## Protocol Section
### Identification Module
**NCT ID:** NCT06435429

**Brief Title:** A Phase 3, Randomized, Open-label, Controlled Study Comparing the Efficacy and Safety of Zanidatamab to Trastuzumab, Each in Combination With Physician's Choice Chemotherapy, for the Treatment of Participants With Metastatic HER2-positive Breast Cancer

**Official Title:** 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 of Participants With Metastatic HER2-positive Breast Cancer Who Have Progressed on, or Are Intolerant to, Previous Trastuzumab Deruxtecan Treatment

#### Organization Study ID Info
**ID:** JZP598-303
#### Organization
**Class:** INDUSTRY
**Full Name:** Jazz Pharmaceuticals
#### Secondary ID Infos
**Domain:** EU CTR
**ID:** 2023-508960-31-00
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2031-04-25

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-30

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-24

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2031-04-25

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-07-16

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-30
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-24
**Study First Submit QC Date:** 2024-05-24
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Jazz Pharmaceuticals

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The efficacy and safety of zanidatamab in combination with physician's choice of chemotherapy compared with trastuzumab in combination with physician's choice of chemotherapy will be evaluated for the treatment of participants with metastatic HER2-positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.

**Detailed Description:** Zanidatamab, as a monotherapy or in combination with other antineoplastic agents, has shown clinically meaningful efficacy against multiple HER2-positive advanced/metastatic tumors, including in patients with metastatic breast cancer (mBC). Zanidatamab may offer a viable treatment option for patients with metastatic HER2-positive breast cancer.

The primary objective of the study is to compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The secondary objectives of the study will include further comparing the efficacy, safety and tolerability, patient-reported tolerability, and patient-reported physical functioning of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The pharmacokinetics and immunogenicity of zanidatamab in combination with chemotherapy will also be evaluated.

### Conditions Module

**Conditions:**

- Metastatic HER2-positive Breast Cancer

**Keywords:**

- Zanidatamab

- Trastuzumab

- Metastatic HER2-positive breast cancer

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 550

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Participants with HER2-positive metastatic breast cancer (mBC) who have progressed on, or are intolerant to, previous T-DXd treatment will be randomized to receive intravenous infusion of zanidatamab plus physician's choice of chemotherapy (eribulin, or vinorelbine, or gemcitabine, or capecitabine).

**Intervention Names:**

- Drug: Zanidatamab

- Drug: Eribulin

- Drug: Vinorelbine

- Drug: Gemcitabine

- Drug: Capecitabine

**Label:** Zanidatamab plus physician's choice of chemotherapy

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Participants with HER2-positive metastatic breast cancer (mBC) who have progressed on, or are intolerant to, previous T-DXd treatment will be randomized to receive intravenous infusion of trastuzumab plus physician's choice of chemotherapy (eribulin, or gemcitabine, or vinorelbine, or capecitabine).

**Intervention Names:**

- Drug: Trastuzumab

- Drug: Eribulin

- Drug: Vinorelbine

- Drug: Gemcitabine

- Drug: Capecitabine

**Label:** Trastuzumab plus physician's choice of chemotherapy

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Zanidatamab plus physician's choice of chemotherapy

**Description:** Administered by intravenous infusion

**Name:** Zanidatamab

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Trastuzumab plus physician's choice of chemotherapy

**Description:** Administered by intravenous infusion

**Name:** Trastuzumab

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Trastuzumab plus physician's choice of chemotherapy

- Zanidatamab plus physician's choice of chemotherapy

**Description:** Administered by intravenous infusion

**Name:** Eribulin

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Trastuzumab plus physician's choice of chemotherapy

- Zanidatamab plus physician's choice of chemotherapy

**Description:** Administered by intravenous infusion

**Name:** Vinorelbine

**Type:** DRUG

#### Intervention 5

**Arm Group Labels:**

- Trastuzumab plus physician's choice of chemotherapy

- Zanidatamab plus physician's choice of chemotherapy

**Description:** Administered by intravenous infusion

**Name:** Gemcitabine

**Type:** DRUG

#### Intervention 6

**Arm Group Labels:**

- Trastuzumab plus physician's choice of chemotherapy

- Zanidatamab plus physician's choice of chemotherapy

**Description:** Given orally

**Name:** Capecitabine

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** PFS is defined as the time in months from randomization to the date of first documented disease progression (as assessed by BICR according to RECIST v1.1) or death from any cause, whichever occurs first.

**Measure:** Progression-free Survival (PFS) Per RECIST Version 1.1 As Assessed by Blinded Independent Central Review (BICR)

**Time Frame:** Until disease progression or death, up to approximately 44 months

#### Secondary Outcomes

**Description:** OS is defined as the time in months from randomization to the date of death due to any cause.

**Measure:** Overall Survival (OS)

**Time Frame:** Until death, up to approximately 80 months

**Description:** The BICR-assessed confirmed ORR is defined as the proportion of participants who had a best overall response of BICR-assessed Complete Response (CR) or Partial Response (PR) after randomization.

**Measure:** Confirmed Objective Response Rate (ORR) Per RECIST Version 1.1, As Assessed by BICR

**Time Frame:** Until disease progression or death, up to approximately 44 months

**Description:** BICR-assessed DOR is defined as the time in months from the first objective response (CR or PR) that is subsequently confirmed to documented progressive disease (PD) as assessed by BICR per RECIST v1.1 or death from any cause.

**Measure:** Duration of Response (DOR) Per RECIST Version 1.1, As Assessed by BICR

**Time Frame:** Until disease progression or death, up to approximately 44 months

**Description:** Investigator-assessed PFS is defined as the time in months from randomization to the date of first documented disease progression (as assessed by investigator according to RECIST v1.1) or death from any cause, whichever occurs first

**Measure:** PFS Per RECIST Version 1.1, As Assessed By Investigator

**Time Frame:** Until disease progression or death, up to approximately 44 months

**Description:** The investigator-assessed confirmed ORR is defined as the proportion of participants who had a best overall response of investigator-assessed confirmed CR or PR after randomization.

**Measure:** Confirmed ORR Per RECIST Version 1.1, As Assessed By Investigator

**Time Frame:** Until disease progression or death, up to approximately 44 months

**Description:** Investigator-assessed DOR is defined as the time in months from the first objective response (CR or PR) that is subsequently confirmed to documented PD as assessed by the investigator per RECIST v1.1 or death from any cause.

**Measure:** DOR Per RECIST Version 1.1, As Assessed By Investigator

**Time Frame:** Until disease progression or death, up to approximately 44 months

**Measure:** Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events As Graded by NCI CTCAE Version 5.0

**Time Frame:** Up to approximately 44 months

**Measure:** Number of Participants With Dose Reductions

**Time Frame:** Up to approximately 44 months

**Measure:** Number of Participants Discontinuing Study Treatment Due to TEAEs

**Time Frame:** Up to approximately 44 months

**Measure:** Serum Concentrations of Zanidatamab

**Time Frame:** Up to approximately 44 months

**Measure:** Number of Participants Positive for Anti-drug Antibodies to Zanidatamab

**Time Frame:** Up to approximately 44 months

**Measure:** Proportion of All Treated Participants, As Treated, Reporting Symptomatic Adverse Events While On Treatment Based on PRO-CTCAE and EORTC Item Library

**Time Frame:** Up to approximately 44 months

**Measure:** Proportion of All Treated Participants, As Treated, Reporting Overall Side-effect Bother on the FACIT-GP5

**Time Frame:** Up to approximately 44 months

**Measure:** Proportion of Treated Participants, As Treated, With Maintained or Improved Physical Function While On Treatment Based On The Physical Functioning Subscale of the EORTC QLQ-C30

**Time Frame:** Up to approximately 44 months

### Eligibility Module

**Eligibility Criteria:** Participants are eligible to be included in the study only if all of the following criteria apply:

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 histologically confirmed HER2-positive breast cancer according to ASCO-CAP Guidelines as evaluated by a central laboratory
3. Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.
4. Has measurable disease per RECIST version 1.1.
5. Is eligible to receive one of the chemotherapy options listed in the physician's choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine).
6. Participants with history of treated or clinically inactive CNS metastases are eligible as specified in the protocol.
7. Has a life expectancy of at least 6 months, in the opinion of the investigator.
8. Has adequate hematologic parameters as defined in the protocol.
9. Has adequate hepatic function as specified in the protocol.
10. Has creatinine clearance ≥ 30 mL/minute as calculated per local institutional guidelines.
11. Has LVEF ≥ 50% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
12. Has ECOG performance status of 0 or 1.
13. Participant agrees to the following based on sex assigned at birth.

    1. Male participants:

       Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer:
       * Refrain from donating fresh unwashed semen.
       * Use contraception as follows as specified in the protocol
    2. Female participants:

       * A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

         * Is a women of nonchildbearing potential OR
         * Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of \< 1% per year), with low user dependency during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer.
       * A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention.
       * Additional requirements for pregnancy testing during and after study intervention are provided in the protocol.
       * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
14. Is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Has known or suspected leptomeningeal disease.
2. Has uncontrolled or significant cardiovascular disease.
3. Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with exceptions as stated in the protocol.
4. Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
5. Has known HIV infection.
6. Has active hepatitis B or C infection.
7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions' requirements and screening guidance are eligible.
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.

    Prior/Concomitant Therapy
13. Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
14. Was treated with any local or systemic antineoplastic therapy (including hormonal therapies for breast cancer) or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to randomization.
15. Has a history of trauma or major surgery within 4 weeks prior to randomization.

    Other Exclusions
16. Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** ClinicalTrialDisclosure@JazzPharma.com

**Name:** Clinical Trial Disclosure & Transparency

**Phone:** 215-832-3750

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000001941

- Term: Breast Diseases

- ID: D000012871

- Term: Skin Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M5220

- Name: Breast Neoplasms

- Relevance: HIGH

- As Found: Breast Cancer

- ID: M5218

- Name: Breast Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000001943

- Term: Breast Neoplasms

### Intervention Browse Module - Ancestors

- ID: D000000964

- Term: Antimetabolites, Antineoplastic

- ID: D000000963

- Term: Antimetabolites

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000972

- Term: Antineoplastic Agents, Phytogenic

- ID: D000050257

- Term: Tubulin Modulators

- ID: D000050256

- Term: Antimitotic Agents

- ID: D000050258

- Term: Mitosis Modulators

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M2985

- Name: Gemcitabine

- Relevance: HIGH

- As Found: Activity

- ID: M377

- Name: Capecitabine

- Relevance: HIGH

- As Found: Function

- ID: M325

- Name: Trastuzumab

- Relevance: HIGH

- As Found: Medication

- ID: M1710

- Name: Vinorelbine

- Relevance: HIGH

- As Found: Subsequent

- ID: M233243

- Name: Trastuzumab deruxtecan

- Relevance: LOW

- As Found: Unknown

- ID: M4281

- Name: Antimetabolites

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: M26197

- Name: Tubulin Modulators

- Relevance: LOW

- As Found: Unknown

- ID: M26196

- Name: Antimitotic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000093542

- Term: Gemcitabine

- ID: D000069287

- Term: Capecitabine

- ID: D000068878

- Term: Trastuzumab

- ID: D000077235

- Term: Vinorelbine

### Misc Info Module

- Version Holder: 2024-05-31
