Clinical trial NCT03493854: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Early Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-04-11
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)
timeFrame: Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Secondary outcomes:
measure: Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)
timeFrame: Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
measure: Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment
timeFrame: Following completion of surgery (up to 33 weeks)
measure: 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
timeFrame: At 1, 2, 3, and 4 years
measure: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria
timeFrame: At 1, 2, 3, and 4 years
measure: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria
timeFrame: At 1, 2, 3, and 4 years
measure: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria
timeFrame: At 1, 2, 3, and 4 years
measure: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria
timeFrame: At 1, 2, 3, and 4 years
measure: Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival
timeFrame: At 1, 2, 3, and 4 years
measure: 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 4.0 (NCI CTCAE v4.0), Over the Course of the Entire Study
timeFrame: From first dose of study treatment until 28 days after last dose of study treatment (up to 1 year, 6 months)
measure: Number of Participants With a Primary Cardiac Event During the Neoadjuvant Phase
timeFrame: From first dose of study treatment until the completion of neoadjuvant therapy (24 weeks)
measure: Number of Participants With a Secondary Cardiac Event During the Neoadjuvant Phase
timeFrame: From first dose of study treatment until the completion of neoadjuvant therapy (24 weeks)
measure: Number of Participants With a Primary Cardiac Event During the Adjuvant Phase
timeFrame: From surgery until 28 days after the last dose of adjuvant treatment (42 weeks)
measure: Number of Participants With a Secondary Cardiac Event During the Adjuvant Phase
timeFrame: From surgery until 28 days after the last dose of adjuvant treatment (42 weeks)
measure: Number of Participants With Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline Over the Course of the Entire Study
timeFrame: From first dose of study treatment until 28 days after last dose of study treatment (up to 1 year, 6 months)
Other outcomes:
Locations:
city: Rockville
country: United States
facility: Maryland Oncology Hematology
state: Maryland
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Lakewood
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Buenos Aires
country: Argentina
facility: Fundación CENIT para la Investigación en Neurociencias
city: La Rioja
country: Argentina
facility: Centro Oncologico Riojano Integral (CORI)
city: Provincia De Buenos Aires
country: Argentina
facility: COIBA
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Charleroi
country: Belgium
facility: GHdC Site Notre Dame
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Hasselt
country: Belgium
facility: Jessa Zkh (Campus Virga Jesse)
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Namur
country: Belgium
facility: Clinique Ste-Elisabeth
city: Goiania
country: Brazil
facility: Hospital Araujo Jorge; Departamento de Ginecologia E Mama
state: GO
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
state: RS
city: Sao Paulo
country: Brazil
facility: Hospital Perola Byington
state: SP
city: Barrie
country: Canada
facility: Royal Victoria Hospital
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Center; R. S. MacLaughlin Durham Regional Cancer Center
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont
state: Quebec
city: Brno
country: Czechia
facility: Masarykuv onkologicky ustav
city: Pardubice
country: Czechia
facility: Multiscan s.r.o.
city: Angers
country: France
facility: ICO Paul Papin; Oncologie Medicale.
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Besançon
country: France
facility: CHRU Besançon
city: Bordeaux
country: France
facility: Institut Bergonie; Oncologie
city: Lyon
country: France
facility: Centre Léon Bérard
city: Paris
country: France
facility: Institut Curie; Oncologie Medicale
city: Paris
country: France
facility: APHP - Hospital Saint Louis
city: Saint Herblain
country: France
facility: ICO - Site René Gauducheau
city: Augsburg
country: Germany
facility: Klinikum Augsburg; Frauenklinik
city: Bad Nauheim
country: Germany
facility: Hochwaldkrankenhaus; Abt.Gynäkologie Geburtshilfe u.Senologie
city: Berlin
country: Germany
facility: Onkologische Schwerpunktpraxis Kurfürstendamm
city: Dortmund
country: Germany
facility: St. Johannes-Hospital
city: Essen
country: Germany
facility: Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
city: Hamburg
country: Germany
facility: Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem
city: Offenbach
country: Germany
facility: Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe
city: Stralsund
country: Germany
facility: Gynäkologie Kompetenzzentrum; Praxis Dr. med. Carsten Hielscher
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica
state: Campania
city: Napoli
country: Italy
facility: Università degli Studi Federico II; Clinica di Oncologia Medica
state: Campania
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica
state: Friuli-Venezia Giulia
city: Genova
country: Italy
facility: Uni Degli Studi Di Genova ; Clinica Di Medicina Interna Ad Indirizzo Oncologico
state: Liguria
city: Lecco
country: Italy
facility: ASST DI LECCO; Oncologia Medica
state: Lombardia
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II
state: Veneto
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Gifu
country: Japan
facility: Gifu University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima City Hiroshima Citizens Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hokkaido
country: Japan
facility: National Hospital Organization Hokkaido Cancer Center
city: Hyogo
country: Japan
facility: Hyogo Medical University Hospital
city: Kagoshima
country: Japan
facility: Sagara Hospital
city: Kanagawa
country: Japan
facility: Kanagawa Cancer Center
city: Kanagawa
country: Japan
facility: Tokai University Hospital
city: Miyagi
country: Japan
facility: Fukushima Medical University Hospital
city: Niigata
country: Japan
facility: Niigata Cancer Center Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Saitama
country: Japan
facility: Saitama Medical University International Medical Center
city: Tokyo
country: Japan
facility: St. Luke's International Hospital
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hosiptal
city: D.f.
country: Mexico
facility: Iem-Fucam
state: Mexico CITY (federal District)
city: Monterrey
country: Mexico
facility: Centro Médico Zambrano Hellion
state: Nuevo LEON
city: San Luis Potosí
country: Mexico
facility: Oncologico Potosino
state: SAN LUIS Potosi
city: Bialystok
country: Poland
facility: Bialostockie Centrum Onkologii im. Marii Sklodowskiej - Curie
city: Gliwice
country: Poland
facility: Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice; Centr.Diagn.i Lecz.Chor.Piersi
city: Kraków
country: Poland
facility: Szpital Uniwersytecki w Krakowie; Oddzial Kliniczny Onkologii i Poradnia Onkologiczna
city: Szczecin
country: Poland
facility: Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych
city: Warszawa
country: Poland
facility: Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr
city: Wroclaw
country: Poland
facility: Dolnoslaskie Centrum Onkologii
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk Regional Clinical Oncology Dispensary
state: Arhangelsk
city: Moscovskaya Oblast
country: Russian Federation
facility: Moscow City Oncology Hospital #62
state: Moskovskaja Oblast
city: Saint-Petersburg
country: Russian Federation
facility: S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
state: Sankt Petersburg
city: Kazan
country: Russian Federation
facility: Clinical Oncology Dispensary of Ministry of Health of Tatarstan
state: Tatarstan
city: Ivanovo
country: Russian Federation
facility: Ivanovo Regional Oncology Dispensary
city: Omsk
country: Russian Federation
facility: Omsk Region Clinical Oncology Dispensary; 1St Sergical Department
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia; Servicio de Oncologia
state: Cordoba
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
state: LA Coruña
city: Barakaldo
country: Spain
facility: Hospital de Cruces; Servicio de Oncología Médica
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Institut Catala d Oncologia Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
city: Taichung
country: Taiwan
facility: China Medical University Hospital; Surgery
city: Taipei
country: Taiwan
facility: VETERANS GENERAL HOSPITAL; Department of General Surgery
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation - Linkou; Dept of Surgery
city: Bangkok
country: Thailand
facility: Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital; Department of Surgery/Head Neck and Breast Unit; Clinical Trial
city: Songkla
country: Thailand
facility: Songklanagarind Hospital; Department of Surgery
city: Kharkiv
country: Ukraine
facility: Municipal Noncommercial Institution Regional Center of Oncology
state: Kharkiv Governorate
city: Dnipropetrovsk
country: Ukraine
facility: Chemotherapy SI Dnipropetrovsk MA of MOHU
city: Kiev
country: Ukraine
facility: National Cancer Institute MOH of Ukraine
city: Lviv
country: Ukraine
facility: Lviv State Oncology Regional Treatment and Diagnostic Centre
city: Sumy
country: Ukraine
facility: RCI Sumy Regional Clinical Oncological Dispensary
city: Brighton
country: United Kingdom
facility: Brighton and Sussex Univ Hosp
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: London
country: United Kingdom
facility: St Georges University Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Trust
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Peterborough
country: United Kingdom
facility: Peterborough City Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.