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.
Voluntarily participate in the clinical trial and sign the informed consent form.
Female, aged ≥18 years.
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).
Histologically or cytologically confirmed locally advanced or metastatic breast cancer that is ER-positive and HER2-negative.
Leptomeningeal metastases, carcinomatous meningitis, spinal cord compression, or symptomatic or clinically unstable central nervous system (CNS) metastases.
Inability to swallow oral medications.
Requirement for intravenous nutrition.
Prior surgery affecting absorption, including total/partial gastrectomy.
Sequential
FWD1802
DrugEligible subjects will receive FWD1802 treatment according to their assigned dose cohort. Dose Escalation Phase: This phase is divided into a Single-Agent Lead-in Period (C0) and a Multiple-Dosing Period (C1). During the single-agent lead-in period, subjects will receive one dose on Day 1, followed by a 6-day dosing pause. In the multiple-dosing period, subjects will be administered FWD1802 once daily. Dose Expansion Phase: Subjects will receive FWD1802 once daily. Each 4-week period constitutes one treatment cycle. Treatment will continue for up to 2 years or until one of the following events occurs (whichever comes first): disease progression, intolerable toxicity, withdrawal of informed consent, loss to follow-up, initiation of new anti-cancer therapy, or death. Patients who remain in the study at the end of the 2-year treatment period and continue to derive clinical benefit may, upon agreement between the investigator and the sponsor, have the option to continue treatment.
Phase I Study
Dose-Limiting Toxicity (DLT) Maximum Tolerated Dose (MTD) Recommended Phase II Dose (RP2D)
Phase II Study
Objective Response Rate (ORR) as assessed by the investigator per RECIST v1.1
Phase I Study
Safety Endpoints: Laboratory parameters, 12-lead electrocardiogram (ECG), vital signs, treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The incidence of AEs/SAEs, their severity and relationship to the study drug will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Pharmacokinetic Endpoints: PK parameters of FWD1802 including time to maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC, including AUC0-t and AUC0-∞), and terminal elimination half-life (T1/2). Efficacy Endpoints: ORR, Clinical Benefit Rate (CBR), Duration of Response (DoR), Disease Control Rate (DCR), and Progression-Free Survival (PFS) as assessed by the investigator per RECIST v1.1. Overall Survival (OS).
Phase II Study
Efficacy Endpoints: CBR, DoR, DCR, PFS, and OS as assessed by the investigator per RECIST v1.1. Safety Endpoints: Laboratory parameters, 12-lead ECG, echocardiogram, vital signs, physical examination, TEAEs and SAEs. Pharmacokinetic Endpoints: Minimum concentration at steady state (Cmin,ss), maximum concentration at steady state (Cmax,ss), degree of fluctuation (DF), average steady-state plasma concentration (Cave,ss), and accumulation index (RAC).
The sponsor will determine whether and when to conduct exploratory investigations based on the study progress.
1. Correlation between estrogen receptor (ER) target inhibition, as assessed by 18F-Fluoroestradiol (18F-FES) PET/CT whole-body scans, and treatment efficacy. 2. FWD1802 metabolic pathway: Identification and concentration measurement of major metabolites of FWD1802 in human plasma (if applicable). 3. Relationship between the baseline ESR1 mutation types/frequencies and the efficacy of FWD1802. \[Time Frame: Approximately 2 years\] 4. Changes in mutation types and frequencies of ESR1 and/or other breast cancer-related biomarkers in ctDNA assays before and after FWD1802 treatment, and the correlation between alterations in the mutational profile and treatment efficacy.(Phase II Study Only)
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