Aún no reclutaNCT07928479Registro de ClinicalTrials.gov

Neoadjuvant Trastuzumab, Pertuzumab and Zongertinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-5 Study

HER2-positive Breast Cancer · Early Breast Cancer (EBC)

Pregúntale a WCR sobre este estudio Registro oficial ↗

LO ESENCIAL

De qué trata este estudio

El registro no identifica actualmente este estudio como reclutando. Consulta su estado antes de planificar una evaluación.

Tipo de estudio: De intervención
Fase: Fase 1
Rango de edad: 18 años - No especificado
Sexo admitido: Todos los sexos
Voluntarios sanos: No aceptados
Participantes: 30 Estimado

Estos son puntos de partida, no una decisión de elegibilidad. El equipo debe revisar todos los requisitos.

Las explicaciones y la navegación están en español. Los textos proporcionados por el registro, incluidos títulos, resúmenes y criterios, se conservan en su idioma original. Puedes pedir orientación en español a WCR.

Acerca de la investigación

This is a single-center, phase 1b study evaluating the safety, feasibility and initial efficacy of a neoadjuvant treatment with zongertinib, trastuzumab and pertuzumab in stage II-IIIA HER2-positive breast cancer.

Leer la descripción completa

Neoadjuvant chemotherapy combined with dual HER2-targeted therapy results in high rates of pathological complete response (pCR) and excellent long-term survival outcomes in patients with HER2-positive breast cancer. However, this intensive treatment carries significant toxicity, leading to both acute and long-term side effects. Long-term and potentially irreversible toxicities such as neuropathy, persistent fatigue, and cognitive impairment frequently occur and may significantly impair long-term quality of life. Additionally, brain recurrence remains a well-documented, devastating complication in HER2-positive disease.

Previous studies have demonstrated that neoadjuvant treatment with dual HER2-targeted therapy consisting of trastuzumab and pertuzumab without chemotherapy can induce pCR in 11% to 47% of patients, while event-free survival appeared non-inferior. These findings suggest that omission of chemotherapy may be feasible in selected patients. Strategies to improve patient selection and to enhance HER2-directed therapy using novel highly selective agents may further increase pCR rates and expand the proportion of patients eligible for chemotherapy-free treatment. The use of agents with adequate central nervous system penetration may additionally reduce the risk of brain recurrence.

Zongertinib is an orally administered, highly selective, and irreversible HER2 tyrosine kinase inhibitor with minimal off-target toxicity. It has demonstrated robust preclinical and clinical activity against HER2-altered solid tumours, including efficacy in patients with brain metastases. Given its favourable pharmacologic profile and promising therapeutic potential, zongertinib is a strong candidate for incorporation into a chemotherapy-free neoadjuvant regimen for HER2-positive breast cancer.

¿Quién podría participar?

La lista siguiente contiene el texto del patrocinador. Puede incluir condiciones, tratamientos previos, resultados de pruebas y otros requisitos. Aparecer en tu búsqueda no significa que califiques.

Inclusion Criteria:

1. Signed written informed consent
2. Pathologically confirmed primary invasive breast cancer
3. Stage II - IIIA primary breast cancer according to TNM-staging (8th edition, AJCC); (largest tumour diameter DCE-MRI \> 2cm (cT2-3) and/or cN1-2 confirmed with FNA or histology)
4. Homogeneous HER2 overexpression (IHC 3+) on pre-treatment biopsy, with confirmatory HER2 amplification by in situ hybridization
5. Known oestrogen- and progesterone-receptor expression of the invasive tumour

a. Hormone receptor negativity is defined as expression of both oestrogen and progesterone receptors being less than 10%
6. WHO performance status of 0 or 1
7. 18 years of age or older
8. LVEF ≥50% measured by echocardiography or MUGA
9. Eligible for neoadjuvant treatment
10. Laboratory requirements within 4 weeks prior to the start of study treatment:

1. Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l, haemoglobin ≥5.6 mmol/L (≥90 g/L); without the use of hematopoietic growth factors within 4 weeks prior to start of trial medication.
2. Adequate hepatic function (ALT and AST ≤3 times upper limit of normal (ULN), Alkaline phosphatase \<5 times ULN, Total bilirubin ≤1.5 times the ULN, except for patients with Gilbert's syndrome: total bilirubin ≤3 times ULN or direct bilirubin ≤1.5 times ULN);
3. Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) ≥30 mL/min/1.73m2 calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula.
4. Either International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times ULN unless on a stable dose of an anticoagulant with no unexplained elevation of INR
5. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 times ULN unless on a stable dose of an anticoagulant with no unexplained elevation of INR
11. Women of childbearing potential (WOCBP) must be ready and able to use dual highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly during study treatment and 7 months after last dose of trastuzumab

Exclusion Criteria:

1. Inflammatory breast cancer, cT4 and/or cN3 tumours
2. Occult breast cancer (cT0)
3. Bilateral breast cancer
4. Current pregnancy or breastfeeding. Women who are breastfeeding can be enrolled if they stop breastfeeding.
5. Current or previous other malignancy unless treated without systemic therapy and more than five years ago
6. HER2 heterogeneity on pre-treatment biopsy
7. Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
8. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction, stroke, or pulmonary embolism within 6 months prior to registration.
9. Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting electrocardiograms
10. Mean resting corrected QT interval (QTcF) \>470 msec (females) or \>450 msec (males) based on screening 12-lead ECG
11. Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy (according to local / institutional standard) who have not been treated with suppressive antiviral therapy prior to initiation of study treatment
12. Patients with a history of HCV infection who meet one or both of the following criteria:

1. Currently receiving curative antiviral treatment
2. HCV viral load is above the limit of quantification (HCV RNA positive)
13. Patients with history of HIV infection who meet one or more of the following criteria;

1. CD4+ count \<350 cells/μL
2. Viral load \>400 copies/μL (local lab assessment)
3. Not receiving antiretroviral therapy
4. Receiving established antiretroviral therapy for less than 4 weeks prior to the start of trial treatment
5. History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment
14. Active or known or history of non-infectious interstitial lung disease/pneumonitis
15. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g., nausea, vomiting, Crohn's disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator
16. Active infectious disease requiring systemic therapy, which puts the patient at increased risk in the opinion of the investigator.
17. Patients with severe hepatic impairment (classified as Child-Pugh C or score 10-15)
18. Known history of allergy to the trial drug(s) or any excipients of the trial drug(s) or contraindication to any of the trial drugs
19. Contraindications for MRI or or non-evaluable MRI

Entiende la evaluación inicial

Tratamiento, grupos y participación

El registro puede describir tratamientos y duración sin incluir un calendario completo. Pide al equipo las visitas, procedimientos, riesgos, costos y alternativas. Mantén tu atención habitual salvo que tu médico te indique un cambio.

Asignación: No aplica
Enmascaramiento: Sin enmascaramiento

This is a single-arm, non-comparative, non-randomized, single-center phase 1b study

Eligible patients are adults (≥18 years) with pathologically confirmed primary stage II-IIIA HER2-positive breast cancer, defined as homogenous HER2 3+ on immunohistochemistry. Additional eligibility criteria include WHO performance status 0-1, left ventricular ejection fraction ≥50%, adequate hepatic, renal and bone marrow function, and absence of current or previous other malignancy unless treated without systemic therapy and disease-free for more than five years.

Drug: Zongertinib is an orally administered, highly selective, and irreversible HER2-tyrosine kinase inhibitor.

Zongertinib is an orally administered, highly selective, and irreversible HER2-tyrosine kinase inhibitor. DRUG

All patients will receive neoadjuvant treatment with trastuzumab, pertuzumab and zongertinib. Patients with hormone receptor-positive tumours will additionally receive concurrent endocrine therapy with an aromatase inhibitor; premenopausal patients will also receive an LHRH antagonist. Breast MRI will be performed at baseline and after three cycles to assess functional tumour volume (FTV). Patients demonstrating ≥65% FTV reduction will continue the chemotherapy-free regimen for an additional three cycles. Patients with \<65% FTV will switch to standard neoadjuvant chemotherapy for three cycles. Following completion of neoadjuvant therapy, patients will undergo surgery within six weeks. Those achieving pCR will continue adjuvant trastuzumab according to ESMO guidelines. Patients without pCR will receive adjuvant chemotherapy according to standard care.

Prepara tus preguntas

Qué evalúan los investigadores

Estas medidas indican qué se estudia. No prueban que un tratamiento funcione.

Medidas principales

Safety

Plazo: Incidence and severity of adverse events (all grades) occuring during treatment and up to 30 days after last administration of study treatment.

The primary objective is to evaluate the safety of neoadjuvant chemotherapy-free regimen consisting of trastuzumab, pertuzumab and zongertinib in patients with stage II-IIIA HER2-positive breast cancer.