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

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)

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: 5-Fluorouracil; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Epirubicin; Drug: Herceptin IV [trastuzumab]; Drug: Herceptin SC [trastuzumab]

• Study Type: Interventional
• Enrollment (Actual): 596
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Tucuman, Argentina, T4000IAK
    • Centro Medico San Roque; Oncology Dept
  • Tucuman, Argentina, T400IAK
    • Caipo; Oncology
• Brazil
  • BA
    • Salvador, BA, Brazil, 41253-190
      • Hospital Sao Rafael - HSR
  • PR
    • Curitiba, PR, Brazil, 80060-900
      • Hospital das Clinicas - UFPR; Quimioterapia
  • RN
    • Natal, RN, Brazil, 59040150
      • Liga Norte Riograndense Contra O Cancer
  • SC
    • Itajai, SC, Brazil, 88301-220
      • Clinica de Neoplasias Litoral
  • SP
    • Jau, SP, Brazil, 17210-080
      • Hospital Amaral Carvalho
    • Sao Paulo, SP, Brazil, 01246-000
      • Instituto do Cancer do Estado de Sao Paulo - ICESP
    • Sao Paulo, SP, Brazil, 01317-000
      • Hospital Perola Byington
    • Sorocaba, SP, Brazil, 18030-245
      • Instituto de Oncologia de Sorocaba - CEPOS
• Canada
  • Quebec, Canada, G1S 4L8
    • CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve- Rosemont; Oncology
• Colombia
  • Bogota, Colombia, 000472
    • Hospital Universitario San Ignacio
  • Bogota, Colombia
    • Grupo Salud Coop
  • Pereira, Colombia, 600004
    • Oncólogos de Occidente
• Czechia
  • Olomouc, Czechia, 779 00
    • Fakultni nemocnice Olomouc; Onkologicka klinika
  • Pardubice, Czechia, 532 03
    • Krajska Nemocnice Pardubice Neurologicka Klinika
  • Praha, Czechia, 140 59
    • Fakultni Thomayerova Nemocnice; Onkologicke Oddeleni
  • Praha, Czechia, 180 81
    • Lekarske Fakulty Univerzity Karlovy Fakultni Nemocnice Na Bulovce; Ustav Radiacni Onkologie
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonia Medical Centre Foundation; Oncology Centre
  • Tartu, Estonia, 50406
    • Tartu University Hospital; Clinic of Hematology and Oncology
• France
  • Besancon, France, 25030
    • HOPITAL JEAN MINJOZ; Oncologie
  • Grenoble, France, 38000
    • Institut Daniel Hollard; Chimiotherapie Ambulatoire
  • La Tronche, France, 38700
    • Hopital Albert Michallon; Oncologie
  • Le Mans, France, 72015
    • Centre Jean Bernard
  • Paris, France, 75475
    • Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)
  • Reims, France, 51056
    • Institut Jean Godinot; Hopital De Jour
  • St Cloud, France, 92210
    • Centre Rene Huguenin; Medecine B
• Germany
  • Berlin, Germany, 10719
    • Praxis Dr. Schoenegg
  • Berlin, Germany, 10117
    • CAMPUS CHARITÉ MITTE; Tagesklinik für Onkologie u.Hämatologie
  • Bonn, Germany, 53113
    • Johanniter GmbH; Johanniter-Krankenhaus; Internistische Onkologie
  • Dortmund, Germany, 44137
    • St. Johannes Hospital
  • Hannover, Germany, 30177
    • Gynaekologisch-Onkologische Schwerpunktpraxis Prof. Dr. med. Lueck, Dr. Schrader und Dr. Noeding
  • Leipzig, Germany, 04277
    • Sankt Elisabeth Krankenhaus; Gynaekology
  • Lemgo, Germany, 32657
    • Klinik Lippe Lemgo; Frauenklinik
  • Offenbach, Germany, 63069
    • Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe
  • Rodewisch, Germany, 08228
    • Klinik Obergöltzsch; Abt. Gynäkologie
  • Tübingen, Germany, 72076
    • Universitätsklinik Tübingen; Frauenklinik
• Guatemala
  • Guatemala, Guatemala, 01010
    • Centro Oncologico S.A.
• Hong Kong
  • Hong Kong, Hong Kong, 852
    • Queen Mary Hospital; Surgery
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem Onkologiai Központ
  • Gyor, Hungary, 9023
    • Hospital of Aladar Petz; Dept of Oncoradiology
  • Szeged, Hungary, 6720
    • Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika
• Israel
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Hospital; Oncology Dept
  • Petach Tikva, Israel, 49100
    • Rabin Medical Center; Oncology Dept
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica
  • Lombardia
    • Cremona, Lombardia, Italy, 26100
      • ASST DI CREMONA; Dip. Medicina - S.C. Oncologia
    • Pavia, Lombardia, Italy, 27100
      • Fondazione Salvatore Maugeri; Servizio Di Prevenzione Oncologica
    • Pavia, Lombardia, Italy, 27100
      • Fondazione Salvatore Maugeri
• Korea, Republic of
  • Incheon, Korea, Republic of, 405-760
    • Gachon Medical School Gil Medical Center; Medical Oncology
  • Seoul, Korea, Republic of, 136-705
    • Korea University Anam Hospital; Oncology Haemotology
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Centre; Division of Hematology/Oncology
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center, Uni Ulsan Collegemedicine; Dept.Internal Medicine / Divisionhematology/Oncology
• Mexico
  • Obregon, Mexico, 85000
    • Hospital Privado San Jose; Oncologia
  • Toluca, Mexico, 50180
    • Centro Oncológico Estatal; ISSSEMYM Oncología
• Panama
  • Panama, Panama, 0834-02723
    • Centro Oncologico America
• Peru
  • Arequipa, Peru, 04001
    • Hospital Nacional Carlos Alberto Seguin Escobedo-Essalud; Oncology & Haemathology
  • Lima, Peru, 41
    • Oncosalud Sac; Oncología
  • Lima, Peru, 11
    • Hospital Nacional Edgardo Rebagliati Martins; Oncologia
  • Piura, Peru, 20011
    • Unidad de Investigacion Oncologia Clinica - Piura; Unidad de Oncología Clínica
  • San Isidro, Peru, Lima 27
    • Clinica Ricardo Palma
• Poland
  • Elblag, Poland, 82-300
    • Wojewodzki Szpital Zespolony; Oddział Onkologii
  • Lublin, Poland, 20-090
    • COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej
  • Olsztyn, Poland, 10-513
    • Olsztyński Ośrodek Onkologiczny Kopernik sp. z o.o.
  • Warszawa, Poland, 02-781
    • Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie Klinika Nowotworów Piersi i Chirurgii
• Russian Federation
  • Ivanovo, Russian Federation, 153040
    • Ivanovo Regional Oncology Dispensary
  • Moscow, Russian Federation, 143423
    • Moscow city oncology hospital #62 of Moscow Healthcare Department
  • Moscow, Russian Federation, 115478
    • Blokhin Cancer Research Center; Combined Treatment
  • Pyatigorsk, Russian Federation, 357502
    • State Budget Institution of Healthcare of Stavropol region Pyatigorsk Oncology Dispensary
  • Ryazan, Russian Federation, 390011
    • SBI for HPE "Ryazan State Medical University n.a. I.P. Pavlov" of MoH of RF
  • Samara, Russian Federation, 443031
    • SBI of Healthcare Samara Regional Clinical Oncology Dispensary
  • Saratov, Russian Federation, 410053
    • Saratov Regional Clinical Hospital & Pathology Centre
  • St Petersburg, Russian Federation, 197022
    • Saint-Petersburg City Clinical Oncology Dispensary
  • Stavropol, Russian Federation, 355045
    • SBI of Healthcare of Stavropol region Stavropol Regional Clinical Oncology Dispensary
  • Tula, Russian Federation, 300053
    • Tula Regional Oncology Dispensary
  • Vladimir, Russian Federation, 600009
    • GUZ Vladimir Regional Clinical Oncological Dispensary
  • Leningrad
    • St Petersburg, Leningrad, Russian Federation, 197758
      • FSBI"National Medical Research Center of Oncology named after N.N.Petrov" MHRF
• Slovakia
  • Kosice, Slovakia, 04001
    • Východoslovenský Onkologický Ústav
  • Poprad, Slovakia, 05801
    • Nzz - Oncology Outpatient Clinic
• South Africa
  • Bloemfontein, South Africa, 9301
    • National Hospital; Oncotherapy Dept
  • Cape Town, South Africa, 7506
    • Groote Schuur Hospital ( Uni of Capetown ); Oncology Dept
  • Cape Town, South Africa, 7506
    • Cancercare
  • Parktown, Johannesburg, South Africa, 2193
    • Wits Donald Gordon Clinical Trial Centre; Medical Oncology
  • Pretoria, South Africa, 0081
    • Pretoria-East Hospital; 1 Sanwood Park
  • Rondebosch, South Africa, 7700
    • Rondebosch Oncology Centre
  • Sandton, South Africa, 2196
    • Sandton Oncology Centre
• Spain
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet; Servicio Oncologia
  • LA Coruña
    • Santiago de Compostela, LA Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
  • Tarragona
    • Reus, Tarragona, Spain, 43204
      • Hospital Universitari Sant Joan de Reus; Servicio de Oncologia
• Sweden
  • Lund, Sweden, 22185
    • Skånes University Hospital, Skånes Department of Onclology
  • Uppsala, Sweden, 75185
    • Akademiska sjukhuset, Onkologkliniken
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital; Dept of Surgery
  • Taipei, Taiwan, 112
    • Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
  • Taipei City, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taoyuan, Taiwan, 333
    • Chang Gung Medical Foundation-Taipei
• Thailand
  • Bangkok, Thailand, 10330
    • Chulalongkorn Hospital; Medical Oncology
  • Bangkok, Thailand, 10700
    • Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology
  • Bangkok, Thailand, 10400
    • National Cancer Inst.
  • Bangkok, Thailand, 10400
    • Phramongkutklao Hospital;Dept Surgery/Surgical Oncology Unit
  • Songkhla, Thailand, 90110
    • Prince of Songkla Uni ; Unit of Medical Oncology
• Turkey
  • Antalya, Turkey, 07070
    • Akdeniz University Medical Faculty; Medical Oncology Department
  • Istanbul, Turkey, 34390
    • Istanbul Uni of Medicine Faculty; Oncology Dept
  • Izmir, Turkey, 35340
    • Dokuz Eylul Uni Medical Faculty; Oncology Dept
  • Sıhhiye, Ankara, Turkey, 06100
    • Hacettepe Uni Medical Faculty Hospital; Oncology Dept

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Herceptin IV + Chemotherapy; Participants will receive Herceptin via IV infusion for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin IV will be given on Day 1 of each 21-day cycle, as 8 milligrams per kilogram (mg/kg) for a loading dose during Cycle 1 and as 6 mg/kg during subsequent cycles.	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.; Drug: 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.; Drug: 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.; Drug: 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.; Drug: 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.
EXPERIMENTAL: Herceptin SC + Chemotherapy; Participants will receive Herceptin via SC injection for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin SC will be given on Day 1 of each 21-day cycle, as a 600-milligram (mg) fixed dose.	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.; Drug: 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.; Drug: 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.; Drug: 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.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 May 1;5(5):e190339. doi: 10.1001/jamaoncol.2019.0339. Epub 2019 May 9.
• Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. doi: 10.1016/S1470-2045(12)70329-7. Epub 2012 Aug 9.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 16, 2009
• Primary Completion (ACTUAL): July 12, 2011
• Study Completion (ACTUAL): January 24, 2017

Study Registration Dates

• First Submitted: July 30, 2009
• First Submitted That Met QC Criteria: July 30, 2009
• First Posted (ESTIMATE): July 31, 2009

Study Record Updates

• Last Update Posted (ACTUAL): January 23, 2018
• Last Update Submitted That Met QC Criteria: December 21, 2017
• Last Verified: December 1, 2017

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Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Trastuzumab; Fluorouracil; Epirubicin
• Other Study ID Numbers: BO22227; 2008-007326-19 (EUDRACT_NUMBER)