A Phase II, Open-Label, Multicenter Clinical Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of TT-00420 (Tinengotinib) Tablets Combined With Fulvestrant Injection in Patients With Hormone Receptor-Positive (HR+) and Human Epidermal Growth Factor Receptor 2 (HER-2) Negative or Low-Expressing Recurrent or Metastatic Breast Cancer Who Have Failed Prior Treatment
The goal of this clinical trial is to learn if tinengotinib combined with fulvestrant works to treat patients with HR-Positive and HER-2-Negative or low-expressing advanced breast cancer. It will also learn about the safety of combination therapy. The main questions it aims to answer are: 1. Does tinengotinib combined with fulvestrant reduce the tumor burden in participants? 2. What medical problems do participants have when taking the combination therapy? Participants will: Take tinengotinib and fulvestrant to find the optimal dose of tinengotinib for the combination therapy in Part A. In Part B, will take tinengotinib at the optimal dose with fulvestrant or tinengotinib alone to see if the combination therapy works better than tinengotinib monotherapy.
• Histologically or cytologically confirmed breast cancer with evidence of local recurrence or distant metastasis and no indication for surgery or radiotherapy;
• Breast cancer confirmed as HR+/HER2- negative or low expression by local laboratory testing based on the most recent tumor tissue sample (from either the primary or metastatic site, excluding bone lesions). HR-positive, HER2-negative or low expression as defined in this study refer to the Chinese Society of Clinical Oncology \[CSCO\] 2024 criteria;
• Participants must meet at least one of the following criteria: a) prior bilateral oophorectomy, or age ≥60 years; b) age \<60 years, with natural amenorrhea (in the absence of medication or pathological conditions) for ≥12 months, and estradiol and FSH levels within the postmenopausal range; c) age \<60 years, currently undergoing ovarian suppression therapy (e.g., LHRH agonist) and requiring continued treatment during the study, with estradiol and FSH levels maintained within the postmenopausal range;
• Participants who have previously failed 1-2 lines of endocrine therapy (including AI, SERD, and SERM) for recurrent or metastatic disease are eligible. Subjects with initial diagnosis showing weak ER positivity by IHC (tumor cells with nuclear staining accounting for 1%-10%) are not eligible for enrollment;
• Participants must have experienced disease progression after prior treatment with at least one CDK4/6 inhibitor (CDK4/6i), including in the neoadjuvant, adjuvant, or systemic treatment settings;
• Participants who have previously failed 0-2 lines of systemic chemotherapy (cytotoxic drugs) for recurrent or metastatic disease. Antibody-drug conjugates (ADCs) are not counted as systemic chemotherapy;
• ECOG ≤ 1;
• Participants must meet at least one of the following criteria (per RECIST v1.1): a) At least one measurable lesion as defined by RECIST v1.1 at baseline; if the only target lesion is a non-nodal lesion, its longest diameter must be ≥15 mm; b) When bone lesions are the only measurable lesions, lytic or mixed bone lesions may be selected as target lesions; subjects with only blastic bone lesions are not eligible for enrollment.
• Adequate organ and bone marrow function;
⁃ Premenopausal participants receiving ovarian suppression therapy must agree to use adequate contraception to avoid pregnancy during the study and for at least 3 months after the end of treatment;
⁃ Able to sign informed consent and comply with the protocol.