Tucatinib and trastuzumab in HER3-mutant and HER2-not amplified metastatic breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Curie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-09-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Institut Curie

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To demonstrate that ERBB3 mutations are actionable in breast cancer in terms of 24 weeks clinical benefit rate

Secondary objectives 4

1. To evaluate the efficacy of the trastuzumab/tucatinib combination, using other endpoints.
2. To evaluate the safety of the trastuzumab/tucatinib combination
3. To assess quality of life (QoL) changes under treatment
4. Exploratory: to evaluate biomarkers associated with treatment efficacy

Conditions and MedDRA coding

HER3-mutant and HER2-not amplified metastatic breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 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).
2. Molecular screening step: the tumor sample must have been obtained less than 5 years before inclusion
3. Molecular screening step: prior signature of a written informed molecular screening consent.
4. Molecular screening step: patients should be eligible for the treatment step according to the investigator’s opinion.
5. Molecular screening step: patients must be covered by a health insurance plan.
6. Molecular screening step: patients able to provide signed informed consent.
7. Age ≥ 18 years
8. Metastatic or unresectable breast cancer
9. 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
10. Having received ≥ 2 previous chemotherapy lines for advanced breast cancer
11. Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step
12. ECOG performance status ≤ 2
13. Evaluable disease, per RECIST v1.1 inclusion criteria
14. 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
15. 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)
16. 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.
17. 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.
18. Patients should be eligible for the treatment step according to the investigator’s opinion.
19. Patients must be covered by a health insurance plan.
20. Patients able to provide signed informed consent.

Exclusion criteria 19

1. 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)
2. History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs
3. Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
4. 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
5. 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)
6. 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
7. Participation in another interventional clinical trial.
8. Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose > 2 mg of dexamethasone (or equivalent)
9. Whole brain radiotherapy < 21 days prior to first dose of treatment, stereotactic radiotherapy < 7 days prior to first dose of treatment
10. Leptomeningeal metastases
11. Major surgery (including surgery of brain metastases) < 21 days prior to first dose of treatment
12. Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
13. Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment
14. 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
15. Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease
16. Are known to be positive for human immunodeficiency virus (HIV)
17. Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
18. Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons
19. Person deprived of liberty or under guardianship

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 4

1. Progression-free survival (PFS), defined as the time from inclusion to progression or death; Objective response rate, defined as the proportion of patients who achieved a CR or PR according to the investigator-assessed RECIST v1.1 criteria; and duration of response, defined as the time between the first observation of a PR or a CR, and progressive disease or death
2. Adverse Events (AEs) and Serious Adverse Events (SAEs), per CTCAE v5.0, considered by the investigator as related to trastuzumab or tucatinib.
3. QLQ-C30 QoL questionnaire with the QLQ-BR42 module will be filled at inclusion, at cycles 1 and 3 and at the end of the treatment.
4. Exploratory: relationship between biomarkers (including, but not limited to, DNA, RNA and proteins analyses) in blood, plasma, and/or tumor and either (1) presence of an ERBB3 mutation and (2) treatment efficacy.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Curie

Sponsor organisation

Institut Curie

Address

26 Rue D Ulm

City

Paris

Postcode

75005

Country

France

Scientific contact point

Organisation

Institut Curie

Contact name

François-Clement BIDARD

Public contact point

Organisation

Institut Curie

Contact name

François-Clement BIDARD

Third parties 2

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications