trastuzumab, pertuzumab for HER2-positive early-stage breast cancer

Inclusion criteria

• {"criterion_text":"- Written informed consent prior to beginning specific protocol procedures.\n- 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.\n- 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\n- Patient must be accessible for treatment and follow-up.\n- 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\n- Willingness and ability to provide tumor tissue samples at baseline and at surgery.\n- 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).\n- 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.\n- Female or male patients ≥ 18 years of age\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n- Histologically proven invasive carcinoma of the breast.\n- 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.\n- Patients must have node-negative breast cancer by clinical exam, MRI and ultrasound according to the American Joint Committee on Cancer (AJCC) 8th edition.\n- Centrally confirmed HER2[+] status with IHC score 3+.\n- 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\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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)\n- Active uncontrolled infection at the time of enrollment.\n- Current known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.\n- Patients with pulmonary disease requiring continuous oxygen therapy.\n- Grade ≥2 neuropathy as per National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI–CTCAE) version (v)5.0.\n- Previous history of bleeding diathesis.\n- Patient is currently receiving 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 study entry or anticipation of need for major surgery within the course of the study treatment\n- Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study.\n- History of having received any investigational treatment within 28 days prior to study entry.\n- Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.\n- HER2 disease with IHC score 0, 1+ or 2+ and in situ hybridization (ISH) positive result.\n- 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).\n- Patients with bilateral breast cancer.\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- Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.\n- 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.\n- 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."}

Primary endpoints

• {"endpoint_text":"- Primary efficacy endpoint: 3y-RFI defined as time from start of treatment in adjuvant setting until recurrence, new invasive disease, or death from breast cancer in the overall population. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria.","definition_or_measurement_approach":"Time-to-event measure: time from start of adjuvant treatment to recurrence, new invasive disease, or breast-cancer death; recurrence defined per STEEP standardized efficacy endpoints."}
• {"endpoint_text":"- Primary safety endpoint Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the Global Health Status/QoL EORTC-QLC-C30 scale and its breast cancer module QLQ-BR23.","definition_or_measurement_approach":"Proportion of patients with ≥10% decline in Global Health Status at 1 year from start of neoadjuvant treatment assessed by EORTC QLQ-C30 global health status scale and QLQ-BR23 breast module."}

Secondary endpoints

• {"endpoint_text":"- pCR rates (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) in the overall study population.","definition_or_measurement_approach":"Pathological complete response rates using ypT0/Tis ypN0 definitions for breast+nodes and ypT0/Tis for breast-only."}
• {"endpoint_text":"- pCR rates (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) according to HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"pCR rates stratified by hormone receptor (HR) status and tumor stage (T1 vs T2) using same ypT definitions."}
• {"endpoint_text":"- RCB score in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Residual Cancer Burden (RCB) scoring assessed at surgery, overall and by HR status and tumor stage."}
• {"endpoint_text":"- Rate of BCS in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2)","definition_or_measurement_approach":"Rate of breast-conserving surgery (BCS) overall and by HR status and tumor stage."}
• {"endpoint_text":"- MRI-guided objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2)","definition_or_measurement_approach":"Objective response rate assessed by MRI using RECIST v1.1 overall and by HR and stage."}
• {"endpoint_text":"- Correlation of MRI-guided objective response rate by RECIST v.1.1 with BCS, pCR, and RCB in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Correlation analyses between MRI RECIST v1.1 responses and surgical/pathological outcomes (BCS, pCR, RCB)."}
• {"endpoint_text":"- 5-year RFI in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"5-year recurrence-free interval (time from treatment to recurrence/new invasive disease or breast-cancer death), overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year EFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Event-free survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year RFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2)","definition_or_measurement_approach":"Relapse-free survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year DRFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2)","definition_or_measurement_approach":"Distant relapse-free survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year DFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Disease-free survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year iDFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Invasive disease-free survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year OS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Overall survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- 3-year and 5-year BCSS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).","definition_or_measurement_approach":"Breast cancer-specific survival at 3 and 5 years overall and by arm/HR/stage."}
• {"endpoint_text":"- Adverse events of cardiotoxicity after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.","definition_or_measurement_approach":"Cardiotoxicity adverse events assessed per NCI-CTCAE v5.0 at 1 year post-adjuvant treatment."}
• {"endpoint_text":"- Toxicity and safety profile at 3 and 5 years as per NCI-CTCAE v.5.0 in the overall study population and in each study arm (A, B, C).","definition_or_measurement_approach":"Safety and toxicity assessments at 3 and 5 years using NCI-CTCAE v5.0 overall and by arm."}
• {"endpoint_text":"- Patient Reported Outcomes (PROs) HRQoL assessment as per EORTC-QLC-C30 and QLQ-BR23 questionnaires in the overall study population and in each study arm (A, B, C)","definition_or_measurement_approach":"HRQoL assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires, overall and by arm."}
• {"endpoint_text":"- Ratio of patients of cohort C who will receive adjuvant chemotherapy before T-DM1.","definition_or_measurement_approach":"Proportion of patients in cohort C receiving adjuvant chemotherapy prior to T-DM1."}

Spain

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

12-03-2026

Processing Time Days

552

Number Of Sites

24

Number Of Participants

286

Italy

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

03-03-2026

Processing Time Days

543

Number Of Sites

7

Number Of Participants

62

Germany

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

10-03-2026

Processing Time Days

550

Number Of Sites

4

Number Of Participants

45

Hungary

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

16-04-2026

Processing Time Days

587

Number Of Sites

2

Number Of Participants

3

Primary sponsor

Full Name

Medica Scientia Innovation Research S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Kapadi Spain S.L.","duties_or_roles":"sponsorDuties codes: 1, 12, 15 (15: As per the contract)","organisation_type":"Pharmaceutical company"}