A Study of the Safety of Subcutaneously Administered Trastuzumab (Herceptin) in Participants With Early and Locally Advanced Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (SCHEARLY)

National Phase IIIb Prospective Two-Cohort Non-Randomized, Multi-centre, Open Label Study to Assess the Safety of Subcutaneous Trastuzumab and Molecular Biomarkers in Patients With Early and Locally Advanced HER2-Positive Breast Cancer

This non-randomized, multicenter, open-label study will assess the safety and efficacy of subcutaneously administered trastuzumab in participants with early and locally advanced HER2-positive breast cancer in two sequential cohorts. First 120 participants will be treated with subcutaneous (SC) trastuzumab 600 milligrams (mg) vial (Cohort A) and the subsequent 120 participants will be treated with SC trastuzumab prefilled single use injection device (SID) (Cohort B). Participants from each cohort will receive neoadjuvant or adjuvant chemotherapy consisting of doxorubicin every 3 weeks (q3w) (1 cycle) for 4 cycles followed by paclitaxel weekly or docetaxel every 3 weeks (q3w) in combination with SC trastuzumab (600 mg) q3w for 4 cycles and a further 14 cycles of SC trastuzumab (600 mg) q3w alone. All participants will be followed up for 24 months after the last participant has received the last dose of study treatment, or earlier in case of withdrawal from the study, loss to follow-up or death.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Doxorubicin; Drug: Docetaxel; Drug: Paclitaxel; Drug: Trastuzumab

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Abruzzo
    • L'aquila, Abruzzo, Italy, 67010
      • Asl 4 - Osp. San Salvatore; Oncologia Medica
  • Basilicata
    • Potenza, Basilicata, Italy, 85100
      • Ospedale San Carlo; Day Hospital Oncologia Medica
  • Calabria
    • Catanzaro, Calabria, Italy, 88100
      • Campus Universitario S.Venuta; Centro Oncologico T.Campanella
    • Reggio Calabria, Calabria, Italy, 89100
      • Az. Osp. ; Divisione Oncologia Medica
  • Campania
    • Avellino, Campania, Italy, 83100
      • Azienda Ospedaliera S.G. Moscati; Division of Medical Oncology
    • Frattamaggiore, Campania, Italy, 80027
      • Presidio Ospedaliero S. Giovanni Di Dio; U.O. Di Oncologia
    • Napoli, Campania, Italy, 80131
      • Seconda Università di Napoli;Day Hospital Clinica Oncologia Medica
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40133
      • Ospedale Bellaria; U.O. Oncologia Medica
    • Bologna, Emilia-Romagna, Italy, 40138
      • Azienda Ospedaliero-Universitaria S.Orsola-Malpighi; Unità Operativa Oncologia Medica
    • Carpi, Emilia-Romagna, Italy, 41012
      • Ospedale Ramazzini ; Day Hospital Oncologico
    • Guastalla, Emilia-Romagna, Italy, 42016
      • Ospedale Civile; Day Hospital Oncologico
    • Reggio Emilia, Emilia-Romagna, Italy, 42100
      • Arcispedale Santa Maria Nuova; Oncologia
  • Friuli-Venezia Giulia
    • Aviano, Friuli-Venezia Giulia, Italy, 33081
      • Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica
    • Udine, Friuli-Venezia Giulia, Italy, 33100
      • Azienda Ospedaliero-Universitaria Dipartimento Interaziendale Di Oncologia
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Uni Cattolica Policlinico Gemelli; Oncologia Medica Ist. Medicina Interna
    • Roma, Lazio, Italy, 00186
      • Ospedale S.G.Calibita Fatebenefratelli; Unità Operativa Oncologia
    • Roma, Lazio, Italy, 00168
      • Policlinico A. Gemelli-Complesso Integrato Columbus-Radioterapia
    • Roma, Lazio, Italy, 00189
      • Villa San Pietro Fatebenefatelli; Divisione Oncologia
  • Liguria
    • Genova, Liguria, Italy, 16132
      • IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A
    • Genova, Liguria, Italy, 16132
      • Az. Osp. Uni Ria San Martino; Cliniche Uni Rie Convenzionate U.O. Oncologia Medical
    • La Spezia, Liguria, Italy, 19125
      • Ospedale Civile S. Andrea; Day Hospital Oncologia
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • Az. Osp. Spedali Civili; Divisione Di Oncologia - Iii Medicina
    • Brescia, Lombardia, Italy, 25124
      • Casa Di Cura Poliambulanza; Unita Operativa Di Oncologia Medica
    • Como, Lombardia, Italy, 22100
      • Ospedale Valduce;U.O.S. Oncologia Ed Ematologia
    • Lecco, Lombardia, Italy, 23900
      • ASST DI LECCO; Oncologia Medica
    • Mantova, Lombardia, Italy, 46100
      • Az. Osp. Carlo Poma; Divisione Di Oncologia Medica
    • Milano, Lombardia, Italy, 20141
      • Istituto Europeo di Oncologia
    • Milano, Lombardia, Italy, 20132
      • Irccs Ospedale San Raffaele;Oncologia Medica
    • Pavia, Lombardia, Italy, 27100
      • Fondazione Salvatore Maugeri; Divisione Di Oncologia Medica
    • Saronno, Lombardia, Italy, 21047
      • Az. Osp. Di Busto P.O. Di Saronno; U.O. Di Oncologia Medica
    • Treviglio, Lombardia, Italy, 24047
      • ASST DI BERGAMO OVEST; Unità Operativa di Oncologia Medica
    • Varese, Lombardia, Italy, 21100
      • Ospedale Di Circolo E Fondazione Macchi; Oncologia Medica
  • Marche
    • Ancona, Marche, Italy, 60121
      • A.O.U. Ospedali Riuniti Umberto I-G.M.Lancisi-G.Salesi Ancona;S.O.D. MED.Interna-Clinica Oncologica
    • Macerata, Marche, Italy, 62100
      • Ospedale Di Macerata; Oncologia
    • Pesaro, Marche, Italy, 61122
      • Ospedale San Salvatore Muraglia;Divisone Oncologia
  • Piemonte
    • Asti, Piemonte, Italy, 14100
      • Azienda Sanitaria Locale Di Asti-P.O. Cardinal Massaia;Oncologia
    • Candiolo, Piemonte, Italy, 10060
      • Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico
    • Cuneo, Piemonte, Italy, 12100
      • Azienda Sanitaria Ospedaliera s. Croce e Carle; Oncologia Medica
    • Ponderano (BI), Piemonte, Italy, 13875
      • Ospedale Degli Infermi Di Biella; Reparto Oncologia Medica
    • Torino, Piemonte, Italy, 10128
      • Ospedale Mauriziano Umberto I; Divisione Onco-Ematologia
  • Sicilia
    • Catania, Sicilia, Italy, 95126
      • Centro Catanese Di Oncologia; Oncologia Medica
  • Toscana
    • Arezzo, Toscana, Italy, 52100
      • Azienda USL8 Arezzo-Presidio Ospedaliero 1 San Donato;U.O.C. Oncologia
    • Firenze, Toscana, Italy, 50139
      • Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1
    • Grosseto, Toscana, Italy, 58100
      • Ospedale della Misericordia; Hospice Terapia del Dolore
    • Lido Di Camaiore, Toscana, Italy, 55043
      • Ospedale Nuovo Della Versilia; Divisione Di Oncologia Medica
    • Livorno, Toscana, Italy, 57100
      • Ospedale Civile; Unita Operativa Di Oncologia Medica
    • Poggibonsi, Toscana, Italy, 53036
      • Azienda Usl 7; Dept. Oncologico
  • Umbria
    • Sant'Andrea Delle Fratte (PG), Umbria, Italy, 06132
      • Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
  • Veneto
    • Castelfranco Veneto, Veneto, Italy, 31033
      • Presidio Ospedaliero - Usl 13; Servizio Di Oncologia
    • Mestre, Veneto, Italy, 30174
      • AZ. Usll12 Veneziana-Ospedale Dell'angelo;Oncologia Medica
    • Mirano, Veneto, Italy, 30035
      • Ospedale Calvi di Noale; U.O. Complessa di Oncologia ed Ematologia Oncologica
    • Negrar, Veneto, Italy, 37024
      • Ospedale Sacro Cuore Don Calabria; U.O. Di Oncologia
    • Treviso, Veneto, Italy, 31100
      • Ospedale Cà Foncello - Divisione di Oncologia Medica
    • Vicenza, Veneto, Italy, 36100
      • Ospedale Di Vicenza; Nefrologia, Oncologia Medica

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast. Stage of disease: T1-4 (T describes size of tumour from 1 to 4), N0-3 (N describes nearby lymph nodes), M0 (M describes distant metastasis)
• HER2-positive disease immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Left ventricular ejection fraction (LVEF) of greater than or equal to (>=) 55 percent (%) measured by echocardiography (ECHO) or multiple gated acquisition (MUGA) scan prior to first dose of trastuzumab SC
• Intact skin at site of SC injection on the thigh

Exclusion Criteria:

• History of other malignancy, except for participants with curatively treated carcinoma in situ of the cervix or basal cell carcinoma and participants with other curatively treated malignancies, other than breast cancer, who have been disease-free for at least 5 years
• Severe dyspnea at rest or requiring supplementary oxygen therapy
• Concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness
• Serious cardiac illness or medical conditions that would preclude the use of trastuzumab, specifically: history of documented congestive heart failure (CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring medication, clinically significant valvular disease, evidence of transmural infarction on electrocardiogram (ECG), diagnosed poorly controlled hypertension
• Known infection with human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV)
• Pregnant or lactating women
• Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment, including hormonal therapy, bisphosphonate therapy and immunotherapy, within 28 days prior to the first dose of study treatment
• Known hypersensitivity to trastuzumab, murine proteins, to any of the excipients of Herceptin including hyaluronidase, or the adhesive of the SC device (for Cohort B), or a history of severe allergic or immunological reactions, for example, difficulty to control asthma
• Inadequate bone marrow, hepatic or renal function
• Hormonal treatment concomitant with chemotherapy (allowed in adjuvant phase with adjuvant trastuzumab SC)
• Pre-existing motor or sensory neuropathy of Grade greater than (>) 1
• Synchronous bilateral invasive breast cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab (Vial); Participants will receive trastuzumab 600 mg SC using a vial q3w (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).	Drug: Doxorubicin; Participants will receive doxorubicin in doses according to the locally-approved regimen q3w (1 cycle), for 4 cycles prior to initiation of trastuzumab treatment.; Drug: Docetaxel; Participants will receive docetaxel in doses according to the locally-approved regimen q3w for 12 weeks, in combination with trastuzumab.; Drug: Paclitaxel; Participants will receive paclitaxel in doses according to the locally-approved regimen weekly for 12 weeks, in combination with trastuzumab.; Drug: Trastuzumab; Participants will receive trastuzumab 600 mg SC (vial or SID) q3w for 18 cycles.; Other Names: Herceptin
Experimental: Trastuzumab (SID); Participants will receive trastuzumab 600 mg SC using SID q3w (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).	Drug: Doxorubicin; Participants will receive doxorubicin in doses according to the locally-approved regimen q3w (1 cycle), for 4 cycles prior to initiation of trastuzumab treatment.; Drug: Docetaxel; Participants will receive docetaxel in doses according to the locally-approved regimen q3w for 12 weeks, in combination with trastuzumab.; Drug: Paclitaxel; Participants will receive paclitaxel in doses according to the locally-approved regimen weekly for 12 weeks, in combination with trastuzumab.; Drug: Trastuzumab; Participants will receive trastuzumab 600 mg SC (vial or SID) q3w for 18 cycles.; Other Names: Herceptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were the AEs occurring from starting on the day of or after first administration of trastuzumab and within 28 days after last dose of trastuzumab. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up to 28 days after last dose of trastuzumab (up to approximately 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Actual Dose of Trastuzumab Administered	Actual dose (mg) administered = (sum over all cycles of actual dose received [mg] divided by number of cycles). Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up last dose of trastuzumab (up to approximately 1 year)
Duration of Treatment With Trastuzumab	Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up last dose of trastuzumab (up to approximately 1 year)
Percentage of Participants Who Received Concomitant Medications		Screening (Day -28 to -1) up to 2.5 years
Percentage of Participants With Pathological Complete Response (pCR) (Neoadjuvant Groups Only) Using Mammography	In the neoadjuvant setting, the activity of two sequential drug regimens, doxorubicin-containing chemotherapy followed by paclitaxel or docetaxel chemotherapy in combination with trastuzumab, was assessed as the percentage of participants with pCR in breast and nodes using mammography. pCR was defined as the absence of histological evidence of invasive breast cancer cells in the tissue specimen removed from the breast after preoperative treatment. Data for this outcome measure were analyzed and reported only for neoadjuvant groups within each treatment arm.	Day 1 up to 24 weeks
Percentage of Participants With Event (Local, Regional or Distant Recurrence, Contralateral Breast Cancer or Death) Using Mammography	A participant was considered as disease free if the participant was free from local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first). Percentage of participants with event at the cut off date were reported. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first [up to approximately 4.5 years])
Disease-Free Survival (DFS) Using Mammography	DFS was defined as the time from the first treatment to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first). Kaplan-Meier estimates were used for analysis. Participants who were disease-free were censored at the data cut off date. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first [up to approximately 4.5 years])
Percentage of Participants Who Died	Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up to death due to any cause (up to approximately 4.5 years)
Overall Survival (OS)	Overall survival was defined as the time from the first treatment to death from any cause. Kaplan-Meier estimates were used for analysis. Participants who did not die were censored on the date they were last known to be alive. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.	Day 1 up to death due to any cause (up to approximately 4.5 years)
Percentage of Participants by Response to Patient Satisfaction Questionnaire (PSQ)	Participants were asked the following 5 questions: (1) "Following the first injection given by the physician/nurse and training on how to use the SID, I felt comfortable injecting the study drug by myself"; (2) "The SID was convenient and easy to use"; (3) "I am confident giving myself an injection in the thigh with the SID"; (4) "Taking all things into account, I find self-administration using the SID satisfactory"; (5) "If given the opportunity, I would choose to continue self-injecting the study drug using the SID at home". Response to each question was recorded as either of the following options: "Unknown", "Strongly Disagree", "Disagree", "Unsure", "Agree", "Strongly Agree". Percentage of participants who provided responses to above questions was reported. Data for this outcome measure were analyzed and reported only for Trastuzumab (SID) arm.	After at least 14 cycles (1 cycle = 21 days; maximum up to 1 year)
Percentage of Health Care Professionals (HCPs) by Response to Health Care Professional Questionnaire (HCPQ)	Percentage of HCPs providing responses to various questions related to overall ease of study drug administration was reported in different categories, where categories indicate all possible responses to such questions.	After at least 4 participants completed 5 cycles of adjuvant treatment (1 cycle = 21 days; maximum up to 1 year)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Zambetti M, Montemurro F, Morandi P, Zamagni C, Brandes AA, Bisagni G, Cagossi K, Bengala C, Gori S, Iannacone C, Stell A, Gianni L. Safety profile of subcutaneous trastuzumab for the treatment of patients with HER2-positive early or locally advanced breast cancer: primary analysis of the SCHEARLY study. Eur J Cancer. 2018 Dec;105:61-70. doi: 10.1016/j.ejca.2018.09.034. Epub 2018 Nov 3.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2013
• Primary Completion (Actual): April 5, 2016
• Study Completion (Actual): March 27, 2018

Study Registration Dates

• First Submitted: September 9, 2013
• First Submitted That Met QC Criteria: September 9, 2013
• First Posted (Estimate): September 12, 2013

Study Record Updates

• Last Update Posted (Actual): November 3, 2020
• Last Update Submitted That Met QC Criteria: October 14, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Paclitaxel; Trastuzumab; Doxorubicin
• Other Study ID Numbers: ML28879; 2013-001161-16 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes