A Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Participants With HER2-Positive Early Breast Cancer (FeDeriCa)

A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Patients With HER2-Positive Early Breast Cancer

This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant/adjuvant setting.

Study Overview

• Status: Completed
• Conditions: Early Breast Cancer
• Intervention / Treatment: Procedure: Surgery; Drug: Hormone Therapy; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Docetaxel; Drug: Paclitaxel; Drug: Pertuzumab IV; Drug: Trastuzumab IV; Drug: Trastuzumab SC; Radiation: Post-operative Radiotherapy; Drug: FDC of Pertuzumab and Trastuzumab SC

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Expanded Access

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Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1125ABD
    • Fundación CENIT para la Investigación en Neurociencias
  • La Rioja, Argentina, F5300COE
    • Centro Oncologico Riojano Integral (CORI)
  • Provincia De Buenos Aires, Argentina, B1884BBF
    • COIBA
• Belgium
  • Anderlecht, Belgium, 1070
    • Institut Jules Bordet
  • Charleroi, Belgium, 6000
    • GHdC Site Notre Dame
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Hasselt, Belgium, 3500
    • Jessa Zkh (Campus Virga Jesse)
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
  • Namur, Belgium, 5000
    • Clinique Ste-Elisabeth
• Brazil
  • GO
    • Goiania, GO, Brazil, 74605-070
      • Hospital Araujo Jorge; Departamento de Ginecologia E Mama
  • RS
    • Porto Alegre, RS, Brazil, 91350-200
      • Hospital Nossa Senhora da Conceicao
  • SP
    • Sao Paulo, SP, Brazil, 01317-000
      • Hospital Perola Byington
• Canada
  • Ontario
    • Barrie, Ontario, Canada, L4M 6M2
      • Royal Victoria Hospital
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Center; R. S. MacLaughlin Durham Regional Cancer Center
    • Ottawa, Ontario, Canada, K2H 6C2
      • The Ottawa Hospital Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont
• Czechia
  • Brno, Czechia, 656 53
    • Masarykuv onkologicky ustav
  • Pardubice, Czechia, 532 03
    • Multiscan s.r.o.
• France
  • Angers, France, 49055
    • ICO Paul Papin; Oncologie Medicale.
  • Avignon, France, 84082
    • Institut Sainte Catherine
  • Besançon, France, 25030
    • Chru Besançon
  • Bordeaux, France, 33076
    • Institut Bergonie; Oncologie
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Paris, France, 75231
    • Institut Curie; Oncologie Medicale
  • Paris, France, 75475
    • APHP - Hospital Saint Louis
  • Saint Herblain, France, 44805
    • ICO - Site René Gauducheau
• Germany
  • Augsburg, Germany, 86156
    • Klinikum Augsburg; Frauenklinik
  • Bad Nauheim, Germany, 61231
    • Hochwaldkrankenhaus; Abt.Gynäkologie Geburtshilfe u.Senologie
  • Berlin, Germany, 10707
    • Onkologische Schwerpunktpraxis Kurfürstendamm
  • Dortmund, Germany, 44137
    • St. Johannes-Hospital
  • Essen, Germany, 45136
    • Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
  • Hamburg, Germany, 20357
    • Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem
  • Offenbach, Germany, 63069
    • Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe
  • Stralsund, Germany, 18439
    • Gynäkologie Kompetenzzentrum; Praxis Dr. med. Carsten Hielscher
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Università degli Studi Federico II; Clinica di Oncologia Medica
    • Napoli, Campania, Italy, 80131
      • Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica
  • Friuli-Venezia Giulia
    • Aviano, Friuli-Venezia Giulia, Italy, 33081
      • Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Uni Degli Studi Di Genova ; Clinica Di Medicina Interna Ad Indirizzo Oncologico
  • Lombardia
    • Lecco, Lombardia, Italy, 23900
      • ASST DI LECCO; Oncologia Medica
  • Veneto
    • Padova, Veneto, Italy, 35128
      • IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II
• Japan
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
  • Fukushima, Japan, 960-1295
    • Fukushima Medical University Hospital
  • Gifu, Japan, 501-1194
    • Gifu University Hospital
  • Hiroshima, Japan, 730-8518
    • Hiroshima City Hiroshima Citizens Hospital
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital
  • Hokkaido, Japan, 003-0804
    • National Hospital Organization Hokkaido Cancer Center
  • Hyogo, Japan, 663-8501
    • Hyogo Medical University Hospital
  • Kagoshima, Japan, 892-0833
    • Sagara Hospital
  • Kanagawa, Japan, 241-8515
    • Kanagawa Cancer Center
  • Kanagawa, Japan, 259-1193
    • Tokai University Hospital
  • Niigata, Japan, 951-8566
    • Niigata Cancer Center Hospital
  • Okayama, Japan, 700-8558
    • Okayama University Hospital
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute
  • Saitama, Japan, 350-1298
    • Saitama Medical University International Medical Center
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR
  • Tokyo, Japan, 104-8560
    • St. Luke's International Hospital
• Korea, Republic of
  • Seongnam-si, Korea, Republic of, 463-707
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Ulsan, Korea, Republic of, 44033
    • Ulsan University Hosiptal
• Mexico
  • Mexico CITY (federal District)
    • D.f., Mexico CITY (federal District), Mexico, 04980
      • Iem-Fucam
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 66278
      • Centro Medico Zambrano Hellion
  • SAN LUIS Potosi
    • San Luis Potosí, SAN LUIS Potosi, Mexico, 78209
      • Oncológico Potosino
• Poland
  • Bialystok, Poland, 15-027
    • Bialostockie Centrum Onkologii im. Marii Sklodowskiej - Curie
  • Gliwice, Poland, 44-101
    • Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice; Centr.Diagn.i Lecz.Chor.Piersi
  • Kraków, Poland, 31-501
    • Szpital Uniwersytecki w Krakowie; Oddzial Kliniczny Onkologii i Poradnia Onkologiczna
  • Szczecin, Poland, 71-730
    • Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych
  • Warszawa, Poland, 02-781
    • Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr
  • Wroclaw, Poland, 53-439
    • Dolnoslaskie Centrum Onkologii
• Russian Federation
  • Ivanovo, Russian Federation, 153040
    • Ivanovo regional oncology dispensary
  • Omsk, Russian Federation, 644013
    • Omsk Region Clinical Oncology Dispensary; 1St Sergical Department
  • Arhangelsk
    • Arkhangelsk, Arhangelsk, Russian Federation, 163045
      • Arkhangelsk Regional Clinical Oncology Dispensary
  • Moskovskaja Oblast
    • Moscovskaya Oblast, Moskovskaja Oblast, Russian Federation, 143423
      • Moscow City Oncology Hospital #62
  • Sankt Petersburg
    • Saint-Petersburg, Sankt Petersburg, Russian Federation, 197758
      • S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
  • Tatarstan
    • Kazan, Tatarstan, Russian Federation, 420029
      • Clinical Oncology Dispensary of Ministry of Health of Tatarstan
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar; Servicio de Oncologia
  • Barcelona, Spain, 08908
    • Institut Catala d Oncologia Hospital Duran i Reynals
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Oncologia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio; Servicio de Oncologia
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Hospital Universitario Reina Sofia; Servicio de Oncologia
  • LA Coruña
    • Santiago de Compostela, LA Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces; Servicio de Oncología Médica
• Taiwan
  • Taichung, Taiwan, 404
    • China Medical University Hospital; Surgery
  • Taipei, Taiwan, 00112
    • VETERANS GENERAL HOSPITAL; Department of General Surgery
  • Taoyuan, Taiwan, 333
    • Chang Gung Medical Foundation - Linkou; Dept of Surgery
• Thailand
  • Bangkok, Thailand, 10700
    • Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital; Department of Surgery/Head Neck and Breast Unit; Clinical Trial
  • Songkla, Thailand, 90110
    • Songklanagarind Hospital; Department of Surgery
• Ukraine
  • Dnipropetrovsk, Ukraine, 49102
    • Chemotherapy SI Dnipropetrovsk MA of MOHU
  • Kiev, Ukraine, 36022
    • National Cancer Institute MOH of Ukraine
  • Lviv, Ukraine, 79031
    • Lviv State Oncology Regional Treatment and Diagnostic Centre
  • Sumy, Ukraine, 40005
    • RCI Sumy Regional Clinical Oncological Dispensary
  • Kharkiv Governorate
    • Kharkiv, Kharkiv Governorate, Ukraine, 61070
      • Municipal Noncommercial Institution Regional Center of Oncology
• United Kingdom
  • Brighton, United Kingdom, BN2 5BD
    • Brighton and Sussex Univ Hosp
  • Cardiff, United Kingdom, CF14 2TL
    • Velindre Cancer Centre
  • London, United Kingdom, SW17 0RE
    • St Georges University Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital NHS Trust
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Peterborough, United Kingdom, PE3 9GZ
    • Peterborough City Hospital
• United States
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Maryland Oncology Hematology
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Washington
    • Lakewood, Washington, United States, 98499
      • Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to comply with the study protocol, in the investigator's judgment
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
• Female and male patients with Stage II - IIIC (T2-T4 plus any N, or any T plus N1-N3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer
• Primary tumor >2 cm in diameter, or node-positive disease (clinically or on imaging, and node positivity confirmed with cytology and/or histopathology)
• HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material.
• Hormone receptor status of the primary tumor, centrally confirmed
• Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy
• Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for central confirmation of HER2 and hormone receptor status and additional biomarker research
• Baseline left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
• For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent or use one highly effective non-hormonal contraceptive method with a failure rate of <1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this same period
• For men: men must remain abstinent or use a condom with a spermicidal product during the treatment period and for 7 months after the last dose of HER2-targeted therapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
• A negative serum pregnancy test must be available prior to randomization for WOCBP, unless they have undergone surgical sterilization
• No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment

Exclusion Criteria:

• Stage IV (metastatic) breast cancer
• Patients with a history of invasive breast cancer
• Patients with a history of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin
• Patients who have received any previous systemic therapy for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer
• Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in situ if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast
• Patients with high-risk for breast cancer who have received chemo-preventative drugs in the past are not allowed to enter the study
• Patients with multicentric breast cancer, unless all tumors are HER2-positive
• Patients with bilateral breast cancer
• Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes
• Axillary lymph node dissection prior to initiation of neoadjuvant therapy
• Sentinel lymph node biopsy prior to neoadjuvant therapy
• Treatment with any investigational drug within 28 days prior to randomization
• Serious cardiac illness or medical conditions
• Inadequate bone marrow function, renal function or impaired liver function
• Current severe, uncontrolled systemic disease that may interfere with planned treatment
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis
• Concurrent, serious, uncontrolled infections, or known infection with HIV
• Known hypersensitivity to study drugs, excipients, and/or murine proteins
• Current chronic daily treatment with corticosteroids
• History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy; Participants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel Q1W for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab will be given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.	Procedure: Surgery; Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.; Drug: Hormone Therapy; For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.; Drug: Cyclophosphamide; Cyclophosphamide 600 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of ddAC Q2W or AC Q3W) for Cycles 1-4.; Drug: Doxorubicin; Doxorubicin 60 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of either ddAC Q2W or AC Q3W) for Cycles 1-4.; Drug: Docetaxel; As part of one of the two investigator's choices of chemotherapy (AC followed by docetaxel), docetaxel 75 mg/m2 will be administered IV on Day 1 of Cycle 5 and then 100 mg/m2 IV at the discretion of the investigator for Cycles 6-8 (Q3W), if no dose-limiting toxicity occurs.; Drug: Paclitaxel; As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks.; Drug: Pertuzumab IV; Pertuzumab will be administered as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W.; Other Names: Perjeta; RO4368451; Drug: Trastuzumab IV; Trastuzumab will be administered as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.; Other Names: Herceptin; RO0452317; Drug: Trastuzumab SC; After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab IV to trastuzumab SC, at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient's weight) will be administered in the adjuvant phase.; Other Names: Herceptin; RO0452317; Radiation: Post-operative Radiotherapy; If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).
Experimental: Arm B: FDC of Pertuzumab and Trastuzumab SC + Chemotherapy; Participants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.	Procedure: Surgery; Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.; Drug: Hormone Therapy; For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.; Drug: Cyclophosphamide; Cyclophosphamide 600 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of ddAC Q2W or AC Q3W) for Cycles 1-4.; Drug: Doxorubicin; Doxorubicin 60 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of either ddAC Q2W or AC Q3W) for Cycles 1-4.; Drug: Docetaxel; As part of one of the two investigator's choices of chemotherapy (AC followed by docetaxel), docetaxel 75 mg/m2 will be administered IV on Day 1 of Cycle 5 and then 100 mg/m2 IV at the discretion of the investigator for Cycles 6-8 (Q3W), if no dose-limiting toxicity occurs.; Drug: Paclitaxel; As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks.; Radiation: Post-operative Radiotherapy; If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).; Drug: FDC of Pertuzumab and Trastuzumab SC; The FDC of pertuzumab and trastuzumab will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.; Other Names: RG6264; RO7198574; Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)	The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.	Pre-dose on Cycle 8, Day 1 (up to 21 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)	The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.	Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment	Total pCR (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists' assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated. The lower bound of the CI will reliably reflect the largest tpCR difference that can be considered unlikely.	Following completion of surgery (up to 33 weeks)
Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)	The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline until the primary completion date (up to 1 year, 1 month)
Number of Participants With a Primary Cardiac Event	A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).	From Baseline until the primary completion date (up to 1 year, 1 month)
Number of Participants With a Secondary Cardiac Event	A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks	From Baseline until the primary completion date (up to 1 year, 1 month)
Number of Participants With Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline	Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test. Abs. = absolute count; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate transaminase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine transaminase	Day 1 of Cycles 1 to 8 (up to 21 weeks)
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria	iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.	Up to 5 years
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria	Invasive disease-free survival (iDFS) including second primary non-breast cancer (SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).	Up to 5 years
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria	Event-free survival (EFS) excluding second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.	Up to 5 years
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria	Event-free survival (EFS) including second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).	Up to 5 years
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria	The distant recurrence-free interval (DRFI) is defined as the time between randomization and the date of distant breast cancer recurrence.	Up to 5 years
Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival	Overall survival is defined as the time from randomization to death from any cause.	Up to 5 years
Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to NCI CTCAE v4, Over the Course of the Entire Study	The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline until end of study (up to 5 years)
Number of Participants With a Primary Cardiac Event Over the Course of the Entire Study	A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).	From Baseline until end of study (up to 5 years)
Number of Participants With a Secondary Cardiac Event Over the Course of the Entire Study	A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks	From Baseline until end of study (up to 5 years)
Number of Participants With Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline Over the Course of the Entire Study	Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test.	Day 1 of Cycles 1 to 22 (1 cycle is 3 weeks), during treatment-free follow-up every 3 months for 1 year, then every 6 months until end of study (up to 5 years)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. doi: 10.1016/S1470-2045(20)30536-2. Epub 2020 Dec 21. Erratum In: Lancet Oncol. 2021 Feb;22(2):e42.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2018
• Primary Completion (Actual): July 4, 2019
• Study Completion (Actual): June 2, 2023

Study Registration Dates

• First Submitted: April 4, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 11, 2018

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

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; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Paclitaxel; Trastuzumab; Doxorubicin; Hormones; Pertuzumab
• Other Study ID Numbers: WO40324; 2017-004897-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical-trials/data-sharing/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No