TRASTUZUMAB for HER2-positive breast cancer

Inclusion criteria

• {"criterion_text":"- Written informed consent prior to beginning specific protocol procedures.\n- 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.\n- Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.\n- Patient must be accessible for treatment and follow-up.\n- Female or male patients ≥ 18 years of age.\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.\n- Histologically proven invasive breast cancer.\n- Operable breast cancer (cT1-3 and/or cN0-2 tumors).\n- 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.\n- Centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.\n- Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry.\n- 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)."}

Exclusion criteria

• {"criterion_text":"- Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.\n- Active uncontrolled infection at the time of enrollment.\n- Current known infection with HIV, hepatitis B virus, or hepatitis C virus.\n- Patients with pulmonary disease requiring continuous oxygen therapy.\n- Previous history of bleeding diathesis.\n- Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).\n- 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.\n- Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, contraindicate her participation in the clinical study.\n- Concurrent participation in other clinical trial, except other translational studies.\n- History of receiving any investigational treatment within 28 days prior to randomization.\n- Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.\n- cT4 and/or cN3 tumors.\n- Bilateral breast cancer.\n- 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.\n- Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.\n- 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.\n- Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).\n- Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.\n- 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]."}

Primary endpoints

• {"endpoint_text":"- The first co-primary endpoint is to evaluate the rate of pCR as 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 patients (cohort B/PET responders) [PET/CT positive predictive value (PPV) for a pCR among patients who are PET responders].","definition_or_measurement_approach":"Pathologic complete response (pCR) defined as absence of invasive disease in breast and axilla (ypT0/isN0) at surgery; primary analysis includes PET/CT positive predictive value (PPV) for pCR among PET responders (cohort B)."}
• {"endpoint_text":"- The second co-primary endpoint is to evaluate 3-year iDFS rate defined as time from the first date of no disease (i.e., date of surgery) to invasive recurrence, new invasive disease, or death by any cause. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. The primary analysis will be to estimate 3-year iDFS rate in cohort B.","definition_or_measurement_approach":"3-year invasive disease-free survival (iDFS): time from date of no disease (date of surgery) to invasive recurrence, new invasive disease, or death from any cause; recurrence defined per STEEP criteria; primary analysis estimates 3-year iDFS in cohort B."}

Secondary endpoints

• {"endpoint_text":"- 3, 5, and 7-year iBCFS defined as time from the first date of no disease (i.e., date of surgery) to invasive breast cancer recurrence, or death by any cause. Recurrence Will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria.","definition_or_measurement_approach":"Invasive breast cancer free survival (iBCFS) at 3, 5, 7 years; time from date of no disease to invasive breast cancer recurrence or death; recurrence per STEEP criteria."}
• {"endpoint_text":"- pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohorts A/B by PET responder status).","definition_or_measurement_approach":"pCR rates measured as ypT0/isN0 in breast and axilla, reported by cohort (A, B) and by PET responder status."}
• {"endpoint_text":"- pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohorts A/B by PET responder status).","definition_or_measurement_approach":"pCR in breast (ypT0/is) by cohort and PET responder status."}
• {"endpoint_text":"- RCB score (cohort A; cohort B; cohorts A/B by PET responder status).","definition_or_measurement_approach":"Residual Cancer Burden (RCB) score assessed on surgical specimen, reported by cohort and PET responder status."}
• {"endpoint_text":"- pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohorts A/B by PET responder status; HR status, HER2 status and tumor stage).","definition_or_measurement_approach":"pCR rates (ypT0/isN0) analyzed by cohort and stratified by hormone receptor (HR) status, HER2 status, and tumor stage."}
• {"endpoint_text":"- Rate of breast conserving surgery (cohort A; cohort B; cohorts A/B by PET responder status).","definition_or_measurement_approach":"Proportion of patients undergoing breast-conserving surgery (lumpectomy) by cohort and PET responder status."}
• {"endpoint_text":"- 18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B).","definition_or_measurement_approach":"FDG PET/CT response rate evaluated per adapted EORTC criteria in cohorts A and B."}
• {"endpoint_text":"- Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B).","definition_or_measurement_approach":"Analysis to identify optimal PET/CT cut-off values predictive of pCR in cohorts A and B."}
• {"endpoint_text":"- Other 18F-FDG PET quantification parameters beside SUVmax for pCR (cohort A; cohort B).","definition_or_measurement_approach":"Exploratory analyses of PET quantification parameters (beyond SUVmax) for association with pCR."}
• {"endpoint_text":"- MRI response rate (according to the RECIST criteria version 1.1) (cohort A; cohort B; cohorts A/B by PET responder status).","definition_or_measurement_approach":"MRI-based response rate assessed using RECIST v1.1 criteria by cohort and PET responder status."}
• {"endpoint_text":"- Health-related quality of life (EORTC QLQ-C30 and QLQBR23 questionnaires) (cohort A; cohort B; cohort C; cohorts A/B by PET responder status).","definition_or_measurement_approach":"Patient-reported outcomes measured by EORTC QLQ-C30 and QLQ-BR23 questionnaires at predefined timepoints."}
• {"endpoint_text":"- 3, 5, and 7-year iDFS (cohort A; cohort B [with the exception of 3-year iDFS]; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18FFDG- PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Invasive disease-free survival at 3, 5, 7 years analyzed by cohorts and subgroups (PET response, pCR, HR, HER2, chemotherapy received)."}
• {"endpoint_text":"- 3, 5, and 7-year iBCR (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Invasive breast cancer recurrence (iBCR) rates at 3, 5, 7 years by cohort and subgroups as specified."}
• {"endpoint_text":"- 3, 5, and 7-year DDFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Distant disease-free survival at 3, 5, 7 years analyzed by cohorts and relevant subgroups."}
• {"endpoint_text":"- 3, 5, and 7-year DFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Disease-free survival at 3, 5, 7 years by cohort and subgroups."}
• {"endpoint_text":"- 3, 5, and 7-year adapted iDFS, DDFS, and DFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).","definition_or_measurement_approach":"Adapted survival endpoints (iDFS, DDFS, DFS) at 3, 5, 7 years for cohort C (subclinical M1 at baseline on PET/CT)."}
• {"endpoint_text":"- 3, 5, and 7-year EFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR).","definition_or_measurement_approach":"Event-free survival at 3, 5, 7 years by cohort and specified subgroups."}
• {"endpoint_text":"- 3, 5, and 7-year OS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Overall survival at 3, 5, 7 years by cohort and subgroups."}
• {"endpoint_text":"- PFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).","definition_or_measurement_approach":"Progression-free survival for cohort C (patients with subclinical M1 at baseline on PET/CT)."}
• {"endpoint_text":"- Adverse events, grade 3-4 adverse events, related adverse events, serious adverse events, related serious adverse events, and adverse events leading to discontinuation (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).","definition_or_measurement_approach":"Safety endpoints: AEs, grade 3-4 AEs, related AEs, SAEs, related SAEs, and AEs leading to discontinuation collected and reported by cohort and subgroups."}

France

Earliest CTIS Part Ii Submission Date

18-07-2024

Latest Decision Or Authorization Date

24-07-2024

Processing Time Days

6

Number Of Sites

4

Number Of Participants

19

Portugal

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

17-07-2024

Processing Time Days

15

Number Of Sites

5

Number Of Participants

17

Italy

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

29-07-2024

Processing Time Days

27

Number Of Sites

5

Number Of Participants

33

Spain

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

16-07-2024

Processing Time Days

14

Number Of Sites

18

Number Of Participants

263

Germany

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

19-07-2024

Processing Time Days

17

Number Of Sites

3

Number Of Participants

13

Primary sponsor

Full Name

Medica Scientia Innovation Research S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain