A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer

Breast Cancer Clinical Trial

Official title:

A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00950300
• Other study ID #: BO22227
• Secondary ID: 2008-007326-19
• Status: Completed
• Phase: Phase 3
• First received: July 30, 2009
• Last updated: December 21, 2017
• Start date: October 16, 2009
• Est. completion date: January 24, 2017

Study information

• Verified date: December 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this open-label multicenter trial, participants with operable or locally advanced breast cancer will be randomized to pre-operative treatment with 8 cycles of chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide) concurrent with either SC Herceptin or IV Herceptin. After surgery, participants will receive a further 10 cycles of SC or IV Herceptin as per randomization to complete 1 year of treatment. All cycles will be 21 days in length. After the end of study treatment, participants will be followed for safety and efficacy for up to 5 years or until disease recurrence, whichever is earlier.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 596
• Est. completion date: January 24, 2017
• Est. primary completion date: July 12, 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult women greater than or equal to (=) 18 years of age

• Non-metastatic primary invasive adenocarcinoma of the breast clinical stage I to IIIC, including inflammatory and multicentric/multifocal breast cancer, with tumor size =1 centimeter (cm) by ultrasound or =2 cm by palpation, centrally confirmed HER2-positive (immunohistochemical score [IHC] 3+ or in situ hybridization [ISH]-positive)

• At least 1 measurable lesion in breast or lymph nodes (=1 cm by ultrasound or =2 cm by palpation), except for inflammatory carcinoma (T4d)

• Baseline left ventricular ejection fraction (LVEF) =55%

• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1

• Adequate organ function at Baseline

Exclusion Criteria:

• History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma

• Past or current history of malignant neoplasms, except for curatively treated basal and squamous cell carcinoma of the skin and in situ carcinoma of the cervix

• Metastatic disease

• Any prior therapy with anthracyclines

• Prior anti-HER2 therapy or biologic or immunotherapy

• Serious cardiac illness

• Pregnant or lactating women

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• 5-Fluorouracil
Participants will receive 5-fluorouracil, 500 milligrams per meter-squared (mg/m^2) via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
• Cyclophosphamide
Participants will receive cyclophosphamide, 500 mg/m^2 via IV bolus, on Day 1 of every 21-day cycle during Cycles 5 to 8.
• Docetaxel
Participants will receive docetaxel, 75 mg/m^2 via IV infusion on Day 1 of every 21-day cycle during Cycles 1 to 4.
• Epirubicin
Participants will receive epirubicin, 75 mg/m^2 via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
• Herceptin IV [trastuzumab]
Herceptin will be administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.
• Herceptin SC [trastuzumab]
Herceptin will be administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.

Locations

Country	Name	City	State
Argentina	Caipo; Oncology	Tucuman
Argentina	Centro Medico San Roque; Oncology Dept	Tucuman
Brazil	Hospital das Clinicas - UFPR; Quimioterapia	Curitiba	PR
Brazil	Clinica de Neoplasias Litoral	Itajai	SC
Brazil	Hospital Amaral Carvalho	Jau	SP
Brazil	Liga Norte Riograndense Contra O Câncer	Natal	RN
Brazil	Hospital Sao Rafael - HSR	Salvador	BA
Brazil	Hospital Perola Byington	Sao Paulo	SP
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP
Brazil	Instituto de Oncologia de Sorocaba - CEPOS	Sorocaba	SP
Canada	Hopital Maisonneuve- Rosemont; Oncology	Montreal	Quebec
Canada	CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY	Quebec
Colombia	Grupo Salud Coop	Bogota
Colombia	Hospital Universitario San Ignacio	Bogota
Colombia	Oncólogos de Occidente	Pereira
Czechia	Fakultni nemocnice Olomouc; Onkologicka klinika	Olomouc
Czechia	Krajska Nemocnice Pardubice Neurologicka Klinika	Pardubice
Czechia	Fakultni Thomayerova Nemocnice; Onkologicke Oddeleni	Praha
Czechia	Lekarske Fakulty Univerzity Karlovy Fakultni Nemocnice Na Bulovce; Ustav Radiacni Onkologie	Praha
Estonia	North Estonia Medical Centre Foundation; Oncology Centre	Tallinn
Estonia	Tartu University Hospital; Clinic of Hematology and Oncology	Tartu
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Institut Daniel Hollard; Chimiotherapie Ambulatoire	Grenoble
France	Hopital Albert Michallon; Oncologie	La Tronche
France	Centre Jean Bernard	Le Mans
France	Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)	Paris
France	Institut Jean Godinot; Hopital De Jour	Reims
France	Centre Rene Huguenin; Medecine B	St Cloud
Germany	CAMPUS CHARITÉ MITTE; Tagesklinik für Onkologie u.Hämatologie	Berlin
Germany	Praxis Dr. Schoenegg	Berlin
Germany	Johanniter GmbH; Johanniter-Krankenhaus; Internistische Onkologie	Bonn
Germany	St. Johannes Hospital	Dortmund
Germany	Gynaekologisch-Onkologische Schwerpunktpraxis Prof. Dr. med. Lueck, Dr. Schrader und Dr. Noeding	Hannover
Germany	Sankt Elisabeth Krankenhaus; Gynaekology	Leipzig
Germany	Klinik Lippe Lemgo; Frauenklinik	Lemgo
Germany	Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe	Offenbach
Germany	Klinik Obergöltzsch; Abt. Gynäkologie	Rodewisch
Germany	Universitätsklinik Tübingen; Frauenklinik	Tübingen
Guatemala	Centro Oncologico S.A.	Guatemala
Hong Kong	Queen Mary Hospital; Surgery	Hong Kong
Hungary	Semmelweis Egyetem Onkologiai Központ	Budapest
Hungary	Hospital of Aladar Petz; Dept of Oncoradiology	Gyor
Hungary	Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika	Szeged
Israel	Hadassah Ein Karem Hospital; Oncology Dept	Jerusalem
Israel	Rabin Medical Center; Oncology Dept	Petach Tikva
Italy	ASST DI CREMONA; Dip. Medicina - S.C. Oncologia	Cremona	Lombardia
Italy	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania
Italy	Fondazione Salvatore Maugeri	Pavia	Lombardia
Italy	Fondazione Salvatore Maugeri; Servizio Di Prevenzione Oncologica	Pavia	Lombardia
Korea, Republic of	Gachon Medical School Gil Medical Center; Medical Oncology	Incheon
Korea, Republic of	Asan Medical Center, Uni Ulsan Collegemedicine; Dept.Internal Medicine / Divisionhematology/Oncology	Seoul
Korea, Republic of	Korea University Anam Hospital; Oncology Haemotology	Seoul
Korea, Republic of	Samsung Medical Centre; Division of Hematology/Oncology	Seoul
Mexico	Hospital Privado San Jose; Oncologia	Obregon
Mexico	Centro Oncológico Estatal; ISSSEMYM Oncología	Toluca
Panama	Centro Oncologico America	Panama
Peru	Hospital Nacional Carlos Alberto Seguin Escobedo-Essalud; Oncology & Haemathology	Arequipa
Peru	Hospital Nacional Edgardo Rebagliati Martins; Oncologia	Lima
Peru	Oncosalud Sac; Oncología	Lima
Peru	Unidad de Investigacion Oncologia Clinica - Piura; Unidad de Oncología Clínica	Piura
Peru	Clinica Ricardo Palma	San Isidro
Poland	Wojewodzki Szpital Zespolony; Oddzial Onkologii	Elblag
Poland	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin
Poland	Olsztynski Osrodek Onkologiczny Kopernik sp. z o.o.	Olsztyn
Poland	Centrum Onkologii - Instytut im. Marii Sklodowskiej-Curie Klinika Nowotworów Piersi i Chirurgii	Warszawa
Russian Federation	Ivanovo Regional Oncology Dispensary	Ivanovo
Russian Federation	Blokhin Cancer Research Center; Combined Treatment	Moscow
Russian Federation	Moscow city oncology hospital #62 of Moscow Healthcare Department	Moscow
Russian Federation	State Budget Institution of Healthcare of Stavropol region Pyatigorsk Oncology Dispensary	Pyatigorsk
Russian Federation	SBI for HPE "Ryazan State Medical University n.a. I.P. Pavlov" of MoH of RF	Ryazan
Russian Federation	SBI of Healthcare Samara Regional Clinical Oncology Dispensary	Samara
Russian Federation	Saratov Regional Clinical Hospital & Pathology Centre	Saratov
Russian Federation	FSBI"National Medical Research Center of Oncology named after N.N.Petrov" MHRF	St Petersburg	Leningrad
Russian Federation	Saint-Petersburg City Clinical Oncology Dispensary	St Petersburg
Russian Federation	SBI of Healthcare of Stavropol region Stavropol Regional Clinical Oncology Dispensary	Stavropol
Russian Federation	Tula Regional Oncology Dispensary	Tula
Russian Federation	GUZ Vladimir Regional Clinical Oncological Dispensary	Vladimir
Slovakia	Vychodoslovensky onkologicky ustav	Kosice
Slovakia	Nzz - Oncology Outpatient Clinic	Poprad
South Africa	National Hospital; Oncotherapy Dept	Bloemfontein
South Africa	Cancercare	Cape Town
South Africa	Groote Schuur Hospital ( Uni of Capetown ); Oncology Dept	Cape Town
South Africa	Wits Donald Gordon Clinical Trial Centre; Medical Oncology	Parktown, Johannesburg
South Africa	Pretoria-East Hospital; 1 Sanwood Park	Pretoria
South Africa	Rondebosch Oncology Centre	Rondebosch
South Africa	Sandton Oncology Centre	Sandton
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Universitari Sant Joan de Reus; Servicio de Oncologia	Reus	Tarragona
Spain	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia	Santiago de Compostela	LA Coruña
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
Sweden	Skånes University Hospital, Skånes Department of Onclology	Lund
Sweden	Akademiska sjukhuset, Onkologkliniken	Uppsala
Taiwan	Changhua Christian Hospital; Dept of Surgery	Changhua
Taiwan	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei City
Taiwan	Chang Gung Medical Foundation-Taipei	Taoyuan
Thailand	Chulalongkorn Hospital; Medical Oncology	Bangkok
Thailand	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok
Thailand	National Cancer Inst.	Bangkok
Thailand	Phramongkutklao Hospital;Dept Surgery/Surgical Oncology Unit	Bangkok
Thailand	Prince of Songkla Uni ; Unit of Medical Oncology	Songkhla
Turkey	Akdeniz University Medical Faculty; Medical Oncology Department	Antalya
Turkey	Istanbul Uni of Medicine Faculty; Oncology Dept	Istanbul
Turkey	Dokuz Eylul Uni Medical Faculty; Oncology Dept	Izmir
Turkey	Hacettepe Uni Medical Faculty Hospital; Oncology Dept	Sihhiye, Ankara

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Argentina,  Brazil,  Canada,  Colombia,  Czechia,  Estonia,  France,  Germany,  Guatemala,  Hong Kong,  Hungary,  Israel,  Italy,  Korea, Republic of,  Mexico,  Panama,  Peru,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  Sweden,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery	Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (µg/mL).	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Primary	Percentage of Participants With Pathological Complete Response (pCR)	Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.	After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
Secondary	Observed Ctrough of Trastuzumab After Surgery	Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in µg/mL.	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	Predicted Ctrough of Trastuzumab Prior to Surgery	Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in µg/mL.	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Secondary	Predicted Ctrough of Trastuzumab After Surgery	Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in µg/mL.	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	Number of Participants With Ctrough of Trastuzumab >20 µg/mL Prior to Surgery	Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough >20 µg/mL was reported.	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Secondary	Number of Participants With Ctrough of Trastuzumab >20 µg/mL After Surgery	Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough >20 µg/mL was reported.	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery	PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in µg/mL.	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Secondary	Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery	PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Secondary	Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery	PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d*µg/mL).	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Secondary	Cmax of Trastuzumab After Surgery	PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in µg/mL.	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	Tmax of Trastuzumab After Surgery	PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	AUC21d of Trastuzumab After Surgery	PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d*µg/mL.	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Secondary	Percentage of Participants With Total Pathological Complete Response (tpCR)	Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.	After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
Secondary	Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline	Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (=) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as =20% relative increase and =5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.	Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall)
Secondary	Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline	Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm with no prior assessment of PD. PR was defined as =30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as =20% relative increase and =5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR.	Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall)
Secondary	Percentage of Participants Who Experienced a Protocol-Defined Event	Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.	Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Secondary	Event-Free Survival (EFS)	Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event.	Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Secondary	Percentage of Participants Who Died	The percentage of participants who died at any time during the study was reported.	Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Secondary	Overall Survival (OS)	OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.	Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Secondary	Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab	Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).	Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18
Secondary	Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20)	Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).	Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18