A Phase I/II Study of FWD1802 in Patients With ER+/HER2- Advanced BC.

A Phase I/II, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Efficacy of FWD1802in Patients With ER+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer

A Phase I/II, Open-label study to assess the safety, tolerability, pharmacokinetic, and antitumor efficacy of FWD1802 monotherapy in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer. This clinical trial aims to explore the role of FWD1802 in the ER+/HER2- advanced breast cancer patient population. The primary objectives are to address the following questions:

Phase I Study:

Determine the Recommended Phase II Dose (RP2D) and/or Maximum Tolerated Dose (MTD) of FWD1802 in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.

Phase II Study:

To evaluate the efficacy of FWD1802 at the RP2D in patients with ESR1-mutated ER-positive/HER2-negative locally advanced or metastatic breast cancer, using objective response rate (ORR) as the efficacy endpoint.

This is a phase I/II, multicenter, open-label, first-in-human study of FWD1802 in patients with locally advanced or metastatic breast cancer that is estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (Phase II: restricted to patients with ESR1-mutated). It consists of three parts: the FWD1802 dose-escalation phase (Phase I Part A), the FWD1802 dose-expansion phase (Phase I Part B), and the dose-expansion study of FWD1802 in patients with ESR1 mutations (Phase II study).

Each study phase includes a screening period (up to 4 weeks), a treatment period (maximum treatment duration of 2 years; continuation beyond 2 years is permitted if the investigator judges the subject is still benefiting, with agreement from both the investigator and sponsor), and a follow-up period. The Phase II study includes a pre-screening period; patients with unknown mutation status may undergo testing that includes ESR1 mutation status prior to the screening period.

Phase I Part A is the FWD1802 dose-escalation study: A dose-escalation trial using a combination of an "accelerated titration" design and a "3+3" design is planned, with a maximum of 27 subjects to be enrolled. The Safety Monitoring Committee (SMC) will evaluate pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety data to guide the determination of potentially effective doses for Part B and the Phase II study.

Phase I Part B is the FWD1802 dose-expansion study: Based on safety, PK, PD, and other data obtained from Part A, 2 to 4 dose cohorts will be selected for further exploration of FWD1802's PK profile and the recommended phase 2 dose (RP2D). Each dose cohort will be expanded to include up to 10 subjects (including subjects from the corresponding dose cohort in Part A). The SMC will decide which dose cohorts to expand and the timing of expansion based on information obtained from Part A. Dose expansion may proceed concurrently with the dose-escalation phase, within dose ranges already confirmed as safe by the SMC.

The Phase II study is cohort expansion study targeting the population with ESR1 mutations: Enrolled subjects will have ER-positive, HER2-negative breast cancer with ESR1 mutations. One to two dose levels will be selected for exploration, with each dose level enrolling no more than 30 subjects, for a maximum total enrollment of 60 subjects.

Inclusion Criteria:

Subjects must meet all of the following criteria to be eligible for enrollment in this clinical study:

1. Voluntarily participate in the clinical trial and sign the informed consent form.

2. Female, aged ≥18 years.

3. Able to provide blood samples for central laboratory testing of ESR1 mutation status and other biomarker assessments. Phase I Study: ESR1 mutation status will be tested retrospectively. Phase II Study: Only subjects with confirmed ESR1 mutations will be enrolled (see Appendix 5 for details).

4. Histologically or cytologically confirmed locally advanced or metastatic breast cancer that is ER-positive and HER2-negative.

   Criteria for ER positivity: Immunohistochemistry staining shows nuclear staining in ≥10% of tumor cells.

   Criteria for HER2 negativity: Immunohistochemistry staining intensity is 0 or 1+; if the intensity is 2+, it must be confirmed negative by in situ hybridization.

5. Confirmed in menopause and not caused by ovarian function suppression drugs, must meet one of the following criteria:

   Previous bilateral oophorectomy. Age ≥ 60 years.

   Age < 60 years (subdivided into the following conditions):

   1. Never received chemotherapy, ovarian function inhibitors, or SERM drugs (tamoxifen, toremifene), with amenorrhea ≥12 months, and E2 and FSH levels in the postmenopausal range.
   2. Received chemotherapy resulting in chemotherapy-induced amenorrhea ≥12 months, with E2 and FSH levels in the postmenopausal range.
   3. Using SERM drugs (tamoxifen, toremifene), with E2 and FSH levels in the postmenopausal range.

6. Premenopausal or perimenopausal female subjects must agree to receive and maintain treatment with ovarian function suppression (LHRH agonists) during the study treatment period (ovarian function suppression treatment must be initiated at least 14 days before the first dose of study drug).

7. Prior treatment history must meet the following requirements:

   1. Disease progression during or intolerance to standard therapy, or unsuitability for standard therapy.
   2. Previous adjuvant endocrine therapy for at least 2 years, with recurrence during treatment or within 1 year after completion; OR at least one line of endocrine therapy for the advanced stage, with progression after at least 6 months of maintenance therapy on any line of advanced endocrine therapy (no limit on the number of endocrine therapy lines).
   3. Previous chemotherapy for the advanced stage is ≤ 2 lines.
   4. Prior use of fulvestrant, with an interval of at least 6 weeks between the last dose of fulvestrant and the first dose in this study.
   5. An interval of at least 6 weeks is required between the last dose of prior tamoxifen and the first dose in this study.
   6. Previous treatment with CDK4/6 inhibitors is ≤ 1 line.

8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (see Appendix 1 for details).

9. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor lesions that have previously received radiotherapy or other local-regional treatment can only be considered measurable lesions if disease progression is confirmed.

10. Expected survival ≥ 3 months.

11. Subjects must have adequate organ and bone marrow function at screening (no blood transfusion, human albumin administration, or use of hematopoietic growth factors within 7 days prior to screening tests), defined as follows:

    1. Complete Blood Count:

       Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L. White blood cell count (WBC) ≥ 3.0 × 10⁹/L and ≤ 15 × 10⁹/L. Platelet count (PLT) ≥ 100 × 10⁹/L. Hemoglobin (HGB) ≥ 100 g/L.

    2. Liver Function:

       Serum total bilirubin (TBIL) ≤ 1.5 × ULN. For subjects without liver metastases: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.

       For subjects with liver metastases: ALT and AST ≤ 5 × ULN.

    3. Renal Function:

       Serum creatinine (Scr) ≤ 1.5 × ULN OR creatinine clearance (Clcr) calculated by the Cockcroft-Gault method ≥ 50 mL/min.

    4. Coagulation Function:

       Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

       International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN (for subjects on anticoagulant therapy, values should be within the therapeutic range):

       1. For patients receiving warfarin, INR must be stable between 2.0 and 3.0.
       2. For patients receiving heparin, APTT should be between 1.5 and 2.5 × ULN (or returned to the value prior to starting heparin therapy).
       3. For prosthetic heart valves requiring anticoagulation, a stable INR between 2.5 and 3.5 is allowed.

    5. Cardiac Function:

    Left ventricular ejection fraction (LVEF) > 50% as shown by echocardiography.

12. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and must be non-lactating. Women of childbearing potential must agree to use effective contraceptive methods from the time of signing the informed consent form until 6 months after the last dose of the study drug. Effective methods include double barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female subjects will be considered of childbearing potential unless they are naturally postmenopausal, have undergone artificial menopause, or have undergone sterilization (e.g., hysterectomy, bilateral salpingo-oophorectomy).

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Leptomeningeal metastases, carcinomatous meningitis, spinal cord compression, or symptomatic or clinically unstable central nervous system (CNS) metastases.

2. History of ongoing gastrointestinal diseases or other malabsorptive conditions that may impact the absorption of orally administered study drugs, including but not limited to:

   1. Inability to swallow oral medications.
   2. Requirement for intravenous nutrition.
   3. Prior surgery affecting absorption, including total/partial gastrectomy.
   4. Crohn's disease, ulcerative colitis.
   5. Treatment for active peptic ulcer disease within 6 months prior to the first dose.
   6. Malabsorption syndrome, or uncontrolled nausea, vomiting, or diarrhea.

3. Patients with symptomatic visceral metastases, or those with clinically significant and unstable pleural, peritoneal, pericardial effusions, or pulmonary lymphangitic carcinomatosis. Patients who have received intracavitary infusion therapy or drainage/paracentesis may be enrolled 14 days or more after the effusion has stabilized. Other conditions deemed by the investigator as unsuitable for endocrine therapy.

4. Prior treatments do not meet the following washout periods:

   1. Use of other investigational drugs or devices within 4 weeks prior to the first dose.
   2. Treatment with CDK4/6 inhibitors or mTOR inhibitors within 2 weeks, or other targeted therapies, chemotherapy, or immunotherapy within 4 weeks prior to the first dose.
   3. Radiotherapy, endocrine drugs, or traditional Chinese medicines with anti-tumor indications within 2 weeks prior to the first dose (washout periods for fulvestrant and tamoxifen refer to Inclusion Criterion 7).
   4. Treatment with mitomycin or nitrosoureas within 6 weeks prior to the first dose.
   5. Use of drugs or herbal supplements known to be moderate/strong inhibitors or inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).
   6. Use of drugs that inhibit gastric acid production within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).
   7. Use of drugs that are P-glycoprotein (P-gp) inhibitors within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).

5. Toxicities from prior anti-tumor therapy have not recovered to Grade ≤1 (except for alopecia, and chemotherapy-induced peripheral neuropathy ≤ Grade 2).

6. Major surgical procedure (excluding biopsy) within 4 weeks prior to the first dose of study drug, or incomplete healing of surgical incision.

7. Known other active malignancy within the past 5 years (except for cured basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, papillary thyroid carcinoma, or ductal carcinoma in situ of the breast).

8. History of interstitial lung disease, drug-induced interstitial lung disease, or any evidence of active pneumonitis on chest CT scan within 4 weeks prior to the first dose of study drug.

9. Poorly controlled hypertension despite antihypertensive therapy (systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg).

10. Active hepatitis B (defined as HBsAg positive and HBV DNA >500 IU/mL or >2000 copies/mL, or HBV DNA above the lower limit of detection if the local lower limit is >500 IU/mL or >2000 copies/mL); hepatitis C virus (HCV) infection (defined as HCV antibody positive and HCV-RNA positive or HCV-RNA above the lower limit of detection at the local site).

    Known HIV infection or history of acquired immunodeficiency syndrome (AIDS); active tuberculosis; active syphilis infection.

11. Any severe infection requiring systemic antibiotics within 14 days prior to dosing, or active infection requiring systemic treatment.

12. Arterial or venous thrombotic events within 6 months, including cerebrovascular accident (e.g., transient ischemic attack, cerebral hemorrhage, etc.), deep vein thrombosis, or pulmonary embolism.

13. History of active cardiac disease or cardiac dysfunction, including any of the following:

    1. Idiopathic symptomatic bradycardia within 2 years prior to screening, or resting heart rate <50 bpm at screening.
    2. History of angina or symptomatic coronary artery disease within 1 year prior to screening.
    3. History of congestive heart failure (NYHA Class ≥3), cardiomyopathy, or myocardial ischemia requiring long-term medication for control.
    4. Acute myocardial infarction event within 6 months prior to screening.
    5. History of ventricular arrhythmia, or any supraventricular arrhythmia ≥ Grade 2 requiring treatment or intervention within 1 year prior to screening, or presence of risk factors for ventricular arrhythmias.
    6. Any factors that increase the risk of QTc prolongation or arrhythmic events, such as symptomatic heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under age 40 in a first-degree relative. Hypertrophic cardiomyopathy and clinically significant valvular stenosis.
    7. Poorly controlled atrial fibrillation, history of coronary/peripheral artery bypass graft within the past 6 months, or cerebrovascular symptoms including transient ischemic attack.
    8. QTcF (Fridericia's correction) > 470 ms on ECG.
    9. Presence of ECG abnormalities considered clinically significant by the investigator, including complete left bundle branch block, second- or third-degree heart block, or sick sinus syndrome.

14. History of severe allergic reactions to the study drug(s) or excipients used in the protocol.

15. Prior use of any selective estrogen receptor degrader (other than fulvestrant) or investigational drugs inhibiting the ER signaling pathway.

16. Patients with active or chronic corneal disease, other active eye disease requiring ongoing treatment, or any clinically significant corneal disease for which drug-induced keratopathy cannot be adequately monitored.

17. History of drug abuse, alcohol abuse, or substance abuse.

18. Use of live or attenuated live vaccines within 4 weeks prior to the first dose of study drug. Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferon, etc., within 14 days prior to the first dose of study drug. History of allogeneic organ transplantation, allogeneic peripheral hematopoietic stem cell transplantation, or bone marrow transplantation.

19. Conditions deemed by the investigator as unsuitable for participation in this study, including but not limited to a clear history of neurological disorders such as epilepsy or dementia, poor compliance, or any other circumstances the investigator believes may render the subject unsuitable for the study.