A Phase 2, randomized, multicenter, open-label neoadjuvant study evaluating zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer
- Trial ID
- 2025-523204-68-00
- Protocol
- EmpowHER 208
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to determine the pathological complete response (pCR) rate, defined as ypT0/Tis ypN0, in each treatment arm. This endpoint assesses the absence of residual invasive cancer in the breast and lymph nodes following neoadjuvant therapy in patients with HER2-positive breast cancer. The pCR rate serves as a validated surrogate marker for long-term clinical benefit and is critical for evaluating the efficacy of novel therapeutic regimens in the neoadjuvant setting.
The secondary objectives include:
• To assess the distribution of residual cancer burden (RCB) classification and scores at the time of surgery in each treatment arm
• To assess the safety and tolerability of zanidatamab in combination with chemotherapy and as monotherapy following surgery
• To evaluate the rate of conversion to breast-conserving surgery (BCS) in each treatment arm
• To evaluate event-free survival (EFS) in each treatment arm
• To evaluate overall survival (OS) in each treatment arm
• To evaluate participant-reported tolerability of zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer
• To evaluate the pharmacokinetics (PK) of zanidatamab
• To evaluate the immunogenicity of zanidatamab
Participants
This clinical trial enrolled a total of **65 participants** diagnosed with **HER2-positive breast cancer**. The study population included both **male and female participants** aged **18 years and older**. Eligible participants presented with **Stage II or III invasive breast carcinoma** with a minimum tumor size of 2 cm, including those with **inflammatory breast cancer**. Participants with **multifocal or multicentric disease** were eligible if the largest tumor was HER2-positive. The trial required participants to have a known **hormone receptor status** and an **ECOG performance status** of 0 or 1, indicating good functional capacity. A **left ventricular ejection fraction** of at least 50% was mandatory for enrollment. Female participants of childbearing potential were required to use highly effective contraceptive methods throughout the study period and for 7 months following the last dose of study intervention. Male participants were also required to adhere to contraceptive measures during treatment and for 7 months thereafter. All participants agreed to undergo either **mastectomy** or **breast-conserving surgery** following neoadjuvant therapy. The trial population was selected based on histologically confirmed disease status, specific tumor characteristics, adequate organ function as demonstrated by baseline laboratory criteria, and cardiac function assessment.
Plans and Procedures
This is a Phase 2, randomized, multicenter, open-label neoadjuvant clinical trial evaluating the efficacy and safety of zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer. The trial employs a randomized design with three treatment arms: Arm A receives zanidatamab with paclitaxel, Arm B receives zanidatamab with docetaxel and carboplatin, and Arm C receives trastuzumab with pertuzumab, docetaxel, and carboplatin. The study is open-label, meaning that both participants and investigators are aware of the treatment assignment. The primary objective is to determine the pathologic complete response rate (ypT0/Tis ypN0) in each treatment arm. The trial is designed to assess pathologic response by Residual Cancer Burden classification and score, incidence and severity of treatment-emergent adverse events, frequency of treatment discontinuations due to adverse events, ovarian function in premenopausal women, surgical outcomes including the rate of breast-conserving surgery, event-free survival, and overall survival. Additional assessments include patient-reported outcomes using PRO-CTCAE and EORTC Item Library, side-effect bother based on FACIT-GP5, pharmacokinetics of zanidatamab, and immunogenicity through evaluation of anti-zanidatamab antibodies.
The trial involves participants aged 18 years or older with Stage II or III histologically confirmed invasive breast carcinoma with a minimum tumor size of 2 cm. Participants with inflammatory breast cancer (T4d) are eligible. HER2-positive status must be confirmed according to ASCO/CAP Guidelines, and hormone receptor status must be known. Participants with multifocal or multicentric disease are eligible if the largest tumor is HER2-positive and measures at least 2 cm in diameter. Eligible participants must have an ECOG performance status of 0 or 1, meet baseline laboratory criteria, and have a left ventricular ejection fraction of at least 50% as determined by echocardiography or MUGA scan within 4 weeks prior to first dose of study intervention. Participants must agree to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy. Female participants of childbearing potential must use highly effective contraception during the study intervention period and for at least 7 months after the last dose of all study interventions.
The investigational medicinal products are administered via intravenous injection or intravenous infusion. Zanidatamab is administered at a maximum daily dose of 2400 mg with a maximum total dose of 45600 mg over a maximum treatment period of 54 weeks. Paclitaxel is administered at a maximum daily dose of 80 mg/m² with a maximum total dose of 1440 mg/m² over 18 weeks. Docetaxel is administered at a maximum daily dose of 75 mg/m² with a maximum total dose of 450 mg/m² over 18 weeks. Carboplatin is administered at a maximum daily dose of 6 dosage forms with a maximum total dose of 36 dosage forms over 18 weeks. Trastuzumab is administered at a maximum daily dose of 8 mg/kg with a maximum total dose of 12 mg/kg over 54 weeks. Pertuzumab is administered at a maximum daily dose of 840 mg with a maximum total dose of 8400 mg over 54 weeks. Paclitaxel albumin-bound may be used as an alternative formulation. Trastuzumab emtansine is included as an auxiliary medicinal product administered at a maximum daily dose of 3.6 mg/kg with a maximum total dose of 50.4 mg/kg over 42 weeks.
The estimated recruitment start date is January 15, 2026, with an estimated study end date of August 1, 2030. The overall trial duration encompasses the recruitment period, treatment period, and follow-up period for assessment of long-term outcomes including event-free survival and overall survival. Participant involvement includes screening procedures to confirm eligibility, randomization to one of the three treatment arms, neoadjuvant treatment administration, surgical intervention following completion of neoadjuvant therapy, and long-term follow-up for survival and recurrence assessment. Participants may be withdrawn from the study in the event of disease progression, unacceptable toxicity, withdrawal of consent, pregnancy, or at the discretion of the investigator if continuation is deemed not in the participant's best interest. Treatment discontinuation may occur due to treatment-emergent adverse events that preclude further therapy administration.
Treatment
The experimental treatment zanidatamab (JZP598) is administered as a solution for infusion via intravenous injection or intravenous infusion. The maximum daily dose is 2400 milligrams, with a maximum total dose of 45600 milligrams administered over a treatment period of up to 54 weeks. Zanidatamab is a protein-based biologic agent used as a test medication in this clinical trial.
Docetaxel is administered as an intravenous injection or intravenous infusion. The maximum daily dose is 75 milligrams per square meter, with a maximum total dose of 450 milligrams per square meter over a treatment period of up to 18 weeks. Docetaxel is classified under ATC code L01CD02 and serves as a test medication in combination regimens.
Carboplatin is administered via intravenous injection or intravenous infusion. The maximum daily dose is 6 dosage forms, with a maximum total dose of 36 dosage forms over a treatment period of up to 18 weeks. Carboplatin is a biologic agent classified under ATC code L01XA02 and functions as a test medication in the study.
Paclitaxel is administered as an intravenous injection or intravenous infusion. The maximum daily dose is 80 milligrams per square meter, with a maximum total dose of 1440 milligrams per square meter over a treatment period of up to 18 weeks. Paclitaxel is classified under ATC code L01CD01 and is used as a test medication in the trial.
Paclitaxel albumin-bound is provided as a powder for dispersion for infusion and administered via intravenous injection or intravenous infusion. The maximum daily dose is 80 milligrams per square meter, with a maximum total dose of 1440 milligrams per square meter over a treatment period of up to 18 weeks. This formulation serves as a test medication in the clinical trial.
Pertuzumab is administered as an intravenous injection or intravenous infusion. The maximum daily dose is 840 milligrams, with a maximum total dose of 8400 milligrams over a treatment period of up to 54 weeks. Pertuzumab is a protein-based agent classified under ATC code L01FD02 and functions as a comparator treatment in this study.
Trastuzumab is administered via intravenous injection or intravenous infusion. The maximum daily dose is 8 milligrams per kilogram, with a maximum total dose of 12 milligrams per kilogram over a treatment period of up to 54 weeks. Trastuzumab is a protein-based comparator treatment classified under ATC code L01FD01.
Trastuzumab emtansine is provided as a solution for infusion and administered via intravenous injection or intravenous infusion. The maximum daily dose is 3.6 milligrams per kilogram, with a maximum total dose of 50.4 milligrams per kilogram over a treatment period of up to 42 weeks. This protein-based agent serves as an auxiliary medication in the clinical trial.
Efficacy
The primary efficacy endpoint is the pathologic complete response rate in the breast and axilla, defined as ypT0/Tis ypN0 according to the American Joint Committee on Cancer staging system. This assessment will be performed by the local site pathologist who will be blinded to treatment assignment. Secondary efficacy endpoints include pathologic response evaluated by residual cancer burden classification and score according to NeoSTEEP criteria. Additional secondary endpoints encompass the rate of participants who receive surgery as intended, the rate of breast-conserving surgery in participants without inflammatory breast cancer, event-free survival defined as the time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral invasive), or death from any cause, and overall survival defined as the time from randomization to death from any cause. Patient-reported outcomes will be assessed using the PRO-CTCAE and EORTC Item Library to evaluate the frequency and severity of symptomatic adverse events prior to the first dose of study intervention and during the on-treatment period. The percentage of all treated participants reporting each level of side-effect bother while on treatment will be measured based on the FACIT-GP5 instrument. Ovarian function in premenopausal women with ovaries will be assessed through clinical measures and laboratory biomarkers.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Is at least 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
- Participant agrees to the following based on sex assigned at birth.
- Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 months after the last dose of all study interventions or the contraception period for the chemotherapy per local guidance/standard practice, whichever is longer.
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: o Is a WONCBP as defined in Appendix 5 Contraceptive and Barrier Guidance. OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency or a highly effective method that is user dependent OR 2 effective nonhormonal contraceptive methods that are user dependent, as described in Table 16 of Appendix 5 Contraceptive and Barrier Guidance, during the study intervention period and for at least 7 months after the last dose of all study interventions. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. This requirement aligns with the contraception period recommended for trastuzumab and is longer than the recommended contraception period for zanidatamab, which is 4 months, and for all other allowed chemotherapy options. Therefore, 7 months is considered sufficient to collect details of all pregnancies.
- Is capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Has newly diagnosed Stage II or III (according to AJCC cancer staging manual anatomic staging table, edition 8) histologically confirmed invasive breast carcinoma. A minimum tumor size of 2 cm determined by imaging is required (for participants whose tumors are node negative or node positive). Participants with inflammatory breast cancer (T4d) are eligible.
- Has histologically confirmed HER2-positive breast cancer according to ASCO/CAP Guidelines
- Has a known HR status of the primary tumor performed by local immunohistochemical methods according to the institution standard protocol. Participants may have HR-positive or HR-negative disease, as defined by ASCO-CAP guidelines.
- Participants with multifocal or multicentric disease are eligible if the largest tumor (which must be larger than or equal to 2 cm in diameter) is HER2-positive, and the treating physician has determined the participant should be treated as HER2-positive.
- Agrees to undergo a mastectomy or BCS after neoadjuvant therapy.
- Has an ECOG performance status of 0 or 1.
- The participant meets the baseline laboratory criteria
- The participant has LVEF ≥ 50% as determined by either ECHO or MUGA obtained within 6 weeks prior to randomized
- Participants with known HIV infection receiving antiretroviral therapy are eligible unless any of the following are present: a. CD4+ T cell count ≤ 350/μL; b. Detectable viral load based on local testing per institutional standard; OR c. Receiving protease inhibitors or cobicistat.
Exclusion Criteria
- Has Stage IV (metastatic) breast cancer. Negative staging imaging (CT chest/abdomen/pelvis with or without bone scan preferred; PET/CT acceptable) is required within 42 days prior to randomization for participants with clinical Stage III disease. If performed in participants with Stage II disease, staging imaging must be negative for evidence of metastatic disease.
- Has bilateral breast cancer.
- Has a history (≤ 6 months before the start of treatment) of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator, could affect the participant’s involvement in the study.
- Has uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (ie, active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to the first dose of study intervention, ventricular arrhythmia requiring therapy, or congestive heart failure of New York Heart Association (NYHA) Class II or higher.
- Has significant symptoms (Grade ≥ 2) from peripheral neuropathy.
- Has an active uncontrolled (febrile within the last 48 hours; no evidence of hypotension; no ongoing systemic sequela) infection (≥ Grade 2).
- Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab or other study interventions.
- Known active hepatitis B or C infection.
- Has another malignancy diagnosed within the last 5 years. Exceptions include previously treated nonmelanomatous skin cancers, carcinoma in-situ, and melanoma in-situ. Participants with prior ipsilateral DCIS or invasive breast cancer are not eligible.
- Was treated with surgery, chemotherapy, anti-HER2 therapy, radiation therapy, endocrine therapy, or experimental therapy for invasive breast cancer (or DCIS if ipsilateral as the invasive breast cancer).
- Is planning to receive concurrent therapy with any other investigational agent or anticancer therapy not specified in the protocol prior to the EOT Visit, including chemotherapy; radiotherapy (except for adjuvant radiotherapy for breast cancer after completion of chemotherapy); immunotherapy; or biological, hormonal or targeted anticancer therapy. Systemic estrogen replacement therapy is not permitted in participants with HR-positive tumors.
- Receipt of a live vaccine within 4 weeks prior to enrollment.
- Female participants who are breastfeeding or pregnant and female and male participants planning a pregnancy.
- Has a known hypersensitivity to any components of the study interventions, including chemotherapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 15 Jan 2026 | 40 |
 Italy | Not Yet Recruiting | 15 Jan 2026 | 25 |
 Spain | Not Yet Recruiting | 15 Jan 2026 | 35 |
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 |
|---|---|---|---|---|---|---|
TRASTUZUMAB EMTANSINE | Other | — | IV INJECTION, IV INFUSION | 3.6 | 42 | SUB35467 |
PACLITAXEL | Test | PHF00230MIG | IV INJECTION, IV INFUSION | 80 | 18 | SCP129816 |
DOCETAXEL | Test | PHF00230MIG | IV INJECTION, IV INFUSION | 75 | 18 | SCP126226 |
PERTUZUMAB | Comparator | PHF00230MIG | IV INJECTION, IV INFUSION | 840 | 54 | SCP831407 |
TRASTUZUMAB DERUXTECAN | Other | — | IV INJECTION, IV INFUSION | 3.6 | 42 | SUB188357 |
TRASTUZUMAB EMTANSINE | Other | — | IV INJECTION, IV INFUSION | 3.6 | 42 | SUB35467 |
JZP598 | Test | SOLUTION FOR INFUSION | IV INJECTION, IV INFUSION | 2400 | 54 | PRD10444189 |
PACLITAXEL ALBUMIN-BOUND | Test | — | IV INJECTION, IV INFUSION | 80 | 18 | SUB127678 |
CARBOPLATIN | Test | PHF00230MIG | IV INJECTION, IV INFUSION | 6 | 18 | SCP10337134 |
TRASTUZUMAB | Comparator | PHF00016MIG | IV INJECTION, IV INFUSION | 8 | 54 | SCP28157103 |