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A Study of Pertuzumab in Combination With Herceptin in Patients With HER2 Positive Breast Cancer.

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT00545688
Collaborator
(none)
417
Enrollment
77
Locations
4
Arms
98.9
Actual Duration (Months)
5.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This 4 arm study will evaluate the efficacy and safety of 4 neoadjuvant treatment regimens in female patients with locally advanced, inflammatory or early stage HER2 positive breast cancer. Before surgery, patients will be randomized to one of 4 treatment arms, to receive 4 cycles of a)Herceptin + docetaxel b)Herceptin + docetaxel + pertuzumab c)Herceptin + pertuzumab or 4)pertuzumab + docetaxel. Pertuzumab will be administered at a loading dose of 840mg iv, then 420mg iv 3-weekly, Herceptin at a loading dose of 8mg/kg iv then 6mg/kg 3-weekly, and docetaxel at a dose of 75mg/m2 escalating to 100mg/m2 3-weekly. During the entire pre- and post-surgery period all patients will receive adequate chemotherapy as per standard of care, as well as any surgery and/or radiotherapy as required. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
417 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open Label Study to Compare the Complete Pathological Response Rate Achieved With 4 Combinations of Herceptin, Docetaxel and Pertuzumab in Patients With Locally Advanced, Inflammatory or Early Stage HER2 Positive Breast Cancer
Actual Study Start Date :
Jun 26, 2006
Actual Primary Completion Date :
Sep 22, 2014
Actual Study Completion Date :
Sep 22, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

Drug: Herceptin
8mg/kg iv loading dose, followed by 6mg/kg iv 3-weekly
Other Names:
  • Trastuzumab

    • Drug: Docetaxel
    75mg/m2 iv escalating to 100mg/m2 iv 3-weekly
    Experimental: 2

    Drug: Herceptin
    8mg/kg iv loading dose, followed by 6mg/kg iv 3-weekly
    Other Names:
  • Trastuzumab

    • Drug: Docetaxel
    75mg/m2 iv escalating to 100mg/m2 iv 3-weekly

    Drug: Pertuzumab
    840mg iv loading dose, followed by 420mg iv 3-weekly
    Experimental: 3

    Drug: Herceptin
    8mg/kg iv loading dose, followed by 6mg/kg iv 3-weekly
    Other Names:
  • Trastuzumab

    • Drug: Pertuzumab
    840mg iv loading dose, followed by 420mg iv 3-weekly
    Experimental: 4

    Drug: Docetaxel
    75mg/m2 iv escalating to 100mg/m2 iv 3-weekly

    Drug: Pertuzumab
    840mg iv loading dose, followed by 420mg iv 3-weekly

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Achieving Pathological Complete Response (pCR) [Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)]

      pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders

    2. Percentage of Participants Achieving pCR by Breast Cancer Type [Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)]

      pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders.

    3. Percentage of Participants Achieving pCR by Hormone Receptor Status [Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)]

      pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders.

    4. Percentage of Participants Achieving pCR by Lymph Node Status [Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)]

      pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders.

    5. Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) [Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)]

      pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders.

    Secondary Outcome Measures

    1. Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography [Baseline up to Cycle 4 (assessed at, Baseline and Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline.

    2. Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.

    3. Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.

    4. Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.

    5. Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined.

    6. Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined.

    7. Time to Clinical Response During Neo-Adjuvant Treatment Period [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment.

    8. Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period [Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months]

      Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease.

    9. Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned [Surgery (Within 2 weeks after Cycle 4) Up to approximately 24 months]

      Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy.

    10. Percentage of Participants Who Were Progression Free and Disease Free [Randomization up to a maximum of 329 weeks]

      Disease-free survival (DFS) was defined as the time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from the study without documented progression and for whom evaluations were made, were censored at date of last assessment when participant was known to be disease-free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease. Participants without post baseline assessments but known to be alive were censored at the time of randomization.

    11. Progression Free and Disease Free Survival [Randomization up to a maximum of 329 weeks]

      DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates.

    Eligibility Criteria

    Criteria

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

    • female patients, >=18 years of age;

    • locally advanced, inflammatory or early stage invasive breast cancer;

    • HER2 positive (HER2+++ by IHC or FISH/CISH+).

    Exclusion Criteria:

    • metastatic disease (Stage IV) or bilateral breast cancer;

    • previous anticancer therapy or radiotherapy for any malignancy;

    • other malignancy, other than cancer in situ of the cervix, or basal cell cancer;

    • insulin-dependent diabetes;

    • clinically relevant cardiovascular disease.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Geelong Hospital; Andrew Love Cancer Centre Geelong Victoria Australia 3220
    2 Mount Medical Center Perth Western Australia Australia 6000
    3 Kaiser Franz Josef Spital; Iii. Medizinische Abt. Mit Onkologie Vienna Austria 1100
    4 Medizinische Universität Wien; Univ.Klinik für Innere Medizin I Wien Austria 1090
    5 Hospital de Caridade de Ijui; Oncologia Ijui RS Brazil 98700-000
    6 Hospital Nossa Senhora da Conceicao Porto Alegre RS Brazil 91350-200
    7 Clinica de Neoplasias Litoral Itajai SC Brazil 88301-220
    8 Hospital Amaral Carvalho Jau SP Brazil 17210-080
    9 Faculdade de Medicina do ABC - FMABC; Oncologia e Hematologia Santo Andre SP Brazil 09060-650
    10 Instituto do Cancer Arnaldo Vieira de Carvalho - ICAVC; Pesquisa Clinica Sao Paulo SP Brazil 01221-020
    11 Hospital Perola Byington Sao Paulo SP Brazil 01317-000
    12 Inst. Brasileiro de Controle Ao Cancer; Oncologia Clinica / Quimioterapia Sao Paulo SP Brazil 03102-002
    13 Instituto de Oncologia de Sorocaba - CEPOS Sorocaba SP Brazil 18030-245
    14 Moncton Hospital Moncton New Brunswick Canada E1C 6Z8
    15 Cancer Centre of Southeastern Ontario; Kingston General Hospital Kingston Ontario Canada K7L 5P9
    16 University Health Network; Princess Margaret Hospital; Medical Oncology Dept Toronto Ontario Canada M5G 2M9
    17 McGill University; Montreal General Hosptial; Oncology Montreal Quebec Canada H3G 1A4
    18 CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY Quebec Canada G1S 4L8
    19 Hadassah Ein Karem Hospital; Oncology Dept Jerusalem Israel 91120-01
    20 Meir Medical Center; Oncology Kfar-Saba Israel 4428164
    21 Sourasky / Ichilov Hospital; Dept. of Oncology Tel Aviv Israel 6423906
    22 Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli Bologna Emilia-Romagna Italy 40138
    23 Ospedale Regionale Di Parma; Divisione Di Oncologia Medica Parma Emilia-Romagna Italy 43100
    24 Azienda Ospedaliero-Universitaria Dipartimento Interaziendale Di Oncologia Udine Friuli-Venezia Giulia Italy 33100
    25 ASST OVEST MILANESE; Oncologia Medica Legnano Lombardia Italy 20025
    26 Ospedale San Raffaele, Servizio di Oncologia e Chemioterapia Milano Lombardia Italy 20132
    27 Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1 Milano Lombardia Italy 20133
    28 Ospedale Calvi di Noale; U.O. Complessa di Oncologia ed Ematologia Oncologica Mirano Veneto Italy 30035
    29 Polo Ospedaliero Santorso Santorso Veneto Italy 36014
    30 Ospedale Di Vicenza; Nefrologia, Oncologia Medica Vicenza Veneto Italy 36100
    31 Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology Seoul Korea, Republic of 03080
    32 Samsung Medical Centre; Division of Hematology/Oncology Seoul Korea, Republic of 135-710
    33 Hospital Miguel Hidalgo Aguascalientes Mexico 20230
    34 ARKE Estudios Clínicos S.A. de C.V. Mexico City Mexico 06700
    35 Issstep Puebla, ; Oncology Puebla Mexico 72530
    36 Instituto Regional de Enfermedades Neoplásicas del Sur; Centro de Inv. de Medicina Oncológica Arequipa Peru 5154
    37 Hospital Nacional Edgardo Rebagliati Martins; Oncologia Lima Peru 11
    38 Samodzielny Publiczny Kliniczny Nr 1 W Lublinie; Klinika Chirurgii Onkologicznej Lublin Poland 20-081
    39 COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej Lublin Poland 20-090
    40 Olsztyński Ośrodek Onkologiczny Kopernik sp. z o.o. Olsztyn Poland 10-513
    41 Oddzial Chemioterapii Szpitala Klinicznego Nr 1 w Poznaniu Poznan Poland 60-569
    42 NZOZ Centrum Medyczne HCP Sp. z o.o. Poznan Poland 61-485
    43 Central Hospital of Military School of Medicine; Oncology Warszawa Poland 00-909
    44 Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie Klinika Nowotworów Piersi i Chirurgii Warszawa Poland 02-781
    45 FSBI "Scientific Research Institute of Oncology named after N.N.Petrov" Ministry of Health of RF St Petersburg Leningrad Russian Federation 197758
    46 SI of Healthcare Kazan Oncology Dispensary Kazan Russian Federation 420111
    47 Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy Moscow Russian Federation 115478
    48 NSI of Healthcare Central Clinical Hospital #2 n.a. N.A.Semashko of the Russian Railways Moscow Russian Federation 129128
    49 State Institution Of Healthcare Republican Oncology Dispensary Petrozavodsk Russian Federation 185007
    50 State Budget Institution of Healthcare of Stavropol region Pyatigorsk Oncology Dispensary Pyatigorsk Russian Federation 357502
    51 SBI for HPE "Ryazan State Medical University n.a. I.P. Pavlov" of MoH of RF Ryazan Russian Federation 390011
    52 SBI of Healthcare Samara Regional Clinical Oncology Dispensary Samara Russian Federation 443031
    53 SI of HealthCare Oncologic Dispensary #2 of department of healthcare of Krasnodar region Soshi Russian Federation 354057
    54 SBI of Healthcare Leningrad Regional Oncology Dispensary St Petersburg Russian Federation 191104
    55 Ulyanovsk Regional Oncology Dispensary; Chemotherapy Ulyanovsk Russian Federation ND
    56 Corporacio Sanitaria Parc Tauli; Servicio de Oncologia Sabadell Barcelona Spain 08208
    57 Hospital de Cruces; Servicio de Oncologia Barakaldo Vizcaya Spain 48903
    58 Hospital Universitario Reina Sofia; Servicio de Oncologia Cordoba Spain 14004
    59 Hospital General Universitario Gregorio Marañon; Servicio de Oncologia Madrid Spain 28007
    60 Hospital Ramon y Cajal; Servicio de Oncologia Madrid Spain 28034
    61 Hospital Universitario La Paz; Servicio de Oncologia Madrid Spain 28046
    62 Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia Valencia Spain 46010
    63 Hospital Universitario Miguel Servet; Servicio Oncologia Zaragoza Spain 50009
    64 Karolinska Hospital; Oncology - Radiumhemmet Stockholm Sweden 17176
    65 Akademiska sjukhuset, Onkologkliniken Uppsala Sweden 75185
    66 Kantonsspital Baden; Frauenklinik Baden Switzerland 5405
    67 Brustzentrum Zürich Switzerland 8008
    68 VETERANS GENERAL HOSPITAL; Department of General Surgery Taipei Taiwan 00112
    69 National Taiwan Uni Hospital; Dept of Oncology Taipei Taiwan 100
    70 Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology Taipei Taiwan 112
    71 Chulalongkorn Hospital; Medical Oncology Bangkok Thailand 10330
    72 Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology Bangkok Thailand 10700
    73 Prince of Songkla Uni ; Unit of Medical Oncology Songkhla Thailand 90110
    74 Dokuz Eylul Uni Medical Faculty; Oncology Dept Izmir Turkey 35340
    75 Hacettepe Uni Medical Faculty Hospital; Oncology Dept Sıhhiye, ANKARA Turkey 06100
    76 Walsgrave Hospital; Dept of Oncology Coventry United Kingdom CV2 2DX
    77 Christie Hospital; Breast Cancer Research Office Manchester United Kingdom M20 4QL

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT00545688
    Other Study ID Numbers:
    • WO20697
    First Posted:
    Oct 17, 2007
    Last Update Posted:
    Aug 15, 2017
    Last Verified:
    Jul 1, 2017
    Additional relevant MeSH terms:
    Breast Neoplasms
    Docetaxel
    Trastuzumab
    Pertuzumab

    Study Results

    Participant Flow

    Recruitment Details A total of 107, 107, 107, and 96 participants (total 417) were randomized to Arms Trastuzumab plus (+) Docetaxel (T+ D) , Trastuzumab+Pertuzumab+Docetaxel (T+Ptz+D), Trastuzumab+Pertuzumab (T+Ptz), and Pertuzumab+Docetaxel (Ptz+D), respectively and were included in intent-to-treat population (as randomized).
    Pre-assignment Detail 3 participants did not receive correct treatment, as randomized, and 1 (in Arm Trastuzumab + Docetaxel) did not receive any treatment. Safety population (as treated) included 107, 107, 108, and 94 participants in Arms 'T+D', 'T+Ptz+D', 'T+Ptz', and 'Ptz+D', respectively. Participant flow was available for "As Treated" participants.
    Arm/Group Title Trastuzumab + Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab intravenous (IV) infusion at a loading dose of 8 milligrams per kilogram (mg/kg) on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 milligrams per square meter (mg/m^2) on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by 5-fluorouracil 600 mg/m^2 IV, epirubicin 90 mg/m^2 IV, and cyclophosphamide 600 mg/m^2 IV (FEC) on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Period Title: Neo-Adjuvant Treatment Period
    STARTED 107 107 108 94
    COMPLETED 103 102 94 88
    NOT COMPLETED 4 5 14 6
    Period Title: Neo-Adjuvant Treatment Period
    STARTED 103 102 94 88
    COMPLETED 98 94 90 74
    NOT COMPLETED 5 8 4 14
    Period Title: Neo-Adjuvant Treatment Period
    STARTED 98 102 98 87
    COMPLETED 77 83 78 60
    NOT COMPLETED 21 19 20 27

    Baseline Characteristics

    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel Total
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21. Total of all reporting groups
    Overall Participants 107 107 107 96 417
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    50.9
    (8.94)
    49.6
    (10.05)
    49.7
    (10.67)
    48.9
    (10.50)
    49.8
    (10.04)
    Sex: Female, Male (Count of Participants)
    Female
    107
    100%
    107
    100%
    107
    100%
    96
    100%
    417
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Achieving Pathological Complete Response (pCR)
    Description pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders
    Time Frame Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    Number (95% Confidence Interval) [percentage of participants]
    29.0
    27.1%
    45.8
    42.8%
    16.8
    15.7%
    24.0
    25%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0094
    Comments Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in Response rates
    Estimated Value 16.82
    Confidence Interval (2-Sided) 95%
    3.5 to 30.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0141
    Comments P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0198
    Comments Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in Response rates
    Estimated Value -12.15
    Confidence Interval (2-Sided) 95%
    -23.8 to -0.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0198
    Comments P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0010
    Comments Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in Response rates
    Estimated Value -21.84
    Confidence Interval (2-Sided) 95%
    -35.1 to -8.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0030
    Comments P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
    Method Cochran-Mantel-Haenszel
    Comments
    2. Secondary Outcome
    Title Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography
    Description Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline.
    Time Frame Baseline up to Cycle 4 (assessed at, Baseline and Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 71 58 61 47
    CR
    18.3
    17.1%
    19.0
    17.8%
    13.1
    12.2%
    19.1
    19.9%
    PR
    49.3
    46.1%
    46.6
    43.6%
    36.1
    33.7%
    46.8
    48.8%
    SD
    31.0
    29%
    32.8
    30.7%
    44.3
    41.4%
    34.0
    35.4%
    PD
    1.4
    1.3%
    1.7
    1.6%
    6.6
    6.2%
    0.0
    0%
    3. Primary Outcome
    Title Percentage of Participants Achieving pCR by Breast Cancer Type
    Description pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders.
    Time Frame Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number (n) equal (=) number of participants included in the specified type of breast cancer.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    Operable Breast Cancer (n=64,65,65,60)
    23.4
    21.9%
    47.7
    44.6%
    16.9
    15.8%
    26.7
    27.8%
    Inflammatory Breast Cancer (n=7,10,7,5)
    14.3
    13.4%
    40.0
    37.4%
    28.6
    26.7%
    40.0
    41.7%
    Locally Advance Breast Cancer (36,32,35,31)
    41.7
    39%
    43.8
    40.9%
    14.3
    13.4%
    16.1
    16.8%
    4. Primary Outcome
    Title Percentage of Participants Achieving pCR by Hormone Receptor Status
    Description pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders.
    Time Frame Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. n = number of participants included in the specified hormone receptor status.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    Estrogen and/or Progesterone +ve (n=50,50,51,46)
    20.0
    18.7%
    26.0
    24.3%
    5.9
    5.5%
    17.4
    18.1%
    Estrogen and/or Progesterone -ve (n=57,57,55,50)
    36.8
    34.4%
    63.2
    59.1%
    27.3
    25.5%
    30.0
    31.3%
    Receptor Status Unknown (0,0,1,0)
    NA
    NaN
    NA
    NaN
    0.0
    0%
    NA
    NaN
    5. Primary Outcome
    Title Percentage of Participants Achieving pCR by Lymph Node Status
    Description pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders.
    Time Frame Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    pCR achieved and Negative Lymph Nodes at Surgery
    21.5
    20.1%
    39.3
    36.7%
    11.2
    10.5%
    17.7
    18.4%
    pCR achieved and Positive Lymph Nodes at Surgery
    7.5
    7%
    6.5
    6.1%
    5.6
    5.2%
    6.3
    6.6%
    6. Primary Outcome
    Title Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)
    Description pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders.
    Time Frame Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    pCR Achieved and No residual DCIS/LCIS at Surgery
    16.8
    15.7%
    36.4
    34%
    9.3
    8.7%
    17.7
    18.4%
    pCR Achieved and Residual DCIS/LCIS at Surgery
    12.1
    11.3%
    9.3
    8.7%
    7.5
    7%
    6.3
    6.6%
    7. Secondary Outcome
    Title Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography
    Description Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 71 53 55 43
    CR
    18.3
    17.1%
    18.9
    17.7%
    12.7
    11.9%
    18.6
    19.4%
    PR
    49.3
    46.1%
    49.1
    45.9%
    34.5
    32.2%
    46.5
    48.4%
    SD
    31.0
    29%
    30.2
    28.2%
    45.5
    42.5%
    34.9
    36.4%
    PD
    1.4
    1.3%
    1.9
    1.8%
    7.3
    6.8%
    0.0
    0%
    8. Secondary Outcome
    Title Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination
    Description Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 99 101 102 91
    CR
    23.2
    21.7%
    30.7
    28.7%
    16.7
    15.6%
    20.9
    21.8%
    PR
    56.6
    52.9%
    57.4
    53.6%
    51.0
    47.7%
    50.5
    52.6%
    SD
    20.2
    18.9%
    11.9
    11.1%
    30.4
    28.4%
    28.6
    29.8%
    PD
    0.0
    0%
    0.0
    0%
    2.0
    1.9%
    0.0
    0%
    9. Secondary Outcome
    Title Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination
    Description Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 97 100 98 88
    CR
    21.6
    20.2%
    25.0
    23.4%
    11.2
    10.5%
    15.9
    16.6%
    PR
    59.8
    55.9%
    63.0
    58.9%
    55.1
    51.5%
    58.0
    60.4%
    SD
    17.5
    16.4%
    12.0
    11.2%
    31.6
    29.5%
    26.1
    27.2%
    PD
    1.0
    0.9%
    0.0
    0%
    2.0
    1.9%
    0.0
    0%
    10. Secondary Outcome
    Title Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography
    Description Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 71 58 61 47
    Primary Breast Tumor (n=71,58,61,47)
    67.6
    63.2%
    65.5
    61.2%
    49.2
    46%
    66.0
    68.8%
    Overall Response (n=71,53,55,43)
    67.6
    63.2%
    67.9
    63.5%
    47.3
    44.2%
    65.1
    67.8%
    11. Secondary Outcome
    Title Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination
    Description Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 99 101 102 91
    Primary Breast Tumor (n=99,101,102,91)
    79.8
    74.6%
    88.1
    82.3%
    67.6
    63.2%
    71.4
    74.4%
    Overall Response (n=97,100,98,88)
    81.4
    76.1%
    88.0
    82.2%
    66.3
    62%
    73.9
    77%
    12. Secondary Outcome
    Title Time to Clinical Response During Neo-Adjuvant Treatment Period
    Description Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 99 101 102 91
    Median (80% Confidence Interval) [months]
    6.3
    6.3
    6.9
    7.3
    13. Secondary Outcome
    Title Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period
    Description Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease.
    Time Frame Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    Number (95% Confidence Interval) [percentage of participants]
    0.0
    0%
    0.9
    0.8%
    7.5
    7%
    2.1
    2.2%
    14. Secondary Outcome
    Title Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned
    Description Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy.
    Time Frame Surgery (Within 2 weeks after Cycle 4) Up to approximately 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 62 56 61 60
    Number (95% Confidence Interval) [percentage of participants]
    22.6
    21.1%
    23.2
    21.7%
    18.0
    16.8%
    31.7
    33%
    15. Secondary Outcome
    Title Percentage of Participants Who Were Progression Free and Disease Free
    Description Disease-free survival (DFS) was defined as the time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from the study without documented progression and for whom evaluations were made, were censored at date of last assessment when participant was known to be disease-free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease. Participants without post baseline assessments but known to be alive were censored at the time of randomization.
    Time Frame Randomization up to a maximum of 329 weeks

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    Progression Free
    82.2
    76.8%
    84.1
    78.6%
    74.8
    69.9%
    75.0
    78.1%
    Disease Free
    82.5
    77.1%
    85.1
    79.5%
    80.2
    75%
    76.1
    79.3%
    16. Secondary Outcome
    Title Progression Free and Disease Free Survival
    Description DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates.
    Time Frame Randomization up to a maximum of 329 weeks

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Analysis was performed according to initial randomization.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    Measure Participants 107 107 107 96
    PFS
    NA
    NaN
    71.0
    66.4%
    NA
    NaN
    NA
    NaN
    DFS
    NA
    NaN
    67.2
    62.8%
    NA
    NaN
    NA
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
    Comments PFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2983
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    0.34 to 1.40
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
    Comments PFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4722
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.25
    Confidence Interval (2-Sided) 95%
    0.68 to 2.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
    Comments PFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0268
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.05
    Confidence Interval (2-Sided) 95%
    1.07 to 3.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
    Comments DFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1805
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.60
    Confidence Interval (2-Sided) 95%
    0.28 to 1.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
    Comments DFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5901
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.83
    Confidence Interval (2-Sided) 95%
    0.42 to 1.64
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
    Comments DFS
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0250
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.16
    Confidence Interval (2-Sided) 95%
    1.08 to 4.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

    Adverse Events

    Time Frame Adverse events were recorded from the date of Screening until the clinical cut off date 20th October 2014 up to 7 years.
    Adverse Event Reporting Description The safety population included all participants who received at least one dose of study medication and at least one safety assessment performed at baseline. Participants were assigned to treatment groups according to treatment actually received.
    Arm/Group Title Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Arm/Group Description Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
    All Cause Mortality
    Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 21/107 (19.6%) 22/107 (20.6%) 19/108 (17.6%) 21/94 (22.3%)
    Blood and lymphatic system disorders
    Febrile neutropenia 10/107 (9.3%) 8/107 (7.5%) 4/108 (3.7%) 12/94 (12.8%)
    Neutropenia 1/107 (0.9%) 6/107 (5.6%) 3/108 (2.8%) 6/94 (6.4%)
    Cardiac disorders
    Left ventricular dysfunction 0/107 (0%) 3/107 (2.8%) 0/108 (0%) 0/94 (0%)
    Angina pectoris 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Cardiac failure congestive 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Gastrointestinal disorders
    Diarrhoea 2/107 (1.9%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Abdominal strangulated hernia 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Duodenal ulcer haemorrhage 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    General disorders
    Pyrexia 1/107 (0.9%) 1/107 (0.9%) 2/108 (1.9%) 1/94 (1.1%)
    Imparied healing 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Hepatobiliary disorders
    Cholecystitis acute 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Hepatitis fulminant 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Immune system disorders
    Drug hypersensitivity 0/107 (0%) 1/107 (0.9%) 1/108 (0.9%) 0/94 (0%)
    Infections and infestations
    Neutropenic infection 1/107 (0.9%) 1/107 (0.9%) 1/108 (0.9%) 0/94 (0%)
    Appendicitis 1/107 (0.9%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Pyelonephritis acute 0/107 (0%) 2/107 (1.9%) 0/108 (0%) 0/94 (0%)
    Urinary tract infection 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Wound infection 2/107 (1.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Breast abscess 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Cellulitis 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Device related infection 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    H1N1 influenza 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Infection 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Neutropenic sepsis 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Pneumonia 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Sepsis 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Septic shock 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Staphylococcal sepsis 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Injury, poisoning and procedural complications
    Femur fracture 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Upper limb fracture 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Wound dehiscence 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Spinal pain 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Nervous system disorders
    Dural arteriovenous fistula 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Reproductive system and breast disorders
    Metrorrhagia 1/107 (0.9%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Ovarian cyst ruptured 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Ovarian disorder 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Uterine haemorrhage 0/107 (0%) 0/107 (0%) 0/108 (0%) 1/94 (1.1%)
    Respiratory, thoracic and mediastinal disorders
    Epistaxis 1/107 (0.9%) 0/107 (0%) 0/108 (0%) 0/94 (0%)
    Skin and subcutaneous tissue disorders
    Rash papular 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Skin mass 0/107 (0%) 0/107 (0%) 1/108 (0.9%) 0/94 (0%)
    Vascular disorders
    Venous insufficiency 0/107 (0%) 1/107 (0.9%) 0/108 (0%) 0/94 (0%)
    Other (Not Including Serious) Adverse Events
    Trastuzumab+Docetaxel Trastuzumab+Pertuzumab+Docetaxel Trastuzumab+Pertuzumab Pertuzumab+Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 107/107 (100%) 105/107 (98.1%) 101/108 (93.5%) 94/94 (100%)
    Blood and lymphatic system disorders
    Neutropenia 80/107 (74.8%) 64/107 (59.8%) 46/108 (42.6%) 67/94 (71.3%)
    Leukopenia 24/107 (22.4%) 13/107 (12.1%) 13/108 (12%) 15/94 (16%)
    Anaemia 9/107 (8.4%) 6/107 (5.6%) 11/108 (10.2%) 12/94 (12.8%)
    Cardiac disorders
    Palpitations 2/107 (1.9%) 5/107 (4.7%) 7/108 (6.5%) 5/94 (5.3%)
    Left ventricular dysfunction 2/107 (1.9%) 6/107 (5.6%) 2/108 (1.9%) 5/94 (5.3%)
    Eye disorders
    Lacrimation increased 3/107 (2.8%) 8/107 (7.5%) 6/108 (5.6%) 6/94 (6.4%)
    Gastrointestinal disorders
    Nausea 70/107 (65.4%) 71/107 (66.4%) 52/108 (48.1%) 61/94 (64.9%)
    Diarrhoea 40/107 (37.4%) 55/107 (51.4%) 46/108 (42.6%) 52/94 (55.3%)
    Vomiting 31/107 (29%) 39/107 (36.4%) 31/108 (28.7%) 37/94 (39.4%)
    Stomatitis 12/107 (11.2%) 22/107 (20.6%) 21/108 (19.4%) 11/94 (11.7%)
    Abdominal pain upper 8/107 (7.5%) 9/107 (8.4%) 12/108 (11.1%) 12/94 (12.8%)
    Constipation 12/107 (11.2%) 14/107 (13.1%) 9/108 (8.3%) 6/94 (6.4%)
    Abdominal pain 9/107 (8.4%) 11/107 (10.3%) 8/108 (7.4%) 10/94 (10.6%)
    Haemorrhoids 5/107 (4.7%) 8/107 (7.5%) 8/108 (7.4%) 4/94 (4.3%)
    Dyspepsia 6/107 (5.6%) 6/107 (5.6%) 6/108 (5.6%) 5/94 (5.3%)
    Abdominal distension 1/107 (0.9%) 1/107 (0.9%) 2/108 (1.9%) 5/94 (5.3%)
    General disorders
    Fatigue 35/107 (32.7%) 35/107 (32.7%) 34/108 (31.5%) 37/94 (39.4%)
    Mucosal inflammation 28/107 (26.2%) 33/107 (30.8%) 18/108 (16.7%) 28/94 (29.8%)
    Asthenia 22/107 (20.6%) 29/107 (27.1%) 19/108 (17.6%) 23/94 (24.5%)
    Pyrexia 16/107 (15%) 25/107 (23.4%) 21/108 (19.4%) 14/94 (14.9%)
    Oedema peripheral 12/107 (11.2%) 7/107 (6.5%) 18/108 (16.7%) 9/94 (9.6%)
    Chills 8/107 (7.5%) 4/107 (3.7%) 10/108 (9.3%) 2/94 (2.1%)
    Chest pain 4/107 (3.7%) 2/107 (1.9%) 4/108 (3.7%) 6/94 (6.4%)
    Pain 2/107 (1.9%) 3/107 (2.8%) 3/108 (2.8%) 7/94 (7.4%)
    Oedema 1/107 (0.9%) 0/107 (0%) 6/108 (5.6%) 4/94 (4.3%)
    General Disorder 17/107 (15.9%) 16/107 (15%) 15/108 (13.9%) 26/94 (27.7%)
    Immune system disorders
    Drug hypersensitivity 2/107 (1.9%) 6/107 (5.6%) 12/108 (11.1%) 6/94 (6.4%)
    Infections and infestations
    Upper respiratory tract infection 12/107 (11.2%) 9/107 (8.4%) 11/108 (10.2%) 13/94 (13.8%)
    Nasopharyngitis 12/107 (11.2%) 8/107 (7.5%) 7/108 (6.5%) 5/94 (5.3%)
    Pharyngitis 8/107 (7.5%) 4/107 (3.7%) 4/108 (3.7%) 5/94 (5.3%)
    Urinary tract infection 7/107 (6.5%) 4/107 (3.7%) 3/108 (2.8%) 6/94 (6.4%)
    Injury, poisoning and procedural complications
    Radiation skin injury 21/107 (19.6%) 19/107 (17.8%) 22/108 (20.4%) 24/94 (25.5%)
    Infusion related reaction 6/107 (5.6%) 7/107 (6.5%) 8/108 (7.4%) 8/94 (8.5%)
    Seroma 6/107 (5.6%) 7/107 (6.5%) 4/108 (3.7%) 5/94 (5.3%)
    Procedural pain 2/107 (1.9%) 3/107 (2.8%) 6/108 (5.6%) 2/94 (2.1%)
    Incision site pain 1/107 (0.9%) 2/107 (1.9%) 3/108 (2.8%) 5/94 (5.3%)
    Investigations
    Alanine aminotransferase increased 9/107 (8.4%) 2/107 (1.9%) 2/108 (1.9%) 5/94 (5.3%)
    Weight increased 4/107 (3.7%) 2/107 (1.9%) 9/108 (8.3%) 1/94 (1.1%)
    Aspartate aminotransferase increased 9/107 (8.4%) 0/107 (0%) 2/108 (1.9%) 2/94 (2.1%)
    Metabolism and nutrition disorders
    Decreased appetite 19/107 (17.8%) 18/107 (16.8%) 15/108 (13.9%) 23/94 (24.5%)
    Musculoskeletal and connective tissue disorders
    Myalgia 24/107 (22.4%) 25/107 (23.4%) 29/108 (26.9%) 22/94 (23.4%)
    Arthralgia 16/107 (15%) 18/107 (16.8%) 13/108 (12%) 19/94 (20.2%)
    Musculoskeletal pain 13/107 (12.1%) 13/107 (12.1%) 5/108 (4.6%) 11/94 (11.7%)
    Bone pain 13/107 (12.1%) 11/107 (10.3%) 7/108 (6.5%) 8/94 (8.5%)
    Back pain 7/107 (6.5%) 7/107 (6.5%) 8/108 (7.4%) 11/94 (11.7%)
    Pain in extremity 9/107 (8.4%) 7/107 (6.5%) 7/108 (6.5%) 6/94 (6.4%)
    Nervous system disorders
    Headache 17/107 (15.9%) 14/107 (13.1%) 25/108 (23.1%) 22/94 (23.4%)
    Dysgeusia 16/107 (15%) 16/107 (15%) 14/108 (13%) 10/94 (10.6%)
    Peripheral sensory neuropathy 14/107 (13.1%) 10/107 (9.3%) 15/108 (13.9%) 14/94 (14.9%)
    Dizziness 8/107 (7.5%) 6/107 (5.6%) 14/108 (13%) 8/94 (8.5%)
    Neuropathy peripheral 10/107 (9.3%) 6/107 (5.6%) 4/108 (3.7%) 5/94 (5.3%)
    Paraesthesia 7/107 (6.5%) 2/107 (1.9%) 3/108 (2.8%) 5/94 (5.3%)
    Psychiatric disorders
    Insomnia 14/107 (13.1%) 13/107 (12.1%) 8/108 (7.4%) 14/94 (14.9%)
    Anxiety 2/107 (1.9%) 3/107 (2.8%) 6/108 (5.6%) 0/94 (0%)
    Reproductive system and breast disorders
    Menstruation irregular 7/107 (6.5%) 4/107 (3.7%) 10/108 (9.3%) 9/94 (9.6%)
    Respiratory, thoracic and mediastinal disorders
    Cough 11/107 (10.3%) 9/107 (8.4%) 19/108 (17.6%) 12/94 (12.8%)
    Epistaxis 6/107 (5.6%) 11/107 (10.3%) 6/108 (5.6%) 6/94 (6.4%)
    Oropharyngeal pain 7/107 (6.5%) 9/107 (8.4%) 2/108 (1.9%) 10/94 (10.6%)
    Dyspnoea 5/107 (4.7%) 7/107 (6.5%) 7/108 (6.5%) 4/94 (4.3%)
    Skin and subcutaneous tissue disorders
    Alopecia 75/107 (70.1%) 73/107 (68.2%) 59/108 (54.6%) 65/94 (69.1%)
    Rash 26/107 (24.3%) 30/107 (28%) 22/108 (20.4%) 30/94 (31.9%)
    Nail disorder 17/107 (15.9%) 13/107 (12.1%) 16/108 (14.8%) 13/94 (13.8%)
    Pruritus 8/107 (7.5%) 5/107 (4.7%) 10/108 (9.3%) 8/94 (8.5%)
    Erythema 5/107 (4.7%) 6/107 (5.6%) 7/108 (6.5%) 11/94 (11.7%)
    Skin hyperpigmentation 5/107 (4.7%) 7/107 (6.5%) 2/108 (1.9%) 6/94 (6.4%)
    Urticaria 1/107 (0.9%) 6/107 (5.6%) 4/108 (3.7%) 7/94 (7.4%)
    Acne 3/107 (2.8%) 7/107 (6.5%) 2/108 (1.9%) 4/94 (4.3%)
    Dry skin 7/107 (6.5%) 2/107 (1.9%) 3/108 (2.8%) 2/94 (2.1%)
    Vascular disorders
    Hot flush 11/107 (10.3%) 12/107 (11.2%) 8/108 (7.4%) 7/94 (7.4%)
    Lymphoedema 4/107 (3.7%) 6/107 (5.6%) 12/108 (11.1%) 5/94 (5.3%)
    Flushing 6/107 (5.6%) 5/107 (4.7%) 5/108 (4.6%) 5/94 (5.3%)
    Hypertension 5/107 (4.7%) 6/107 (5.6%) 4/108 (3.7%) 3/94 (3.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmannb-LaRoche
    Phone 1-800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT00545688
    Other Study ID Numbers:
    • WO20697
    First Posted:
    Oct 17, 2007
    Last Update Posted:
    Aug 15, 2017
    Last Verified:
    Jul 1, 2017