Chemotherapy-Free pCR-Guided Strategy With Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer

NCT ID: NCT04733118

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 393 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-05
• Study Completion Date: 2028-03-31

Brief Summary

This is a multicenter, open-label, single-arm, one-stage, phase II study to assess the efficacy of a chemotherapy-free pathological complete response (pCR)-guided strategy with trastuzumab and pertuzumab (given as a subcutaneous fixed-dose combination) and T-DM1, for patients with previously untreated HER2-positive early breast cancer.

Detailed Description

Patients ≥ 18 years of age with previously untreated HER2 IHC 3+ invasive carcinoma according to ASCO/CAP 2018 guidelines.

Tumor size between >5 to 30 mm by breast MRI and node-negative status by clinical exam, MRI, and ultrasound. In patients with suspected axillary node involvement, a negative fine needle aspiration biopsy (FNAB) will be mandatory.

Central review for:

Breast MRI. HER2 status. Neoadjuvant treatment will consist In 8 cycles of fixed-dose subcutaneous (SC FDC) HP combination (± ET according to HR status).

urgery will be performed within 4 weeks from the last cycle of HP (sentinel node biopsy will be mandatory; subsequent axillary dissection will be performed according to local guidelines). Surgery will require free margins for any infiltrating or DCIS lesion.

Radiotherapy will be mandatory for patients with breast preservation.

Adjuvant systemic therapy will be started within 4 weeks from surgery depending on pathological report:

Arm A: pCR (breast and axilla): HP SC FDC x 10 cycles. Arm B: Residual invasive breast tumor and/or ypN0(i+), ypN0(mol+), ypN1mi: T-DM1 x 10 cycles Arm C: ypN1 to N3: T-DM1 x 10 cycles, with physician's choice chemotherapy allowed between surgery and T-DM1.

All patients with HR[+] tumors will receive adjuvant ET up to at least 5 years (ET will also be administered in association with adjuvant HP or T-DM1, with the exception of the cycles involving the use of chemotherapy in Arm C).

Conditions

Early Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Patient HER 2+ IHC 3+

Patients ≥18 years of age with previously untreated HER2-positive (HER2\[+\]) (Immunohistochemistry \[IHC\] 3+) invasive carcinoma according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and tumor size between \>5 to 25 mm by breast magnetic resonance imaging (MRI) and node-negative status by clinical exam, MRI, and ultrasound. Patients must have not been previously treated with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy (ET) for invasive breast cancer. Patients with metastatic disease are not eligible. In patients with suspected axillary node involvement, a negative fine needle aspiration biopsy (FNAB) will be mandatory

Group Type: EXPERIMENTAL

Trastuzumab and Pertuzumab (FDC SC) and T-DM1

Intervention Type: DRUG

Patients will receive Trastuzumab and Pertuzumab as a subcutaneous fixed-dose combination (PH FDC SC) (± ET depending on HR status) for 8 3-week cycles, on day 1 only. ET will consist of letrozole for post-menopausal women or tamoxifen ± ovarian function suppression (OFS) for pre-menopausal women administered continuously. Men will receive tamoxifen.

After completing neoadjuvant therapy, a final breast MRI will be performed 2 weeks prior to surgery. Surgery will be performed within 4 weeks after completion of the last cycle of PH FDC SC.

Adjuvant systemic therapy will start within 4 weeks from surgery. There will be three different cohorts depending on pathological report:

• Cohort A: PH FDC SC ± ET for 10 additional 3-week cycles
• Cohort B: T-DM1 ± ET for 10 cycles
• Cohort C: T-DM1 ± ET for 10 cycles, with possibility of physician's choice chemotherapy before adjuvant T-DM1.

Interventions

Trastuzumab and Pertuzumab (FDC SC) and T-DM1

Patients will receive Trastuzumab and Pertuzumab as a subcutaneous fixed-dose combination (PH FDC SC) (± ET depending on HR status) for 8 3-week cycles, on day 1 only. ET will consist of letrozole for post-menopausal women or tamoxifen ± ovarian function suppression (OFS) for pre-menopausal women administered continuously. Men will receive tamoxifen.

After completing neoadjuvant therapy, a final breast MRI will be performed 2 weeks prior to surgery. Surgery will be performed within 4 weeks after completion of the last cycle of PH FDC SC.

Adjuvant systemic therapy will start within 4 weeks from surgery. There will be three different cohorts depending on pathological report:

• Cohort A: PH FDC SC ± ET for 10 additional 3-week cycles
• Cohort B: T-DM1 ± ET for 10 cycles
• Cohort C: T-DM1 ± ET for 10 cycles, with possibility of physician's choice chemotherapy before adjuvant T-DM1.

Intervention Type: DRUG

Other Intervention Names

Trastuzumab emtansine; Phesgo; Kadcyla

Eligibility Criteria

Inclusion Criteria

Patients will be included in the study only if they meet ALL of the following criteria:

1. Written informed consent prior to beginning specific protocol procedures.

2. Female or male patients ≥ 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Histologically proven invasive carcinoma of the breast.

5. Tumor size must be between ≥ 5mm and ≤30mm in greatest dimension using breast MRI. Note: Although tumors between ≥ 5mm and ≤ 10mm are not considered target lesions by RECIST v1.1, we will consider these lesions as targets to follow-up.

6. Patients must have node-negative breast cancer by clinical exam, MRI and ultrasound according to the American Joint Committee on Cancer (AJCC) 8th edition.

7. Centrally confirmed HER2[+] status with IHC score 3+.

8. Known estrogen receptor (ER) and progesterone receptor (PgR) status prior to study entry that should be performed by immunohistochemical methods according to the local institution standard protocol.

10. Normal left ventricular function and diastolic function (left ventricular ejection fraction [LVEF] ≥55%) as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment.

11. Adequate bone marrow, liver, and renal function:

1. Hematological: White blood cell (WBC) count > 3.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100.0 × 109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).

2. Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN.

3. Renal: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

4. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

12. Patient must be accessible for treatment and follow-up.

13. Willingness and ability to provide blood samples at baseline, C3D1 before treatment infusion, pre-surgery and then after surgery: every 6 months for the first 5 years, and every year thereafter until the EoS.

14. Willingness and ability to provide tumor tissue samples at baseline and at surgery.

15. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for seven months after the last dose of study treatment.

Note: Acceptable forms of effective contraception should include two of the following:

i. Placement of non-hormonal intrauterine device (IUD) ii. Condom with spermicidal foam/gel/film/cream/suppository iii. Diaphragm or cervical/vault caps with spermicidal foam/film/cream/suppository The above contraception is not a requirement in the case the male patient, or male partner of a female patient, is surgically sterilized, the female patient is post-menopausal or the patient remains abstinent and truly abstains from sexual activity (refrains from heterosexual intercourse).

16. Negative serum pregnancy test for premenopausal women including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.

Exclusion Criteria

Any patient meeting ANY of the following criteria will be excluded from the study:

1. Any previous treatment, including chemotherapy, anti-HER2 therapy, radiation therapy, or ET for invasive breast cancer (except for breast carcinoma in situ of the contralateral breast cancer, in the last five years before treatment initiation in this study).

2. HER2 disease with IHC score 0, 1+ or 2+ and in situ hybridization (ISH) positive result.

3. Evidence of metastatic disease. Note: All patients must be willing to undergo chest and pelvis computed tomography (CT)/MRI scan before enrolment to prove no evidence of metastatic disease. Bone scan will be performed at baseline only if there is suspicion of bone metastases. If a bone scan cannot be performed, an alternative is PET/CT using 18F-labeled sodium fluoride (18F-fluoride PET/CT).

4. Patients with bilateral breast cancer.

5. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.

6. History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma.

7. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.

8. Serious cardiac illness or medical conditions including, but not confined to, the following:

• History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II.
• High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-degree AV-block).
• Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate medication.
• Angina pectoris requiring anti-angina medication.
• Clinically significant valvular heart disease.
• Evidence of transmural infarction on electrocardiogram (ECG).
• Evidence of myocardial infarction within the last 12 months prior to study entry.

9. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.

10. Active uncontrolled infection at the time of enrollment.

11. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.

12. Patients with pulmonary disease requiring continuous oxygen therapy.

13. Grade ≥2 neuropathy as per National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)5.0.

14. Previous history of bleeding diathesis.

15. Patient is currently receiving chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).

16. Major surgical procedure or significant traumatic injury within 14 days prior to study entry or anticipation of need for major surgery within the course of the study treatment.

17. Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study.

18. History of having received any investigational treatment within 28 days prior to study entry.

19. Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

MedSIR

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio Llombart-Cussac, MD

Role: PRINCIPAL_INVESTIGATOR

Arnau de Vilanova Hospital, Valencia (Spain)

Locations

UMHAT Sveti Ivan Rilski EAD Department of Medical Oncology

Sofia, , Bulgaria

Praxisnetzwerk Hämatologie und intern. Onkologie

Cologne, , Germany

Evangelisches Krankenhaus Bethesda

Duisburg, , Germany

Kliniken Essen Mitte

Essen, , Germany

Universitätsklinikum Essen Frauenklinik

Essen, , Germany

Universitätsklinikum Mannheim GmbH

Manheim, , Germany

Klinikum Ernst von Bergmann

Potsdam, , Germany

Békés county hospital

Békés, , Hungary

Tolna County Balassa János Hospital

Szekszárd, , Hungary

Azienda Ospedaliero Universitaria Di Bologna - Policlinico S.Orsola-Malpighi

Bologna, , Italy

AO Ospedale Civile Legnano

Milan, , Italy

Istituto Europeo di Oncologia - NC

Milan, , Italy

Ospedale San Gerardo

Monza, , Italy

Azienda Ospedaliero-Universitaria di Parma

Parma, , Italy

Ospedale Guglielmo da Saliceto

Piacenza, , Italy

Fondazione Policlinico Universitario Agostino Gemelli

Roma, , Italy

ICO L'Hospitalet - Instituto Catalán de Oncología

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitario Reina Sofia

Córdoba, Cordoba, Spain

Hospital Universitari San Joan de Reus

Reus, Tarragona, Spain

Centro Oncológico de Galicia

A Coruña, , Spain

Hospital Universitario A Coruña

A Coruña, , Spain

Hospital General Universitario de Alicante

Alicante, , Spain

Institut Català d' Oncologia Badalona (ICO)

Badalona, , Spain

Hospital Universitari Dexeus - Grupo Quirónsalud

Barcelona, , Spain

VHIO Vall d'Hebron Institute of Oncology

Barcelona, , Spain

Hospital Universitario de Basurto

Bilbao, , Spain

Consorcio Hospitalario Provincial De Castelló

Castellon, , Spain

Hospital Universitario Clínico San Cecilio de Granada

Granada, , Spain

Complejo Hospitalario de Jaen

Jaén, , Spain

Complejo Asistencial Universitario de León

León, , Spain

Hospital Universitari Arnau de Vilanova de Lleida

Lleida, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Quirón San Camilo- Ruber Juan Bravo

Madrid, , Spain

Hospital Ramón y Cajal

Madrid, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital Universitario de Torrejón

Torrejón, , Spain

Instituto Valenciano de Oncología (IVO)

Valencia, , Spain

Hospital La Fe

Valencia, , Spain

Consorcio Hospital General de Valencia

Valencia, , Spain

Hospital Arnau de Vilanova de Valencia

Valencia, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Countries

Bulgaria; Germany; Hungary; Italy; Spain

Other Identifiers

MedOPP293

Identifier Type: -

Identifier Source: org_study_id