Status:
NOT_YET_RECRUITING
Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer
Lead Sponsor:
Institut Curie
Collaborating Sponsors:
Pfizer
Eurofins
Conditions:
Metastatic Breast Cancer ( HER2 Negative)
Unresectable Breast Cancer
Eligibility:
All Genders
18+ years
Phase:
PHASE2
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 l...
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 pe...
Eligibility Criteria
Inclusion
- 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)
- 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:
- 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.
- Patients able to provide signed informed consent.
Exclusion
- 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
Key Trial Info
Start Date :
December 5 2025
Trial Type :
INTERVENTIONAL
Allocation :
ESTIMATED
End Date :
June 8 2029
Estimated Enrollment :
20 Patients enrolled
Trial Details
Trial ID
NCT07193394
Start Date
December 5 2025
End Date
June 8 2029
Last Update
September 25 2025
Active Locations (9)
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1
Polyclinique Bordeaux Nord Aquitaine
Bordeaux, France, 33 300
2
Chu Dupuytren- Limoges
Limoges, France, 87 042
3
Institut Paoli-Calmettes
Marseille, France, 13009
4
Centre Antoine Lacassagne
Nice, France, 06 189