A Phase 3, randomized, open-label, multicenter, controlled study to evaluate the efficacy and safety of zanidatamab in combination with physician’s choice chemotherapy compared to trastuzumab in combination with physician’s choice chemotherapy for the treatment (EmpowHER 303)

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

3 Dec 2024 → ongoing

Decision date (initial)

2024-11-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Jazz Pharmaceuticals Ireland Limited.

External identifiers

EU CT number

2023-508960-31-00

ClinicalTrials.gov

NCT06435429

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Efficacy

Compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy

Secondary objectives 6

1. Further compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy
2. Evaluate the safety and tolerability of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy
3. Evaluate the PK of zanidatamab in combination with chemotherapy
4. Evaluate the immunogenicity of zanidatamab plus chemotherapy
5. Evaluate patient-reported tolerability of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy
6. Evaluate the effect of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy on patient-reported physical functioning

Conditions and MedDRA coding

Metastatic HER2-positive breast cancer

Study design 1 period

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 16

1. Is 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
2. Has creatinine clearance ≥ 50 mL/minute as calculated per local institutional guidelines.
3. Has LVEF ≥ 55% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
4. Has ECOG performance status of 0 or 1.
5. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice. 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.
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: - Is a WONCBP; - Is a WOCBP and using a contraceptive method that is highly effective during the study intervention period and for at least 7 months after the last 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 5 months, and for all other allowed chemotherapy options. Therefore, 7 months is considered sufficient to collect details of all pregnancies.
7. Is capable of giving signed informed consent
8. Has histologically confirmed HER2-positive breast cancer according to ASCO–CAP Guidelines as evaluated by a sponsor-designated central laboratory (Wolff, 2018)
9. Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.
10. Has measurable disease per RECIST version 1.1.
11. Is eligible to receive one of the chemotherapy options listed in the physician’s choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine).
12. Participants with history of treated or clinically inactive CNS metastases are eligible
13. Has a life expectancy of at least 6 months, in the opinion of the investigator.
14. Has adequate hematologic parameters
15. Has adequate hepatic function
16. Must have received at least 2 lines of HER2-directed therapy for their metastatic disease

Exclusion criteria 21

1. Has clinically confirmed leptomeningeal disease, in the opinion of the investigator.
2. Has uncontrolled or significant cardiovascular disease
3. Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1
4. Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
5. Has an infection with HIV-1 or HIV-2. (Exception: Participants with well‑controlled HIV [ie, CD4 > 350/mm3 and undetectable viral load] are eligible.)
6. Has active hepatitis B or C infection.
7. Has an active SARS-CoV-2 infection.
8. Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab.
9. Is unable to receive trastuzumab treatment due to medical contraindications
10. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.
11. Has any condition that would prevent treatment with the physician’s choice of chemotherapy.
12. Has any issue or condition that in the opinion of the investigator would contraindicate the participant’s participation in the study or confound the results of the study
13. Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
14. Has a history of trauma or major surgery within 4 weeks prior to randomization.
15. Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
16. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.
17. The washout periods for prior anticancer therapies before randomization are as follows: a. Prior therapies with monoclonal antibodies including ADCs: washout period ≤ 3 weeks b. Prior therapies with small molecule targeted therapies: washout period of ≤ 2 weeks or 5 half-lives, whichever is shorter c. No washout period needed for endocrine therapy. − No washout period for gonadotropin-releasing hormone agonists.
18. Prior participation in a zanidatamab clinical study.
19. Receipt of a live vaccine within 4 weeks prior to enrollment.
20. Participants known to have a complete lack of the enzyme dihydropyrimidine dehydrogenase who are assigned to receive chemotherapy capecitabine in combination with the study treatment.
21. Primary cancer in the previous 3 years prior to randomization, except non-melanoma skin cancer/in situ disease.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival per RECIST version 1.1, assessed by BICR

Secondary endpoints 16

1. Overall survival
2. Confirmed ORR per RECIST version 1.1, assessed by BICR
3. DOR per RECIST version 1.1, assessed by BICR
4. PFS per RECIST version 1.1, assessed by investigator
5. Confirmed ORR per RECIST version 1.1, assessed by investigator
6. DOR per RECIST version 1.1, assessed by investigator
7. Frequency of TEAEs and SAEs as graded by NCI CTCAE version 5.0
8. Frequency of dose reductions
9. Frequency of discontinuations of treatment due to TEAEs
10. Serum concentrations of zanidatamab as a function of time postdosing
11. Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable
12. Descriptive summary of the proportion of all treated patients, as treated, reporting symptomatic AEs while on treatment based on the PRO‑CTCAE and EORTC Item Library
13. Descriptive summary of the proportion of all treated patients, as treated, reporting overall side-effect bother on the FACIT-GP5
14. The proportion of treated patients, as treated, with maintained or improved physical function while on treatment based on the physical functioning subscale of the EORTC QLQ-C30
15. The proportion of treated patients, as treated, with maintained or improved role function while on treatment based on the role functioning subscale of the EORTC QLQ-C30
16. Change from baseline and time to worsening of select scores from the EORTC QLQC30, EORTC IL341, and PGI-S

Investigational products

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

Test 1

Comparator 1

Auxiliary 4

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 10

Locations

8 EU/EEA countries · 94 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 98 files

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

Application history

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