Phase Ib/II Study of Zanidatamab, Tucatinib, and Chemotherapy in HER2-Positive Advanced Breast Cancer
- Trial ID
- 2025-524613-89-00
- Protocol
- MEDOPP0776
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the Phase Ib portion of this study is to determine the recommended phase II dose of zanidatamab in combination with tucatinib and either capecitabine (Cohort A) or eribulin mesylate (Cohort B) in patients with HER2-positive advanced breast cancer. In the Phase II portion, the primary objective is to evaluate investigator-assessed progression-free survival using the combination of zanidatamab, tucatinib, and capecitabine or eribulin mesylate.
Secondary objectives include:
- Assessment of preliminary efficacy through investigator-assessed endpoints in Phase Ib.
- Evaluation of intracranial progression-free survival and intracranial objective response rate in patients with newly diagnosed or progressing brain metastases.
- Evaluation of the investigator-assessed objective response rate, time to response, duration of response, and clinical benefit rate.
- Assessment of the best percentage of change from baseline in the size of target tumor lesions.
- Comparison of investigator-assessed progression-free survival for treatments involving trastuzumab in specific cohorts.
Participants
The sponsor did not provide the total number of participants. The study population consists of male and female patients aged 18 years or older diagnosed with HER2-positive advanced breast cancer. Participants must have unresectable locally advanced or metastatic disease and have experienced progression following one to three lines of anti-HER2 therapy. Inclusion requires an ECOG performance status of 0-1, a minimum life expectancy of 12 weeks, and adequate bone marrow, coagulation, hepatic, and renal function. Specific requirements regarding brain metastases exist, including stability or the absence of an immediate need for local therapy. The study objectives are:
- To determine the recommended phase II dose of zanidatamab in combination with tucatinib and capecitabine or tucatinib and eribulin.
- To evaluate progression-free survival using zanidatamab, tucatinib, and capecitabine or eribulin.
Plans and Procedures
This phase Ib/II clinical trial evaluates the safety and preliminary efficacy of zanidatamab in combination with tucatinib and chemotherapy, specifically capecitabine or eribulin mesylate, for the treatment of HER2-positive advanced breast cancer. The phase Ib portion aims to determine the recommended phase II dose (RP2D) across two cohorts: Cohort A utilizes capecitabine and Cohort B utilizes eribulin mesylate. The phase II component focuses on evaluating progression-free survival (PFS) in participants receiving the combination therapy. The study design includes a screening visit to assess eligibility, including requirements for bone marrow, coagulation, liver, and renal function, as well as brain metastases status. Participants will undergo subsequent treatment and follow-up visits to monitor dose-limiting toxicities (DLTs), objective response rate (ORR), and intracranial efficacy using RANO-BM criteria. Study involvement is contingent upon the ability to provide blood samples and tumor tissue. Early termination may occur based on safety profiles or clinical progression.
Treatment
The investigational treatment regimen involves zanidatamab administered via intravenous administration. This substance is evaluated in combination with other therapeutic agents for the treatment of HER2-positive advanced breast cancer.
Tucatinib is administered as a film-coated tablet through an oral route in strengths of 50 mg and 150 mg.
Capecitabine is provided as a film-coated tablet for oral administration in strengths of 150 mg and 500 mg.
Eribulin mesylate is administered as a solution for injection via intravenous administration at a concentration of 0.44 mg/mL.
Auxiliary medications used in the study include loperamide hydrochloride in hard capsule form for oral use, diphenhydramine hydrochloride in tablet form, and paracetamol available as 650 mg or 1 g tablets for oral administration. Additionally, hydrocortisone sodium succinate and dexamethasone sodium phosphate are utilized as solutions for injection or infusion via intravenous injection.
Efficacy
In the Phase Ib portion of the study, the primary efficacy objective is to establish the recommended phase II dose (RP2D) based on the maximum tolerated dose (MTD) and early efficacy data. The MTD is determined by the proportion of dose-limiting toxicities (DLTs) observed in Cohort A (zanidatamab, tucatinib, and capecitabine) and Cohort B (zanidatamab, tucatinib, and eribulin). Secondary efficacy endpoints in Phase Ib include objective response rate (ORR) and progression-free survival (PFS), both assessed by the investigator using RECIST v1.1. For participants with brain metastases (BM), efficacy is further evaluated through intracranial ORR (IC-ORR) and intracranial PFS (IC-PFS) using RANO-BM criteria.
In the Phase II portion, the primary efficacy endpoint for Arm A is progression-free survival (PFS), defined as the time from treatment initiation to the first occurrence of documented radiographic disease progression or death from any cause, as assessed per RECIST v1.1. Secondary endpoints include ORR, time to response (TTR), duration of response (DoR), and clinical benefit rate (CBR), all evaluated according to RECIST v1.1. For participants with BM, IC-PFS and IC-ORR at 3 months are assessed using RANO-BM criteria. Additionally, the best percentage change from baseline in the size of target lesions as measured by computed tomography (CT) is recorded.
Inclusion and Exclusion Criteria
Inclusion Criteria
- PHASE Ib: Participants, or legal representative (if applicable) must be capable of understanding the purpose of the Study and have signed a written informed consent form (ICF) prior to beginning specific protocol procedures.
- PHASE Ib: Female or male participants ≥ 18 years of age at the time of signing the ICF.
- PHASE Ib: ECOG PS of 0-1.
- PHASE Ib: Minimum life expectancy of ≥ 12 weeks at screening.
- PHASE Ib: Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
- PHASE Ib: Locally confirmed HER2-positive breast cancer (immunohistochemistry [IHC] score of 3+ or ICH score of 2+ with confirmation of HER2 amplification by in situ hybridization [ISH]) per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018 criteria on the most recent analyzed biopsy.
- PHASE Ib: Evaluable disease by RECIST v.1.1.
- PHASE Ib: All participants need to have experienced disease progression after at least one line, but no more than 3 lines, of anti-HER2-therapy for advanced disease.
- PHASE Ib: Able to provide the most recently available FFPE tumor tissue blocks at the time of inclusion.
- PHASE Ib: Able to provide blood samples at the established time points.
- PHASE Ib: Participant must have adequate bone marrow, coagulation, liver, and renal function: Absolute neutrophil count (ANC) ≥ 1.5 × 103/μL, platelet count ≥ 100 x 103/μL, and hemoglobin (Hgb) ≥ 9 g/dL. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × the upper limit of normal (ULN), unless on medication known to alter INR and aPTT. Total bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for participants with Gilbert’s disease (if the conjugated bilirubin is ≤ 1.5 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (for participants with liver metastases, AST and ALT ≤ 5.0 × ULN are acceptable). Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min
- PHASE Ib: Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of Study treatments.
- PHASE Ib: Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to use two methods of birth control with a failure rate of less than 1% per year starting at the screening, throughout the study, and for 12 months after the last dose of Study treatments.
- PHASE Ib: Female participants must refrain from oocyte donation and breastfeeding, and male participants must not donate or bank sperm starting at the screening, throughout the study, and for 12 months after the last dose of Study treatments.
- PHASE Ib: Participants must be accessible for treatment and follow-up visits.
- PHASE Ib: Specific inclusion criteria for BMs: 1. Stable BMs were defined as BMs radiographically stable for ≥4 weeks since completion of treatment.
- PHASE Ib: Specific inclusion criteria for BMs: 2. Untreated BM without immediate need for local therapy. For participants with untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment.
- PHASE Ib: Specific inclusion criteria for BMs: 3. BMs that had progressed since local CNS therapy, with no clinical indication for immediate retreatment with local therapy.
- PHASE Ib: Specific inclusion criteria for BMs: 4. Washout periods before the first day of dosing were >7 days for SRS or gamma knife, and >24 days for WBRT, respectively. The use of systemic corticosteroids for control of symptoms of BM is not permitted if the total daily dose is > 2 mg of dexamethasone (or equivalent). However, participants on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible following discussion and approval by the medical monitor. Participants receiving an anticonvulsant therapy must be on stable dosing regimen for ≥ 14 days prior to the first dose of Study treatment.
- At least 50% of participants enrolled in phase II must have BMs.
Exclusion Criteria
- PHASE Ib: Participation in another clinical trial, interventional or observational, until the Study's safety visit.
- PHASE Ib: Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, or experimental agent within ≤ 3 weeks prior to the first dose of Study treatments.
- PHASE Ib: Prior treatment with capecitabine and eribulin.
- PHASE Ib: Known or suspected leptomeningeal disease (LMD) as documented by the investigator.
- PHASE Ib: Advanced, symptomatic, visceral spread that is at risk of lifethreatening complications in the short term (including massive uncontrolled effusions [pleural, pericardial, peritoneal] or pulmonary lymphangitis).
- PHASE Ib: Receipt of a live vaccine within 4 weeks prior to enrollment.
- PHASE Ib: History of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
- PHASE Ib: The washout periods for prior anticancer therapies before randomization are as follows: Prior therapies with chemotherapy and/or monoclonal antibodies including ADCs: washout period up to 3 weeks. Prior therapies with small molecule targeted therapies: washout period of ≤ 2 weeks or 5 half-lives, whichever is shorter. No washout period needed for endocrine therapy. No washout period for gonadotropin-releasing hormone agonists.
- PHASE Ib: Requirement for ongoing therapy with any prohibited medications listed in the protocol.
- PHASE Ib: Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances, including life-threatening hypersensitivity to monoclonal antibodies or excipients in zanidatamab.
- PHASE Ib: Ongoing, clinically significant toxicity associated with prior cancer therapies that has not resolved to ≤ Grade 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion).
- PHASE Ib: Has a concurrent malignancy or malignancy within 5 years of Study enrollment except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor’s medical monitor is required.
- PHASE Ib: Major surgical procedure or significant traumatic injury within 4 weeks before the first dose of Study treatment or anticipation of the need for major surgery within the course of the Study treatment.
- PHASE Ib: Have clinically significant cardiac disease such as: Ventricular arrhythmia requiring therapy, uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), any history of symptomatic congestive heart failure (CHF) classified as New York Heart Association (NYHA) Class II to IV, or any Grade ≥2 CHF related to prior therapy. Participants with Grade 1 CHF from prior treatment are eligible only if the condition has fully resolved at the time of screening, presence of ≥ Grade 2 QTc prolongation on screening electrocardiogram (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). Myocardial infarction or unstable angina within 6 months prior to first dose of study treatment, Left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of Study treatments.
- PHASE Ib: Having a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
- PHASE Ib: Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the Study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
- PHASE Ib: Having peripheral neuropathy ≥ Grade 2.
- PHASE Ib: Known history of clinically significant bleeding, thrombosis, intestinal obstruction, or gastrointestinal perforation within 3 months of study initiation.
- PHASE Ib: Known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if the polymerase chain reaction (PCR) is negative for HCV RNA.
- PHASE Ib: Known infection with Human Immunodeficiency Virus (HIV). (Participants with HIV on antiretroviral therapy (ART) with well-controlled HIV infection/disease are allowed, participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening, participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening, participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to Study entry, the combination of the ART regimen must not contain any medications that may interfere with the Study treatments).
- PHASE Ib: Other systemic uncontrolled infection at the time of enrollment.
- PHASE Ib: Having known dihydropyridine dehydrogenase deficiency (DPD). This must be checked before treatment with capecitabine, according to current guidelines.
- PHASE Ib: Having an inability to swallow pills or significant gastrointestinal disease, which would preclude the adequate oral absorption of medications.
- PHASE Ib: Any other serious medical condition and/or abnormality in clinical laboratory tests that, in the Investigator's judgment, precludes the participant's safe participation in and completion of the Study.
- PHASE II: Prior treatment with HER2 tyrosine kinase inhibitors (TKIs).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 01 Jul 2026 | 129 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
paracetamol cinfa 1 g comprimidos EFG | Other | COMPRIMIDOS | ORAL | — | — | PRD11892826 |
Dexamethasone Phosphate 4mg/ml Solution for Injection or Infusion | Other | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | — | — | PRD11555906 |
Capecitabina Glenmark 150 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | — | — | PRD10095269 |
Soñodor difenhidramina 50 mg comprimidos | Other | COMPRIMIDOS | INTRAVENOUS INJECTION | — | — | PRD933504 |
HYDROCORTISONE PHARMIS 100 mg, poudre et solvant pour solution injectable/pour perfusion | Other | POUDRE ET SOLVANT POUR SOLUTION INJECTABLE/POUR PERFUSION | INTRAVENOUS INJECTION | — | — | PRD10168106 |
Paracetamol Cinfa 650 mg comprimidos EFG | Other | COMPRIMIDOS | ORAL | — | — | PRD11892831 |
Loperan 2 mg cápsulas duras. | Other | CÁPSULAS DURAS | ORAL | — | — | PRD320899 |
ZANIDATAMAB | Test | — | INTRAVENOUS ADMINISTRATION | — | — | SUB203836 |
Eribulin Baxter 0.44 mg/mL solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS ADMINISTRATION | — | — | PRD11452302 |
TUKYSA 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD11359035 |