Evaluation of Tucatinib and Trastuzumab in HER3-Mutant, HER2-Non-Amplified Metastatic Breast Cancer
- Trial ID
- 2024-519624-24-00
- Protocol
- IC 2024-01
- Sponsor
- Institut Curie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to demonstrate that **ERBB3 mutations** are actionable in **breast cancer** in terms of the 24-week clinical benefit rate. This is clinically relevant as it aims to establish a targeted therapeutic approach for patients with HER3-mutant and HER2-not amplified metastatic breast cancer, potentially leading to improved treatment outcomes.
Secondary objectives include:
- Evaluating the efficacy of the **trastuzumab/tucatinib** combination using other endpoints.
- Assessing the safety profile of the trastuzumab/tucatinib combination.
- Monitoring changes in quality of life (QoL) under treatment.
- Exploratory evaluation of biomarkers associated with treatment efficacy.
Participants
The clinical trial involves participants diagnosed with **HER3-mutant and HER2-not amplified metastatic breast cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who have previously undergone at least two chemotherapy lines for advanced breast cancer. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection process involves a molecular screening step, ensuring the presence of a Class IV or V somatic ERBB3 mutation in the tumor sample. Participants must have adequate organ function and a left ventricular ejection fraction of 50% or higher. Lifestyle considerations include the requirement for women of childbearing potential and men with partners of childbearing potential to use highly effective birth control methods during the study and for three months after the completion of the investigational treatment. The trial includes a vulnerable population, and all participants must be covered by a health insurance plan and able to provide signed informed consent.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **trastuzumab** and **tucatinib** in patients with HER3-mutant and HER2-not amplified metastatic breast cancer. This is a Phase II, randomized, double-blind, controlled trial with an estimated duration extending until May 2029. The trial aims to demonstrate that ERBB3 mutations are actionable in breast cancer, focusing on a 24-week clinical benefit rate as the primary endpoint. Secondary endpoints include progression-free survival, objective response rate, duration of response, and the assessment of adverse events per CTCAE v5.0.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having received at least two previous chemotherapy lines for advanced breast cancer, a Class IV or V somatic ERBB3 mutation, and an ECOG performance status of ≤ 2. The screening will also involve molecular analysis of a tumor sample obtained within the last five years. Following successful screening, participants will be randomized to receive either the investigational treatment or a control, with follow-up visits scheduled at regular intervals to monitor treatment response and safety.
The expected length of participant involvement is up to 18 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The end-of-study visit will occur after the completion of the treatment period or upon early termination, during which final assessments will be conducted. Participants are required to adhere to study protocols, including the use of effective birth control methods if applicable, and must be covered by a health insurance plan. The trial will also explore the relationship between biomarkers and treatment efficacy, providing valuable insights into the potential of targeted therapies in this patient population.
Treatment
The clinical trial involves the administration of **Ogivri**, a **trastuzumab**-based medication, which is provided as a 150 mg powder for concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous** administration. The maximum daily dose is 8 mg/kg, with a total maximum dose of 146 mg/kg over a treatment period of up to 18 weeks. The active substance, trastuzumab, is a protein of non-human origin, and the product is manufactured by Biosimilar Collaborations Ireland Limited. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
In addition to Ogivri, the trial includes the use of **TUKYSA**, which contains the active substance **tucatinib**. TUKYSA is available in two dosages: 50 mg and 150 mg film-coated tablets. Both formulations are administered orally. The maximum daily dose for tucatinib is 600 mg, with a total maximum dose of 302,400 mg over the same 18-week treatment period. Tucatinib is a chemical compound, and the product is manufactured by Pfizer Europe MA EEIG. The trial protocol specifies the association of tucatinib with trastuzumab for the treatment of HER2-not amplified metastatic breast cancer, with compliance monitored throughout the study duration.
Efficacy
Efficacy in the clinical trial titled "H3RAKLES: Tucatinib and trastuzumab in HER3-mutant and HER2-not amplified metastatic breast cancer" will be assessed using several parameters. The primary endpoint is the **Clinical Benefit Rate (CBR)**, which is defined as the proportion of patients who achieve a complete response (CR), partial response (PR), or maintain stable disease (SD) for 24 weeks or more, as evaluated by the investigator using RECIST v1.1 criteria.
Secondary endpoints include **Progression-Free Survival (PFS)**, which measures the time from inclusion to disease progression or death, and the **Objective Response Rate**, defined as the proportion of patients achieving a CR or PR according to RECIST v1.1 criteria. The **Duration of Response** will also be evaluated, defined as the time between the first observation of a PR or CR and the onset of progressive disease or death. Additionally, the trial will monitor **Adverse Events (AEs)** and **Serious Adverse Events (SAEs)**, as per CTCAE v5.0, that are considered related to trastuzumab or tucatinib by the investigator.
Patient-reported outcomes will be collected using the QLQ-C30 Quality of Life questionnaire with the QLQ-BR42 module, administered at inclusion, during cycles 1 and 3, and at the end of treatment. Exploratory analyses will investigate the relationship between biomarkers, including DNA, RNA, and protein analyses in blood, plasma, and/or tumor samples, and the presence of an ERBB3 mutation or treatment efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Molecular screening step: availability of a formalin-fixed paraffin-embedded (FFPE) block with >10% tumor tissue (it is recommended to provide the most recently collected tumor sample).
- Molecular screening step: the tumor sample must have been obtained less than 5 years before inclusion
- Molecular screening step: prior signature of a written informed molecular screening consent.
- Molecular screening step: patients should be eligible for the treatment step according to the investigator’s opinion.
- Molecular screening step: patients must be covered by a health insurance plan.
- Molecular screening step: patients able to provide signed informed consent.
- Age ≥ 18 years
- Metastatic or unresectable breast cancer
- HER2-negative (defined as having an IHC 0+, IHC 1+, or IHC 2+ and ISH non-amplified, per ASCO/CAP guidelines) on last assessable tumor sample
- Having received ≥ 2 previous chemotherapy lines for advanced breast cancer
- Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step
- ECOG performance status ≤ 2
- Evaluable disease, per RECIST v1.1 inclusion criteria
- Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
- Adequate organ function: a.Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines; b.Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN; c.Transaminases (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 X ULN (≤ 5 X ULN if the patient has liver metastases)
- Women of childbearing potential (WCBP) must have a negative serum pregnancy test < 7 days prior to first dose of treatment. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as the absence of menses for 12 months without an alternative cause.
- WCBP (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method during the study and for 3 months after completion of investigational treatment.
- Patients should be eligible for the treatment step according to the investigator’s opinion.
- Patients must be covered by a health insurance plan.
- Patients able to provide signed informed consent.
Exclusion Criteria
- Having received any prior treatment targeting HER2. Prior treatment with trastuzumab deruxtecan is allowed, per label, in patients with HER2-low metastatic breast cancer (IHC 1+ or 2+, ISH non-amplified)
- History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs
- Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
- Inability to swallow pills or having a significant gastro-intestinal disease or a history of surgery which would preclude the adequate oral absorption of medications
- Having used a strong CYP2C8 inhibitor within a duration of 5 half-lives prior to the first dose of study treatment, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment (see Appendix B and Appendix C)
- Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks prior to the first dose of study treatment, except gonadotropin releasing hormone (GnRH) agonists
- Participation in another interventional clinical trial.
- Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose > 2 mg of dexamethasone (or equivalent)
- Whole brain radiotherapy < 21 days prior to first dose of treatment, stereotactic radiotherapy < 7 days prior to first dose of treatment
- Leptomeningeal metastases
- Major surgery (including surgery of brain metastases) < 21 days prior to first dose of treatment
- Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
- Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment
- Have clinically significant cardiopulmonary disease such as: • Ventricular arrhythmia requiring therapy, • Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mm Hg on antihy) due to complications of advanced malignancy, • Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea, • Presence of ≥ Grade 2 QTc prolongation on screening ECG, • Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: o Congenital or acquired long QT syndrome, o Family history of sudden death, o History of previous drug-induced QT prolongation, o Current use of medications with known and accepted associated risk of QT prolongation
- Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease
- Are known to be positive for human immunodeficiency virus (HIV)
- Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
- Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons
- Person deprived of liberty or under guardianship
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 15 Nov 2025 | 20 |
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 |
|---|---|---|---|---|---|---|
Ogivri 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 8 | 18 | PRD11000552 |
TUKYSA 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 18 | PRD11359038 |
TUKYSA 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 18 | PRD11359037 |