A Phase 2, randomized, multicenter, open-label neoadjuvant study evaluating zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer combination with chemotherapy in participants with HER2-positive breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Jazz Pharmaceuticals Ireland Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Mar 2026 → ongoing

Decision date (initial)

2026-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Jazz Pharmaceuticals Ireland Limited.

External identifiers

EU CT number

2025-523204-68-00

ClinicalTrials.gov

NCT07102381

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Safety

To determine the pCR rate (ypT0/Tis ypN0) in each treatment arm (Arm A: zanidatamab + paclitaxel, Arm B: zanidatamab + docetaxel + carboplatin, Arm C: trastuzumab + pertuzumab + docetaxel + carboplatin)

Secondary objectives 8

1. To assess the distribution of RCB classification and scores at time of surgery in each treatment arm
2. To assess the safety and tolerability of zanidatamab in combination with chemotherapy and as monotherapy following surgery
3. To evaluate the rate of conversion to BCS in each treatment arm
4. To evaluate EFS in each treatment arm
5. To evaluate OS in each treatment arm
6. To evaluate participant-reported tolerability of zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer
7. To evaluate the PK of zanidatamab
8. To evaluate the immunogenicity of zanidatamab

Conditions and MedDRA coding

HER2-positive breast cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

Investigational medicine not yet approved by EMA or FDA for this indication

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Is at least 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
2. Has 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.
3. Has histologically confirmed HER2-positive breast cancer according to ASCO/CAP Guidelines
4. 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.
5. 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.
6. Agrees to undergo a mastectomy or BCS after neoadjuvant therapy.
7. Has an ECOG performance status of 0 or 1.
8. The participant meets the baseline laboratory criteria
9. The participant has LVEF ≥ 50% as determined by either ECHO or MUGA obtained within 4 weeks prior to first dose of study intervention.
10. Participant agrees to the following based on sex assigned at birth.
11. 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.
12. 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.
13. 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.

Exclusion criteria 14

1. Has Stage IV (metastatic) breast cancer.
2. Has bilateral breast cancer.
3. 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.
4. 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.
5. Has significant symptoms (Grade ≥ 2) from peripheral neuropathy.
6. Has an active uncontrolled (febrile within the last 48 hours; no evidence of hypotension; no ongoing systemic sequela) infection (≥ Grade 2).
7. 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.
8. Known active hepatitis B or C infection.
9. Has another malignancy diagnosed within the last 5 years. Exceptions include previously treated nonmelanomatous skin cancers, carcinoma in-situ, and melanoma in-situ.
10. Was treated with chemotherapy, anti-HER2 therapy, radiation therapy, endocrine therapy, or experimental therapy for invasive breast cancer (or DCIS if ipsilateral as the invasive breast cancer).
11. 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. Estrogen replacement therapy is not permitted in participants with HR-positive tumors.
12. Receipt of a live vaccine within 4 weeks prior to enrollment.
13. Female participants who are breastfeeding or pregnant and female and male participants planning a pregnancy.
14. Has a known hypersensitivity to any components of the study interventions, including chemotherapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Local evaluation of pCR rate in the breast and axilla (defined as ypT0/Tis ypN0 per AJCC), as determined by local site pathologist blinded to treatment assignment

Secondary endpoints 12

1. Pathologic response by RCB classification and score (per NeoSTEEP criteria)
2. Incidence, nature, and severity of TEAEs
3. Frequency of discontinuations of treatment due to TEAEs
4. Ovarian function in premenopausal women with ovaries as assessed by clinical measures and laboratory biomarkers
5. Rate of participants who receive surgery as intended
6. Rate of BCS in participants without inflammatory breast cancer
7. EFS, defined as time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive]), or death from any cause
8. Overall Survival, defined as time from randomization to death from any cause
9. The frequency and severity of symptomatic AEs as assessed by the PRO-CTCAE and EORTC Item Library prior to first dose of study intervention and during the on-treatment period
10. The percentage of all treated participants, as treated, reporting each level of side-effect bother while on treatment, based on the FACIT-GP5
11. Serum concentrations of zanidatamab
12. Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable

Investigational products

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

Test 5

Comparator 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Jazz Pharmaceuticals Ireland Limited

Sponsor organisation

Jazz Pharmaceuticals Ireland Limited

Address

5th Floor, Waterloo Exchange, Waterloo Road Waterloo Exchange Waterloo Road

City

Dublin 4

Postcode

D04 E5W7

Country

Ireland

Scientific contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Public contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Third parties 9

Locations

3 EU/EEA countries · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

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

Documents 49 files

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

Application history

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