.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.78
	Estimation Comments	Unstratified analysis.

2. Secondary Outcome

Title	Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6.
Description	Samples of blood were taken pre-dose on Cycles 1, 2, 4, 5, and 6, and at 1 hour post dose on Cycles 1 and 5 for pharmacokinetic evaluation.
Time Frame	Cycles 1 through 6

Outcome Measure Data

Analysis Population Description

All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	101	89
Cycle 1/Day 1 0 hours N= 101, 88	2.313 (17.949)	1.318 (12.366)
Cycle 1/Day 1 1 hour N= 97, 80	160.4 (57.329)	164.8 (47.033)
Cycle 2/Day 21 0 hours N= 99, 88	24.29 (13.796)	27.20 (10.650)
Cycle 4/Day 63 0 hours N= 98, 89	33.43 (14.488)	37.33 (15.629)
Cycle 5/Day 84 0 hours N= 101, 87	35.01 (15.571)	40.44 (26.765)
Cycle 5/Day 84 1 hour N= 90, 80	137.0 (37.748)	138.8 (37.417)
Cycle 6/Day 105 0 hours N= 101, 89	37.77 (17.523)	40.10 (16.670)

3. Secondary Outcome

Title	Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes.
Description	Following surgery after treatment completion, tumors were assessed as Complete Pathological Response, Partial Pathological Response, or No Pathological Response.
Time Frame	Cycle 6/End of treatment

Outcome Measure Data

Analysis Population Description

All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	100	86
Number (95% Confidence Interval) [Percentage of participants]	47.0 41.2%	50.0 44.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.81
	Confidence Interval	(2-Sided) 95%; -16.58 to 10.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.03
	Estimation Comments	Stratified analysis was based on the normal approximation to the binomial distribution, adjusting for the randomization strata of primary tumor size, estrogen receptor status and by progesterone receptor status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.00
	Confidence Interval	(2-Sided) 95%; -17.40 to 11.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.35
	Estimation Comments	Unstratified analysis.

4. Secondary Outcome

Title	Objective Response Rate (ORR) Defined as the Percentage of Participants Having Complete or Partial Response at End of Treatment, Based on Radiographic Assessments of the Tumor.
Description	ORR was defined as Complete Response (CR), Partial Response (PR), Stable (SD), Progressive Disease (PD) or Indeterminate (IND). ORR was the percentage of participants who had CR or PR at Cycle 6/End of treatment.
Time Frame	Cycle 6/End of treatment

Outcome Measure Data

Analysis Population Description

All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	101	89
Number (95% Confidence Interval) [Percentage of participants]	88.1 77.3%	82.0 73.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.96
	Confidence Interval	(2-Sided) 95%; -4.01 to 15.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.09
	Estimation Comments	Stratified analysis was based on the normal approximation to the binomial distribution, adjusting for the randomization strata of primary tumor size, estrogen receptor status and by progesterone receptor status.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PF-05280014, Trastuzumab-EU
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.10
	Confidence Interval	(2-Sided) 95%; -4.08 to 16.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.19
	Estimation Comments	Unstratified analysis.

5. Secondary Outcome

Title	Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6.
Description	The number of participants with positive (titer >=1.00) pre-dose ADA samples, participants counted towards the total if for at least one sample, the ADA was positive.
Time Frame	Cycles 1 through 6

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	113	112
Cycle 1 (n=113,112)	0 0%	1 0.9%
Cycle 2 (n=111,112)	0 0%	0 0%
Cycle 4 (n=108,109)	0 0%	0 0%
Cycle 6 (n=108,108)	0 0%	0 0%

6. Secondary Outcome

Title	Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6.
Description	The number of participants with positive (NAb response >=1.48) pre-dose NAb samples, participants counted towards the total if for at least one sample, the NAb was positive.
Time Frame	Cycles 1 through 6

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	PF-05280014	Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.	Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
Measure Participants	113	112
Cycle 1 (n=113,112)	0 0%	0 0%
Cycle 2 (n=110,112)	0 0%	0 0%
Cycle 4 (n=108,110)	0 0%	0 0%
Cycle 6 (n=108,108)	0 0%	0 0%

Adverse Events

Time Frame	Serious adverse events were captured from the beginning of the study drug treatment up to 6 months after the last dose. Treatment emergent adverse events were captured from the beginning of the study drug treatment up to 50 days after the last dose.
Adverse Event Reporting Description	Treatment emergent adverse events were defined as any adverse event that occurred or any preexisting adverse event that worsened within the reporting time frame.
Arm/Group Title	PF-05280014		Trastuzumab-EU
Arm/Group Description	Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.		Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle.
All Cause Mortality
	PF-05280014		Trastuzumab-EU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	PF-05280014		Trastuzumab-EU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/113 (6.2%)		6/112 (5.4%)
Blood and lymphatic system disorders
Febrile neutropenia	1/113 (0.9%)		2/112 (1.8%)
Neutropenia	1/113 (0.9%)		1/112 (0.9%)
Anaemia	0/113 (0%)		1/112 (0.9%)
Pancytopenia	1/113 (0.9%)		0/112 (0%)
Gastrointestinal disorders
Proctitis	1/113 (0.9%)		0/112 (0%)
Infections and infestations
Device related sepsis	1/113 (0.9%)		0/112 (0%)
Gastrointestinal infection	0/113 (0%)		1/112 (0.9%)
Injection site abscess	1/113 (0.9%)		0/112 (0%)
Tooth infection	0/113 (0%)		1/112 (0.9%)
Injury, poisoning and procedural complications
Hip fracture	0/113 (0%)		1/112 (0.9%)
Investigations
Blood creatinine increased	1/113 (0.9%)		0/112 (0%)
Metabolism and nutrition disorders
Dehydration	0/113 (0%)		1/112 (0.9%)
Hypokalaemia	0/113 (0%)		1/112 (0.9%)
Other (Not Including Serious) Adverse Events
	PF-05280014		Trastuzumab-EU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/113 (93.8%)		106/112 (94.6%)
Blood and lymphatic system disorders
Anaemia	56/113 (49.6%)		51/112 (45.5%)
Neutropenia	37/113 (32.7%)		41/112 (36.6%)
Leukopenia	16/113 (14.2%)		25/112 (22.3%)
Thrombocytopenia	16/113 (14.2%)		19/112 (17%)
Febrile neutropenia	3/113 (2.7%)		6/112 (5.4%)
Gastrointestinal disorders
Nausea	38/113 (33.6%)		34/112 (30.4%)
Diarrhoea	16/113 (14.2%)		19/112 (17%)
Vomiting	7/113 (6.2%)		10/112 (8.9%)
General disorders
Asthenia	36/113 (31.9%)		23/112 (20.5%)
Fatigue	15/113 (13.3%)		19/112 (17%)
Pyrexia	6/113 (5.3%)		5/112 (4.5%)
Investigations
Alanine aminotransferase increased	7/113 (6.2%)		10/112 (8.9%)
Aspartate aminotransferase increased	3/113 (2.7%)		7/112 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	13/113 (11.5%)		9/112 (8%)
Musculoskeletal and connective tissue disorders
Arthralgia	16/113 (14.2%)		8/112 (7.1%)
Bone pain	13/113 (11.5%)		5/112 (4.5%)
Nervous system disorders
Peripheral sensory neuropathy	7/113 (6.2%)		4/112 (3.6%)
Dysgeusia	4/113 (3.5%)		6/112 (5.4%)
Neuropathy peripheral	6/113 (5.3%)		4/112 (3.6%)
Skin and subcutaneous tissue disorders
Alopecia	72/113 (63.7%)		69/112 (61.6%)

Limitations/Caveats

It was decided that the secondary study objective to explore the relationship between drug exposure and pCR for PF-05280014 versus trastuzumab-EU would not be analyzed.

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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.