A Trial to Evaluate Ovarian Suppression Following Subcutaneous ZOLADEX 10.8 mg in Premenopausal Women With Early-stage and Advanced HR+ Breast Cancer

Phase 1 Single-arm, Open-label, Multicenter Trial to Evaluate Ovarian Suppression Following Subcutaneous ZOLADEX 10.8 mg in 2 Parallel Cohorts of Premenopausal Women With Early-stage and Advanced Hormone Receptor-positive (HR+) Breast Cancer

The primary objective of this trial is to evaluate ovarian suppression following treatment with ZOLADEX 10.8 mg by luteinizing hormone (LH) within each cohort.

The purpose of this study is to assess the degree and consistency of ovarian suppression achieved following administration of ZOLADEX 10.8 mg. Ovarian suppression will be evaluated by measuring LH levels over the treatment period.

Inclusion Criteria:

1. Age and gender: Female participants aged 18 to 55 years, inclusive.

2. Hormone receptor positive (HR+): Either estrogen receptor positive (ER+) or progesterone receptor positive (PR+) breast cancer, defined as 1% to 100% of tumor nuclei are positive for ER or PR via immunohistochemistry.

3. Participants must be of premenopausal status.

4. Recent radiotherapy:

   1. Prior radiotherapy is allowed.
   2. All radiotherapy-related toxicities (except alopecia) must have recovered to Common Terminology Criteria for Adverse Events (CTCAE) v6.0 Grade ≤1 before trial enrollment.

5. Concurrent medications:

   1. Cyclin-dependent kinase 4 (CDK4/6) inhibitors are permitted.
   2. PIK3CA/AKT inhibitors are permitted.
   3. Concomitant use of bisphosphonates is permitted.
   4. Concomitant use of endocrine therapy (eg, aromatase inhibitor, fulvestrant, or other FDA-approved selective estrogen receptor degrader [SERDs]) is permitted.
   5. Concurrent standard-of-care human epidermal growth factor receptor 2 (HER2)- targeted therapy (including but not limited to trastuzumab, pertuzumab, trastuzumab deruxtecan, or T-DM1) is permitted.

6. Informed consent: Able to understand and willing to provide informed consent and able to comply with the trial procedures and restrictions.

7. Abstinence and contraception: Female participants may be enrolled if they are:

   1. Practicing true abstinence for at least 28 days prior to investigational product (IP) administration until 12 weeks after the last IP administration and having a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day -1, OR
   2. Using 2 forms of highly effective nonhormonal contraception, including 1 physical barrier (condom or diaphragm) plus another nonhormonal method (eg, intrauterine device, spermicidals) from Screening or at least 2 weeks prior to IP administration (whichever is earlier) until 12 weeks after the last IP administration and having a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day -1.

8. Performance status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

   Inclusion Criteria specific to the advanced breast cancer cohort:

9. Advanced breast cancer diagnosis: Histological confirmation of breast cancer with evidence of locally advanced or metastatic disease, which is not amenable to surgical resection or radiation therapy with curative intent per investigator's assessment.

10. Chemotherapy History:

    1. A participant may have received chemotherapy provided the criteria for premenopausal status, as defined in Inclusion Criterion #3, are met at trial screening.
    2. All chemotherapy-related toxicities must have recovered to CTCAE v6.0 ≤Grade 1 before trial participation, except for alopecia, peripheral neuropathy, or paresthesia (≤Grade 2).

11. Prior treatment:

    1. Participants may have received prior radiotherapy.
    2. Participants may have received or be receiving a cyclin-dependent kinase (CDK) 4/6 inhibitor, a PIK3CA-AKT inhibitor, or bisphosphonates.
    3. Gonadotropin-releasing hormone (GnRH) treatment-naïve participants will have no history of GnRH agonist or other endocrine therapy in the advanced/metastatic setting.
    4. GnRH treatment-exposed participants may have received a GnRH agonist or other endocrine therapy in the advanced/metastatic setting, provided they had established premenopausal status (Inclusion Criterion #3) prior to initiating GnRH agonist therapy, within 6 months prior to trial enrollment.
    5. Participants may have received HER2-targeted therapy (including but not limited to trastuzumab, pertuzumab, trastuzumab deruxtecan, or T-DM1).

    Inclusion Criteria specific to the early-stage breast cancer cohort:

12. Early-stage breast cancer diagnosis:

    1. Histologically confirmed unilateral or bilateral invasive adenocarcinoma of the breast.
    2. Pathologically staged as Stage I, II, or III (specifically T1-T4, N0-N3, M0) at the time of definitive surgery, according to the current American Joint Committee on Cancer (AJCC) Staging Manual.

13. Chemotherapy history:

    1. A participant may have received adjuvant or neoadjuvant chemotherapy provided the criteria for premenopausal status, as defined in Inclusion Criterion #3, are met at trial Screening.
    2. All chemotherapy-related toxicities must have recovered to CTCAE v6.0 ≤Grade 1 before trial participation except for alopecia, peripheral neuropathy, or paresthesia (≤Grade 2).

14. Prior treatment:

    1. Participants may have received prior radiotherapy.
    2. Participants may have received or be receiving a CDK 4/6 inhibitor, a PIK3CA-AKT inhibitor, or bisphosphonates.
    3. GnRH treatment-naïve participants will have no history of GnRH agonist or other endocrine therapy.
    4. GnRH treatment-exposed participants may have received a GnRH agonist or other endocrine therapy provided they had established premenopausal status (Inclusion Criterion #6) prior to initiating GnRH agonist therapy, within 6 months prior to trial enrollment.
    5. Participants may have received HER2-targeted therapy (including but not limited to trastuzumab, pertuzumab, trastuzumab deruxtecan, or T-DM1).

Exclusion Criteria:

1. Postmenopausal: Naturally or surgically postmenopausal (regardless of age).

2. Body mass index (BMI): <18 kg/m^2 or >35.0 kg/m^2.

3. Prior surgical or radiation procedures: History of bilateral oophorectomy or prior radiotherapy to the ovaries.

4. Selective estrogen receptor modulator (SERM) use during trial: Participants may not receive tamoxifen or other SERMs during the trial and must discontinue any SERMs prior to enrollment, other endocrine therapies (eg, aromatase inhibitor, fulvestrant, or other FDA-approved SERDs) are allowed.

5. Hypersensitivity: Known hypersensitivity, idiosyncratic, or allergic reactions to goserelin, GnRH, GnRH agonists/analogs, or any trial drug components.

6. Expected survival: Estimated life expectancy <6 months from the start of trial therapy, based on the principal investigator's (PI) clinical judgment.

7. Performance status: ECOG performance status ≥3.

8. Life-threatening disease or metastasis: Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, symptomatic pulmonary lymphangitic spread, symptomatic pleural disease, or any symptomatic brain/leptomeningeal metastases (proven or suspected). Participants with asymptomatic or stable/treated brain metastases are eligible to enroll if neurologically stable and are receiving a stable or decreasing corticosteroid dose at the time of enrollment. Participants with discrete pulmonary parenchymal metastases are eligible if respiratory function is not compromised.

9. Hepatic function:

   1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2×upper limit of normal (ULN) if no liver metastases, or >5×ULN with liver metastases.
   2. Total bilirubin ≥1.5×ULN (≥2.5×ULN for Gilbert's syndrome).

10. Renal function: Creatinine clearance (CrCl) ≤30 mL/min as calculated by the Cockcroft-Gault formula.

11. Hematologic parameters:

    1. Hemoglobin (Hgb) <8.0 g/dL.
    2. White blood cell (WBC) count <3000/mm^3.
    3. Platelets <100,000/mm^3.
    4. Eligibility for participants taking CDK4/6 inhibitors should be based on D-1 labs.
    5. An absolute neutrophil count (ANC) <1500/mm3 on D-1 is exclusionary.

12. Other malignancies: Active malignancy within the past 3 years, except for adequately treated basal or squamous cell skin cancer or in situ cervical carcinoma.

13. Concurrent medical conditions: Presence of any severe, uncontrolled, or serious illness, medical condition (including psychiatric/addictive disorders), or clinical finding that could compromise trial adherence, as assessed by the investigator.

14. Investigational drug exposure: Exposure to any investigational drug or device within 30 days prior to trial enrollment.

15. Pregnancy: Participant has childbearing potential with a positive serum pregnancy test or positive urine pregnancy test at Screening or Day 1.

16. Breastfeeding: Participant is currently breastfeeding.

17. Contraceptive use: Sexually active with a male partner and not willing to use nonhormonal contraceptive methods throughout the trial. Exceptions: male partner is vasectomized (provided he is her sole sexual partner, and he has received medical assessment of the surgical success), participant has had bilateral salpingectomy or tubal occlusion hysterectomy.

18. Cardiac conditions:

    1. Corrected QT interval (QTc) using Fridericia's correction (QTcF) >450 ms at Screening.
    2. Uncontrolled or symptomatic heart disease, including:

    i. New York Heart Association (NYHA) Class III or IV heart failure.

    ii. Myocardial infarction within the past 6 months.

    iii. Unstable angina or significant arrhythmias requiring intervention.

    c. Documented congenital QT syndrome.

19. Clinically relevant abnormal medical history or abnormal findings on physical examination, vital signs, echocardiogram (ECG), or laboratory tests at Screening that the investigator judges as likely to interfere with the objectives of the trial or the safety of the participant.

20. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.

21. History of alcohol abuse or drug addiction (including soft drugs like cannabis products) within the last 1 year prior to IP administration.

22. Major surgery within 30 days prior to IP dosing or a major surgical procedure planned during the trial.

23. Any other condition that precludes adequate understanding, cooperation, and compliance with trial procedures or any condition that could pose a risk to the participant's safety, as per the investigator's judgment.