Clinical trial NCT04733118: Chemotherapy-Free pCR-Guided Strategy With Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer
Official title: Chemotherapy-Free pCR-Guided Strategy With Subcutaneous Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer (PHERGAIN-2)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Early Breast Cancer
Lead sponsor: MedSIR
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2021-02-01
Enrollment: 393
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.
9. Patients with multifocal or multicentric breast cancer are eligible; patients with 2 lesions or less are eligible only if both lesions are sampled and meet the inclusion criteria #5, #6, and #7.
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.

Primary outcomes:
measure: 3-year recurrence-free interval (3y-RFI)
timeFrame: 3 years
measure: Global health status decline
timeFrame: 1 year
Secondary outcomes:
measure: pathological complete response (pCR)
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: pathological complete response (pCR) according to hormone receptor (HR) status
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Residual cancer burden (RCB)
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Breast-conserving surgery (BCS)
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Response rate BCS
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Response rate pCR
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Response rate RCB
timeFrame: after neoadjuvant treatment (8 cycles, an average of 6months)
measure: Survival rates EFS
timeFrame: 3 years and 5 years
measure: Survival rates relapse-free survival (RFS)
timeFrame: 3 years and 5 years
measure: Survival rates invasive disease-free survival (iDFS)
timeFrame: 3 years and 5 years
measure: Survival ratesdistant relapse-free survival (DRFS)
timeFrame: 3 years and 5 years
measure: Survival rates disease-free survival (DFS)
timeFrame: 3 years and 5 years
measure: Survival rates overall survival (OS)
timeFrame: 3 years and 5 years
measure: Survival ratesbreast cancer-specific survival (BCSS).
timeFrame: 3 years and 5 years
measure: Survival rates relapse-free interval (RFI)
timeFrame: 5 years
measure: Safety adverse events (AEs)
timeFrame: Baseline up to 3 years
measure: Safety adverse events (AEs)
timeFrame: Baseline up to 5 years
measure: Health-Related Quality of Life (HRQoL) - QLQ-C30
timeFrame: Baseline up to 5 years
measure: Health-Related Quality of Life (HRQoL) - QLQ-BR23
timeFrame: Baseline up to 5 years
measure: To assess the cardiac toxicity profile after 1 year of adjuvant treatment
timeFrame: after 1 year of adjuvant treatment
measure: To assess the general toxicity profile according to CTCAE v.5.0.
timeFrame: at 3 and 5 year
measure: To evaluate the ratio of patients who have needed chemotherapy.
timeFrame: before T-DM1
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: UMHAT Sveti Ivan Rilski EAD Department of Medical Oncology
city: Cologne
country: Germany
facility: Praxisnetzwerk Hämatologie und intern. Onkologie
city: Duisburg
country: Germany
facility: Evangelisches Krankenhaus Bethesda
city: Essen
country: Germany
facility: Kliniken Essen Mitte
city: Essen
country: Germany
facility: Universitätsklinikum Essen Frauenklinik
city: Manheim
country: Germany
facility: Universitätsklinikum Mannheim GmbH
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann
city: Békés
country: Hungary
facility: Békés county hospital
city: Szekszárd
country: Hungary
facility: Tolna County Balassa János Hospital
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria Di Bologna - Policlinico S.Orsola-Malpighi
city: Milan
country: Italy
facility: AO Ospedale Civile Legnano
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia - NC
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO L'Hospitalet - Instituto Catalán de Oncología
state: Barcelona
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
state: Cordoba
city: Reus
country: Spain
facility: Hospital Universitari San Joan de Reus
state: Tarragona
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruña
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Badalona
country: Spain
facility: Institut Català d' Oncologia Badalona (ICO)
city: Barcelona
country: Spain
facility: Hospital Universitari Dexeus - Grupo Quirónsalud
city: Barcelona
country: Spain
facility: VHIO Vall d'Hebron Institute of Oncology
city: Bilbao
country: Spain
facility: Hospital Universitario de Basurto
city: Castelló De La Plana
country: Spain
facility: Consorcio Hospitalario Provincial De Castelló
city: Granada
country: Spain
facility: Hospital Universitario Clínico San Cecilio de Granada
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: León
country: Spain
facility: Complejo Asistencial Universitario de León
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Quirón San Camilo- Ruber Juan Bravo
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Torrejón
country: Spain
facility: Hospital Universitario de Torrejón
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología (IVO)
city: Valencia
country: Spain
facility: Hospital La Fe
city: Valencia
country: Spain
facility: Consorcio Hospital General de Valencia
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova de Valencia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
affiliation: Arnau de Vilanova Hospital, Valencia (Spain)
name: Antonio Llombart-Cussac, MD
role: PRINCIPAL_INVESTIGATOR
References: