A Two-part, Seamless, Multicenter, Randomized, Open-label, Adaptive Phase II/III Study of the Blood-brain Barrier Penetrant RO7771950 Versus Tucatinib, Both in Combination With Trastuzumab and Capecitabine, in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2-Positive Breast Cancer, With or Without Central Nervous System Metastases

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Investigational drug late phase More information Active drug More information Moderate burden on patient More information

Trial Details

Sponsor: Hoffmann-La Roche (industry)

Phase: 2/3

Start date: May 21, 2026

Planned enrollment: 650

Trial ID: NCT07413939
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More trial details at ClinicalTrials.gov More info

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Investigational Drug AI Analysis

chevron Show for: ZN-A-1041 (RO7771950, Perzebertinib, RG6596, bizrolertinib)

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Goal: To determine whether the blood-brain barrier–penetrant HER2 tyrosine kinase inhibitor RO7771950, combined with trastuzumab and capecitabine, improves efficacy relative to tucatinib with the same backbone, while assessing safety, tolerability, patient-reported outcomes, and pharmacokinetics. The study is designed to evaluate both systemic and intracranial disease control.

Patients: Patients have centrally confirmed HER2-positive unresectable locally advanced or metastatic breast cancer after at least one prior metastatic anti-HER2 regimen. Prior anti-HER2 antibody-drug conjugate therapy is generally required; patients must be TKI-naïve in the advanced-disease setting, have ECOG performance status 0–1, LVEF at least 50%, and adequate organ and marrow function. Patients with previously treated, untreated, stable, or progressive CNS metastases, including leptomeningeal metastases, are eligible. Stage 1 requires RECIST-measurable disease, whereas stage 2 allows nonmeasurable disease.

Design: This is a multicenter, randomized, open-label, seamless adaptive phase II/III study. Participants are assigned to one of two RO7771950 dose groups or an active-control tucatinib group, each with trastuzumab and capecitabine. The adaptive two-part structure is intended to support dose selection and subsequent comparative efficacy assessment. Blinded independent central review is used for key radiographic endpoints.

Treatments: The experimental groups receive one of two dose levels of oral RO7771950 plus trastuzumab and capecitabine. RO7771950, also known as ZN-A-1041, is a selective HER2-targeted TKI engineered for blood-brain barrier penetration and is not a substrate of the P-gp or BCRP efflux transporters. Early-phase studies have reported intracranial activity, including a 73.7% intracranial response rate among 19 evaluable patients in one expansion cohort, with mostly low-grade nausea and vomiting in monotherapy testing; these preliminary, small-cohort findings remain unconfirmed. The comparator is oral tucatinib, an established HER2-selective TKI with demonstrated CNS activity, combined with trastuzumab and capecitabine.

Outcomes: The primary endpoint is progression-free survival by blinded independent central review using RECIST v1.1, assessed over approximately 35 months. Secondary efficacy endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, and corresponding CNS-specific measures, including PFS-CNS, ORR-CNS, DOR-CNS, and CBR-CNS. Additional assessments include adverse-event incidence and severity, cardiac function, suicidality, RO7771950 pharmacokinetics, brain-tumor symptoms, global function and health-related quality of life, treatment-related symptoms and side-effect burden, and EQ-5D-5L health utility.

Burden on patient: Estimated burden is moderate to high. Treatment includes ongoing oral therapy plus repeated trastuzumab infusions, requiring regular clinic attendance, laboratory monitoring, and tumor and CNS imaging; pharmacokinetic blood sampling may add visits or extend selected visits. Serial echocardiography or MUGA, adverse-event evaluations, ECG and electrolyte monitoring as clinically required, and multiple quality-of-life and symptom questionnaires add further burden. No mandatory research biopsy is specified, so most procedures overlap with intensive standard monitoring for metastatic HER2-positive breast cancer, but the cumulative travel and assessment schedule is substantial.

Last updated: Sep 2026

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Parma, Emilia-Romagna, 43100, Italy

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City of Johannesburg, 2196, South Africa

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Gyeonggi-do, 16499, South Korea

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Seoul, 05505, South Korea

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Daegu, 41404, South Korea

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Seville, 41013, Spain

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Barcelona, 08035, Spain

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EL Palmar (EL Palmar), Murcia, 30120, Spain

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Bilbao, Vizcaya, 48013, Spain

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Taoyuan City, 333, Taiwan

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Tainan, 00704, Taiwan

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Taipei, 10041, Taiwan

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Taichung, 407219, Taiwan

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Taipei, 112201, Taiwan

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Wachira Phayaban, 10300, Thailand

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Lak Si, 10210, Thailand

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Bangkok, 10700, Thailand

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Bangkok, 10400, Thailand

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Songkhla, 90110, Thailand

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Khon Kaen, 40002, Thailand

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Ankara, 06200, Turkey (Türkiye)

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Izmir, 35630, Turkey (Türkiye)

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Akdeniz University Medical Faculty

Antalya, 07058, Turkey (Türkiye)

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Ankara, 06490, Turkey (Türkiye)

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Bakirkoy / Istanbul, 34147, Turkey (Türkiye)

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Ege University Medical Faculty

Bornova, Izmir, 35100, Turkey (Türkiye)

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Hacettepe University Medical Faculty

Altındağ, 06230, Turkey (Türkiye)

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Istinye University Liv Hospital Topkapi

Istanbul, 34010, Turkey (Türkiye)

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Istanbul, 34722, Turkey (Türkiye)

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Samsun, 55200, Turkey (Türkiye)

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Mersin, 33240, Turkey (Türkiye)

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Trakya University Medical Faculty

Erdine, 22030, Turkey (Türkiye)

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Barts Health NHS Trust

London, EC1A 7BE, United Kingdom

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Manchester, M20 4GJ, United Kingdom

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Leicester, LE2 7LG, United Kingdom

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Montacute, TA1 5DA, United Kingdom

No email / No phone

Status: Recruiting

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

No email / No phone

Status: Recruiting

Royal Marsden Hospital - Sutton

London, SW3 6JJ, United Kingdom

No email / No phone

Status: Recruiting

UCLH

London, WC1E 6AG, United Kingdom

No email / No phone

Status: Recruiting

Astera Cancer Care East Brunswick

East Brunswick, New Jersey, 08816, United States

No email / No phone

Status: Recruiting

New York Cancer and Blood Specialists

Shirley, New York, 11967, United States

No email / No phone

Status: Recruiting

New York Oncology Hematology, P.C.

Albany, New York, 12206, United States

No email / No phone

Status: Recruiting

The West Clinic, PC dba West Cancer Center

Germantown, Tennessee, 38138, United States

No email / No phone

Status: Recruiting

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