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 who are pregnant or breastfeeding;
Conditions judged by the investigator as making the participant unsuitable for study drug treatment, including but not limited to: a history of severe allergy to the components or excipients of the study drug, prior treatment history with the study drug, or presence of complications that may be life-threatening in the short term (such as pleural, pericardial, or abdominopelvic effusions that cannot be controlled by drainage or other methods);
Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg), allowing for the lowest value from up to two repeat measurements;
Participants with brain or central nervous system (CNS) metastases that have progressed as confirmed by imaging or clinically within 28 days before the start of treatment (e.g., evidence of new or enlarging brain metastases on imaging, new neurological symptoms attributable to brain/CNS metastases);
Parallel
Tinengotinib at the optimal dose combined with Fulvestrant
DrugParticipants will receive tinengotinib at the optimal dose once daily with fulvestrant in 28-day cycles per protocol defined schedule.
Tinengotinib
DrugParticipants will receive tinengotinib once daily in 28-day cycles per protocol defined schedule.
tinengotinib combined with fulvestrant
DrugParticipants will take tinengotinib at the starting dose of 10 mg once daily with fulvestrant to determine the optimal dose of tinengotinib in combination with fulvestrant. If not tolerated, the dose of tinengotinib will be reduced to 8 mg or 6 mg once daily.
Part A: safety evaluation parameters
Including incidence, duration, and severity of DLTs and treatment-related adverse events (TRAEs)
Part B: Objective Response Rate (ORR) (RECIST v1.1)
The proportion of subjects who achieved a complete response (CR) or a partial response (PR) based on RECIST version 1.1.
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