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

NCT07193394 | Recruiting Phase 2 DMC

• 2 other identifiers: IC 2024-012024-519624-24-00
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 9

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.

Conditions

Metastatic Breast Cancer ( HER2 Negative); Unresectable Breast Cancer

Keywords

Breast; Cancer; HER2; tucatinib; trastuzumab; HER3; metastatic; unresectable

Outcome Measures

Primary Outcomes (1)

• Clinical benefit rate (CBR)

  Clinical benefit rate (CBR), defined as the proportion of patients who achieved a complete response (CR), a partial response (PR), or had stable disease (SD) for 24 weeks or more, according to the investigator-assessed RECIST v1.1 criteria.

  24 weeks

Secondary Outcomes (4)

• Progression-free survival (PFS)

  18 months

• Overall survival (OS)

  18 months

• Objective response rate (ORR)

  18 months

• Safety of the trastuzumab/tucatinib combination

  18 months

Study Arms (1)

Treatment with tucatinib and trastuzumab combination

EXPERIMENTAL

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

Drug: Tucatinib (ONT-380); Drug: Trastuzumab (Herceptin)

Interventions

Tucatinib (ONT-380) 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

Treatment with tucatinib and trastuzumab combination

Trastuzumab (Herceptin) 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

Treatment with tucatinib and trastuzumab combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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,

Sponsors & Collaborators

• Institut Curie: lead
• Pfizer: collaborator
• Eurofins: collaborator
• UNICANCER: collaborator

Study Sites (9)

Polyclinique Bordeaux Nord Aquitaine

Bordeaux, 33 300, France

NOT YET RECRUITING

Chu Dupuytren- Limoges

Limoges, 87 042, France

NOT YET RECRUITING

Institut Paoli-Calmettes

Marseille, 13009, France

NOT YET RECRUITING

Centre Antoine Lacassagne

Nice, 06 189, France

NOT YET RECRUITING

CHU de Nîmes

Nîmes, 30 029, France

NOT YET RECRUITING

Centre Eugène Marquis

Rennes, 35 042, France

NOT YET RECRUITING

Institut Curie_ Site Saint-Cloud

Saint-Cloud, 92 210, France

RECRUITING

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

Toulouse, 31 059, France

NOT YET RECRUITING

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, 54 519, France

NOT YET RECRUITING

MeSH Terms

Conditions

Breast Neoplasms; Neoplasms; Neoplasm Metastasis

Interventions

tucatinib; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• François-Clément Bidard, Prof.

  Institut Curie

  PRINCIPAL INVESTIGATOR

• Sandra BIDARD

  Institut Curie

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sandra Clinical Project Manager

CONTACT

+33156245944; drci.promotion@curie.fr

Sandra Regulatory Assistant

CONTACT

+33156245765; drci.promotion@curie.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 12, 2025
• First Posted: September 25, 2025
• Study Start: January 31, 2026
• Primary Completion (Estimated): December 7, 2028
• Study Completion (Estimated): June 8, 2029
• Last Updated: February 23, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months.
• Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).

Locations

FR (9)