Evaluation of Trastuzumab and Pertuzumab with FDG-PET Response-Adapted Strategy in HER2-Positive Breast Cancer: The PHERGain Study
- Trial ID
- 2023-509923-42-00
- Protocol
- MedOPP096 - MO39229
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the early metabolic effects of neoadjuvant treatment with **trastuzumab** and **pertuzumab** (with or without endocrine therapy) on the primary tumor and axillary lymph nodes, and their predictive value for pathologic complete response (pCR) in the breast and axilla. Additionally, the study aims to evaluate the 3-year invasive disease-free survival (iDFS) in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab using an FDG-PET response-adapted strategy. These objectives are clinically relevant as they aim to improve treatment outcomes and survival rates in patients with HER2-positive breast cancer by utilizing a chemotherapy-free approach.
The secondary objectives include: - Assessing efficacy by other pCR definitions, such as pCR in the breast only and Residual Cancer Burden (RCB) score. - Comparing the rate of pCR between treatment groups by 18F-FDG PET/CT response, hormone receptor (HR) status, HER2 status, and tumor stage. - Comparing the rate of conversion to breast-conserving surgery between treatment groups. - Comparing the overall response rate (ORR) by 18F-FDG PET/CT and MRI between treatment groups. - Analyzing optimal 18F-FDG PET/CT cut-off for pCR and other 18F-FDG PET quantification parameters beside SUVmax for pCR. - Evaluating changes in health-related quality of life assessments from baseline using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. - Assessing 3, 5, and 7-year iDFS, distant disease-free survival (DDFS), disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) between treatment groups by 18F-FDG PET/CT response, HR status, and HER2 status. - Assessing progression-free survival (PFS) in patients with subclinical M1 at baseline by 18F-FDG PET/CT. - Assessing safety outcomes between treatment groups by 18F-FDG PET/CT response, HR status, and HER2 status.
Participants
The clinical trial involves participants diagnosed with **HER2-positive breast cancer**. The study population includes both female and male patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have histologically proven invasive breast cancer that is operable, with tumor sizes larger than or equal to 1.5 centimeters in diameter, confirmed by magnetic resonance imaging (MRI) or ultrasound. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria require participants to have centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria, and known estrogen receptor (ER) and progesterone receptor (PR) status prior to study entry. Participants must meet specific hematological and hepatic function criteria, and be accessible for treatment and follow-up. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a chemotherapy-free regimen involving **trastuzumab** and **pertuzumab** in patients with **HER2-positive breast cancer**. This is a multicenter, open-label, randomized phase II trial. The study employs a **FDG-PET** response-adapted strategy to assess the early metabolic effects of the neoadjuvant treatment on the primary tumor and axillary lymph nodes, with the primary objective of predicting pathologic complete response (pCR) and evaluating 3-year invasive disease-free survival (iDFS). The trial is expected to run from June 2017 to November 2026, with a maximum treatment period of 90 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific laboratory values. Following the screening, participants will be randomized into treatment cohorts. The trial includes several follow-up visits to monitor treatment response and safety, utilizing imaging techniques like **FDG-PET/CT** and **MRI**. The end-of-study visit will assess the primary and secondary endpoints, including pCR rates and iDFS.
The expected length of participant involvement is approximately 90 days, with conditions for early termination including adverse events, non-compliance with the protocol, or withdrawal of consent. The trial's primary endpoints focus on the rate of pCR and the 3-year iDFS rate, while secondary endpoints include various response rates, health-related quality of life assessments, and long-term survival metrics. The study aims to provide valuable insights into the potential of a chemotherapy-free approach in treating **HER2-positive breast cancer**.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Letrozole**, marketed as Letrozol Kern Pharma 2.5 mg, is provided in the form of a **film-coated tablet**. The active substance, letrozole, is of chemical origin. The medication is administered orally at a maximum daily dose of 2.5 mg, with a treatment period not exceeding 90 days.
**Tamoxifen citrate**, available as Tamoxifeno Teva 20 mg, is also administered in tablet form. This chemical-origin medication is taken orally, with a maximum daily dose of 20 mg, and the treatment duration is limited to 90 days.
**Pertuzumab**, marketed as Perjeta 420 mg, is provided as a concentrate for solution for infusion. This protein-based medication is administered intravenously, with a maximum dose of 840 mg per administration. The treatment period is capped at 90 days.
**Carboplatin**, available as Carboplatino Teva 10 mg/ml, is administered as an injection. The active substance is of chemical origin, and the medication is delivered intravenously. The maximum daily dose is 6 mg/ml, with a treatment duration of up to 90 days.
**Docetaxel**, marketed as Docetaxel Accord 160 mg/8 ml, is provided as a concentrate for solution for infusion. This chemical-origin medication is administered intravenously, with a maximum dose of 7.5 mg/m². The treatment period is limited to 90 days.
**Trastuzumab**, available as Herceptin 600 mg, is provided as a solution for injection in a vial. This protein-based medication is administered subcutaneously, with a maximum daily dose of 120 mg/ml. The treatment duration is capped at 90 days.
All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The administration of these medications is conducted under strict clinical supervision to ensure participant safety and adherence to the trial protocol.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include evaluating the rate of **pathologic complete response (pCR)**, defined by the absence of invasive disease in the breast and axilla (ypT0/isN0) at the time of surgery, achieved with the combination of trastuzumab and pertuzumab (± endocrine therapy) as exclusive neoadjuvant treatment in PET responders. Additionally, the 3-year invasive disease-free survival (iDFS) rate will be evaluated, defined as the time from the first date of no disease to invasive recurrence, new invasive disease, or death by any cause.
Secondary endpoints encompass a range of efficacy measures, including pCR rates in the breast and axilla, the Residual Cancer Burden (RCB) score, and the rate of breast-conserving surgery. The trial will also assess the 18F-FDG PET/CT response rate according to the adapted EORTC criteria, the optimal 18F-FDG PET/CT cut-off for pCR, and other 18F-FDG PET quantification parameters. MRI response rate will be evaluated according to the RECIST criteria version 1.1. Health-related quality of life will be measured using the EORTC QLQ-C30 and QLQBR23 questionnaires. Long-term outcomes such as 3, 5, and 7-year iDFS, distant disease-free survival (DDFS), disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) will also be analyzed.
The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, with the primary analysis focusing on estimating the 3-year iDFS rate in cohort B. The trial will utilize standardized efficacy endpoints (STEEP) criteria for defining recurrence and will employ validated tools and instruments for measuring patient-reported outcomes and imaging responses.
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 0-1.
- Histologically proven invasive breast cancer.
- Operable breast cancer (cT1-3 and/or cN0-2 tumors).
- Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as maximum standardized uptake value (SUVmax) ≥1.5 x SUVmean liver + 2 SD. Multicentric/multifocal tumors will be allowed only if: 1. Histological confirmation of at least two lesions. 2. All tumors must be HER2-positive. 3. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound.
- Centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.
- Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry.
- Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
- 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.
- Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- Patient must be accessible for treatment and follow-up.
Exclusion Criteria
- Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
- cT4 and/or cN3 tumors.
- Bilateral breast cancer.
- Evidence of metastatic disease by routine clinical assessment [chest x-ray, liver ultrasound, and bone scan; or computed tomography (CT) scan of thorax and and abdomen and bone scan], except patients with subclinical M1 at baseline only according to 18Ffluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) that will be allowed to be included into Cohort C.
- 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.
- Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).
- Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
- Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrytmhias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication].
- Active uncontrolled infection at the time of enrollment.
- Current known infection with HIV, hepatitis B virus, or hepatitis C virus.
- Patients with pulmonary disease requiring continuous oxygen therapy.
- Previous history of bleeding diathesis.
- Patient is currently receiving anti-coagulant therapy, 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 randomization or anticipation of need for major surgery within the course of the study treatment.
- Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, contraindicate her participation in the clinical study.
- Concurrent participation in other clinical trial, except other translational studies.
- History of receiving any investigational treatment within 28 days prior to randomization.
- 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 |
|---|---|---|---|
 France | Not Recruiting | 01 Jun 2017 | 19 |
 Germany | Not Recruiting | 01 Jun 2017 | 13 |
 Italy | Not Recruiting | 01 Jun 2017 | 33 |
 Portugal | Not Recruiting | 01 Jun 2017 | 17 |
 Spain | Not Recruiting | 01 Jun 2017 | 263 |
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 |
|---|---|---|---|---|---|---|
Herceptin 600 mg solution for injection in vial | Test | SOLUTION FOR INJECTION IN VIAL | SUBCUTANEOUS | 120 | 90 | PRD2154036 |
Perjeta 420 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 840 | 90 | PRD2154581 |
Docetaxel Accord 160 mg/8 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 7.5 | 90 | PRD3445547 |
Tamoxifeno Teva 20 mg comprimidos EFG | Test | COMPRIMIDOS EFG | ORAL | 20 | 90 | PRD603991 |
Carboplatino Teva 10 mg/ml Concentrado para solución para perfusión | Test | CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | INTRAVENOUS | 6 | 90 | PRD664512 |
Letrozol Kern Pharma 2,5 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 2.5 | 90 | PRD413405 |