Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer

NCT ID: NCT07193394

Last Updated: 2026-01-21

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-01-31
• Study Completion Date: 2029-06-08

Brief Summary

The H3RAKLES trial would allow patients with a progressive metastatic breast cancer to have access to one more line of systemic therapy. Patients included in this trial will have already received at least two lines of chemotherapy (and potentially several lines of endocrine therapy for patients with a HR+ disease). In this setting, few treatments have demonstrated a clinically meaningful benefit, and any additional option is valuable. Furthermore, the pre-clinical and clinical rationale indicate a high probability of clinical benefit, as previously shown in Table 1, with all patients treated with trastuzumab and a TKI targeting HER2 displaying a response. Besides, with several years of hindsight for the combination of lapatinib, trastuzumab and capecitabine, we expect excellent tolerance with the same treatment without capecitabine.

The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation. To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles.

Detailed Description

For breast cancers in which HER2 is not overexpressed, activating mutations in the ERBB3 gene, coding for the HER3 tyrosine kinase receptor, have an oncogenic role, and targeting them may offer new perspectives of treatment.

Pre-clinical data suggest that HER2 is essential for the pro-tumoral effect of HER3, which does not have a functional tyrosine kinase domain and requires heterodimerization with other members of the HER family of tyrosine kinase receptors for signaling. There is limited clinical evidence of the activity of drugs targeting HER2 in cancers harboring ERBB3 mutations, but few patients with breast cancer have been evaluated. Furthermore, the distribution of ERBB3 mutations seems to differ in breast carcinoma when compared to other cancer types. A few patients with a HER2 non-amplified metastatic breast cancer were treated at Institut Curie with the combination of a HER2-directed antibody and of a HER2 tyrosine kinase inhibitor (TKI) and all responded, warranting further explorations in this setting.

The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody, with a Bayesian design in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation.

To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles, until cancer progression, inacceptable toxicity or patient's withdrawal from the trial.

Tumor radiological assessments will be performed every 6 weeks during the 6 first months (first 8 cycles), then every 9 weeks until disease progression. In addition, Quality of Life will be evaluated throughout the treatment.

Blood samples (at baseline, cycles 1, 2 and 3, and at end of treatment) and tissue samples (at baseline and optionally at progression) will be collected as part as exploratory objective analyses on biomarkers (ctDNA monitoring and next-generation sequencing (NGS)).

Conditions

Metastatic Breast Cancer ( HER2 Negative); Unresectable Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment with tucatinib and trastuzumab combination

Patients with HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation, treated with a combination of tucatinib and trastuzumab

Group Type: EXPERIMENTAL

Tucatinib (ONT-380)

Intervention Type: DRUG

Patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation will receive experimental treatment with tucatinib and trastuzumab combination

Trastuzumab (Herceptin)

Intervention Type: DRUG

Patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation will receive experimental treatment with tucatinib and trastuzumab combination

Interventions

Tucatinib (ONT-380)

Patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation will receive experimental treatment with tucatinib and trastuzumab combination

Intervention Type: DRUG

Trastuzumab (Herceptin)

Patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation will receive experimental treatment with tucatinib and trastuzumab combination

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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: including at least one line of conjugated antibody, at the investigator's discretion or if a germinal BRCA mutation is present, a PARP inhibitor.
• Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step
• ECOG performance status ≤ 2 (Appendix A)
• 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:

1. Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines

2. 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.

3. 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 antihypertensive medications)
• Any history of symptomatic congestive heart failure
• Severe dyspnea at rest (CTCAE v5.0 Grade 3 or above) 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:

• Congenital or acquired long QT syndrome
• Family history of sudden death
• History of previous drug-induced QT prolongation
• Current use of medications with known and accepted associated risk of QT prolongation (see row "Accepted Association" in Appendix D)
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Eurofins

INDUSTRY

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: collaborator

Institut Curie

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

François-Clément Bidard, Prof.

Role: PRINCIPAL_INVESTIGATOR

Institut Curie

Sandra BIDARD

Role: PRINCIPAL_INVESTIGATOR

Institut Curie

Locations

Polyclinique Bordeaux Nord Aquitaine

Bordeaux, , France

Chu Dupuytren- Limoges

Limoges, , France

Institut Paoli-Calmettes

Marseille, , France

Centre Antoine Lacassagne

Nice, , France

CHU de Nîmes

Nîmes, , France

Centre Eugène Marquis

Rennes, , France

Institut Curie_ Site Saint-Cloud

Saint-Cloud, , France

Institut Universitaire du Cancer de Toulouse (IUCT) - Oncopole Claudius Regaud

Toulouse, , France

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, , France

Countries

France

Central Contacts

Sandra Clinical Project Manager

Role: CONTACT

drci.promotion@curie.fr

+33156245944

Sandra Regulatory Assistant

Role: CONTACT

drci.promotion@curie.fr

+33156245765

Facility Contacts

Laura POETSCH, MD

Role: primary

Elise DELUCHE, MD

Role: primary

Alexandre TASSIN DE NONNEVILLE, MD

Role: primary

Marc PUJALTE-MARTIN, MD

Role: primary

Frédéric FITENI, MD

Role: primary

Antoine DELEUZE, MD

Role: primary

Nicolas KIAVUE, MD

Role: primary

Florence DALENC, MD

Role: primary

Vincent MASSARD, MD

Role: primary

Other Identifiers

2024-519624-24-00

Identifier Type: CTIS

Identifier Source: secondary_id

IC 2024-01

Identifier Type: -

Identifier Source: org_study_id