Evaluation of a Chemotherapy-Free Pathological Complete Response-Guided Strategy Using Subcutaneous Trastuzumab, Pertuzumab, and Trastuzumab Emtansine in HER2-Positive Early Breast Cancer
- Trial ID
- 2023-508738-32-00
- Protocol
- MEDOPP293
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **3-year recurrence-free interval (3y-RFI)** in patients with previously untreated HER2-positive (HER2[+]) node-negative early-stage breast cancer. This objective is clinically relevant as it evaluates the effectiveness of a chemotherapy-free strategy in preventing cancer recurrence, which is crucial for improving long-term patient outcomes. Additionally, the study aims to assess the global health status decline rate at 1 year from the start of neoadjuvant treatment, providing insights into the safety profile of the treatment regimen.
Secondary objectives include:
- Assessing pathological complete response (pCR).
- Comparing the rate of pCR by hormone receptor (HR) status and tumor stage.
- Evaluating residual cancer burden (RCB).
- Evaluating the rate of breast-conserving surgery (BCS).
- Evaluating objective response rate.
- Evaluating the correlation between final MRI results and BCS, pCR, and RCB at surgery.
- Analyzing the rate of recurrence-free interval (RFI) at 5 years.
- Analyzing the rate of event-free survival (EFS) at 3 and 5 years.
- Analyzing the rate of relapse-free survival (RFS) at 3 and 5 years.
- Analyzing the rate of distant relapse-free survival (DRFS) at 3 and 5 years.
- Analyzing the rate of disease-free survival (DFS) at 3 and 5 years.
- Analyzing the rate of invasive disease-free survival (iDFS) at 3 and 5 years.
- Analyzing overall survival (OS) at 3 and 5 years.
- Analyzing the rate of breast cancer-specific survival (BCSS) at 3 and 5 years.
- Assessing the cardiac toxicity profile after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.
- Assessing the general toxicity profile according to CTCAE v.5.0.
- Evaluating health-related quality of life (HRQoL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC)-QLC-C30 and QLQBR23 questionnaires.
- Evaluating the ratio of patients who have needed chemotherapy.
Participants
The clinical trial involves participants diagnosed with **HER2-Positive early-stage breast cancer** who have not received prior treatment. The study population includes both female and male patients aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of invasive carcinoma of the breast, with tumor sizes ranging from 5mm to 25mm as determined by ultrasound and mammography, or up to 30mm by MRI. The trial includes individuals with node-negative breast cancer, confirmed by clinical examination, MRI, and ultrasound. Participants must have a centrally confirmed HER2-positive status with an IHC score of 3+. The trial population was selected based on specific health criteria, including normal cardiac function and adequate bone marrow, liver, and renal function. Participants are expected to maintain a certain level of physical health, as indicated by an ECOG performance status of 0 or 1. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a chemotherapy-free strategy using **trastuzumab** and **pertuzumab** in patients with previously untreated, histologically confirmed HER2-positive early-stage breast cancer. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the 3-year recurrence-free interval (3y-RFI) and the global health status decline rate at 1 year from the start of neoadjuvant treatment. The trial is expected to conclude by January 31, 2030, with recruitment having commenced on August 5, 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as normal left ventricular function, adequate bone marrow, liver, and renal function, and a negative serum pregnancy test for premenopausal women. Following the screening, participants will receive treatment with either **trastuzumab emtansine** or **Phesgo** (a combination of trastuzumab and pertuzumab) administered via intravenous or subcutaneous routes, respectively. The maximum treatment period for trastuzumab emtansine is 30 weeks, while for Phesgo, it is 51 weeks.
Study visits will include regular follow-up assessments to monitor the participants' health status and treatment response. These visits will occur every 6 months for the first 5 years and annually thereafter until the end-of-study visit. The end-of-study visit will involve a comprehensive evaluation of the participants' health and the collection of final data for analysis. Participants are expected to be involved in the study for the entire duration unless conditions such as significant adverse events, withdrawal of consent, or non-compliance with study procedures necessitate early termination.
Treatment
The clinical trial involves the administration of **Trastuzumab Emtansine**, a pharmaceutical agent classified under the ATC code L01XC14. This medication is provided in a specific pharmaceutical form denoted as PHF00230MIG. The administration route is **intravenous use**, with a dosage of 3.6 mg/kg. The maximum total dose is 36 mg/kg, and the treatment period extends up to 30 days. The medication is of chemical origin and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.
Another treatment used in the study is **Phesgo 600 mg/600 mg solution for injection**, which contains the active substances **Trastuzumab** and **Pertuzumab**. This solution is administered via **subcutaneous use**. The maximum daily dose is 1200 mg, with a total maximum dose of 20400 mg over a treatment period of 51 days. The active substances are of protein origin, and the formulation is not intended for pediatric use. The administration schedule and participant adherence will be closely monitored.
The study also includes the administration of **Phesgo 1200 mg/600 mg solution for injection**, which similarly contains **Trastuzumab** and **Pertuzumab**. This formulation is also administered subcutaneously. The maximum daily dose is 1800 mg, with a total maximum dose of 1800 mg over a treatment period of 3 days. The active substances are derived from protein sources, and this formulation is not designed for pediatric patients. Compliance with the dosing regimen will be assessed throughout the study duration.
Efficacy
The efficacy of the clinical trial titled "Chemotherapy-Free pCR-Guided Strategy with subcutaneous trastuzumab-pertuzumab and T-DM1 in HER2-positive early breast cancer (PHERGAIN-2)" will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is the 3-year **recurrence-free interval (3y-RFI)**, defined as the time from the start of treatment in the adjuvant setting until recurrence, new invasive disease, or death from breast cancer in the overall population. Recurrence will be defined according to the standardized efficacy endpoints (STEEP) criteria.
Secondary efficacy endpoints include pathologic complete response (pCR) rates, which are further categorized into pCRBREAST+LYMPH NODES (ypT0/Tis ypN0) and pCRBREAST (ypT0/Tis) in the overall study population. These rates will also be evaluated according to hormone receptor (HR) status and tumor stage. Additional secondary endpoints include the Residual Cancer Burden (RCB) score, the rate of breast-conserving surgery (BCS), and the MRI-guided objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The correlation of MRI-guided objective response rate with BCS, pCR, and RCB will also be assessed.
Long-term efficacy will be evaluated through 3-year and 5-year endpoints, including event-free survival (EFS), recurrence-free survival (RFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), invasive disease-free survival (iDFS), overall survival (OS), and breast cancer-specific survival (BCSS). These will be analyzed in the overall study population and according to study arm, HR status, and tumor stage.
The efficacy assessments will be conducted at specified intervals throughout the trial, with data collection and analysis adhering to established clinical trial protocols. The use of validated scales and criteria ensures the reliability and accuracy of the efficacy evaluations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent prior to beginning specific protocol procedures.
- Female or male patients ≥ 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Histologically proven invasive carcinoma of the breast.
- Tumor size must be ≥5mm and ≤25mm using ultrasound and mammography (tumor size between ≥5mm and ≤30mm by MRI is also accepted given the precision of the technique). 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.
- Patients must have node-negative breast cancer by clinical exam, MRI and ultrasound according to the American Joint Committee on Cancer (AJCC) 8th edition.
- Centrally confirmed HER2[+] status with IHC score 3+.
- 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 protoco
- Patients with multifocal or multicentric breast cancer are eligible; only patients with a total number of lesions ≤ 2 are eligible and if all lesions sampled meet the inclusion criteria #5, #6, and #7. Note: If two lesions are in such proximity that it is suspected to be the same lesion, it would not be necessary to biopsy both.
- 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.
- Adequate bone marrow, liver, and renal function: a. 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). b. 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. c. Renal: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. d. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
- Patient must be accessible for treatment and follow-up.
- 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
- Willingness and ability to provide tumor tissue samples at baseline and at surgery.
- 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 postmenopausal or the patient remains abstinent and truly abstains from sexual activity (refrains from heterosexual intercourse).
- 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 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)
- HER2 disease with IHC score 0, 1+ or 2+ and in situ hybridization (ISH) positive result.
- 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 screening only if there is suspicion of bone metastases. If a bone scan cannot be performed at screening, an alternative is PET/CT using 18F-labeled sodium fluoride (18F-fluoride PET/CT).
- Patients with bilateral breast cancer.
- Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
- 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.
- Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
- 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 highergrade 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.
- 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.
- Active uncontrolled infection at the time of enrollment.
- Current known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.
- Patients with pulmonary disease requiring continuous oxygen therapy.
- Grade ≥2 neuropathy as per National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI–CTCAE) version (v)5.0.
- Previous history of bleeding diathesis.
- Patient is currently receiving chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
- 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
- Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study.
- History of having received any investigational treatment within 28 days prior to study entry.
- Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 05 Aug 2021 | 45 |
 Hungary | Not Recruiting | 05 Aug 2021 | 3 |
 Italy | Not Recruiting | 05 Aug 2021 | 62 |
 Spain | Not Recruiting | 05 Aug 2021 | 286 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Phesgo 600 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1200 | 51 | PRD8601830 |
Phesgo 1200 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1800 | 3 | PRD8600161 |
TRASTUZUMAB EMTANSINE | Test | PHF00230MIG | INTRAVENOUS USE | 3.6 | 30 | SCP177784 |