Phase I Study to Evaluate SIM0270 Alone or in Combination in ER+, HER2- Locally Advanced or Metastatic Breast Cancer

The study is comprised of two parts: Phase Ia and Phase Ib. Phase Ia includes dose-escalating stage and dose expansion stageof SIM0270 monotherapy to determine the MTD/ RP2D and the preliminary safety and efficacy of SIM0270; Phase Ib includes 2 arms, armA: dose escalation and dose expansion of SIM0270 in combination with palbociclib; armB: dose escalation and dose expansion of SIM0270 in combination with palbociclib everolimus; phase Ib is designed to determine the MTD/RP2D and the preliminary safety and efficacy of SIM0270 in combination with palbociclib or everolimus.

key Inclusion Criteria:

• voluntary participation in clinical trials and signature of informed consent.
• age ≥ 18 years, male or female.
• Histologically or cytologically confirmed metastatic/locally advanced ER-positive, HER-2 negative breast cancer subjects.
• previous treatment meets the criteria of the protocol defined.
• ECOG score of 0 or 1 .
• at least one measurable lesion that meets RECISTv1.1 criteria. Osteolytic lesions can be included in the Ia dose-escalating .
• expected survival ≥ 12 weeks.
• Adequate organ and bone marrow function.
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose.
• Postmenopausal women; Premenopausal or perimenopausal female subjects met protocol requirements.

key Exclusion Criteria:

• Documented medical history or ongoing gastrointestinal disease or other malabsorption that may affect the absorption of oral study drug.
• Participated in other clinical trials of investigational drugs or investigational devices within 28 days before the first medication; or received chemotherapy, targeted therapy, immunotherapy and clinical trial medication and other anti-tumor treatment within 4 days or 5 half-lives of the first medication (whichever is shorter), or received radiotherapy, endocrine drugs or Chinese patent medicines with anti-tumor indications 2 weeks before the first medication;
• The toxicity of previous anti-tumor treatment has not recovered to grade 0 or 1 (alopecia, chemotherapy-induced peripheral neurotoxicity ≤ grade 2 can be included).
• Major surgical surgery (except biopsy) or incomplete healing of the surgical incision 4 times before the first study drug treatment;
• Known other malignant tumors within 2 years before enrollment (except treated basal cell carcinoma, scaly cell carcinoma and/or radical carcinoma in situ);
• Leptomeningeal metastasis confirmed by MRI or known cytology of CSF, or cranial Increased internal pressure or brain metastases with unstable central nervous symptoms (within 2 weeks prior to initial medication Treatment with any craniotropic, glucocorticokinin, or anticonvulsant);
• Previous history of interstitial lung disease, drug-induced interstitial lung disease, symptomatic interstitial lung disease or any evidence of active pneumonia on chest CT scan 4 before the first study drug treatment;
• known to interfere with the test requirements of mental illness or drug abuse disease.
• History of human immunodeficiency virus HIV infection, or active bacterial or fungal infection requiring systemic treatment .
• presence of active syphilis infection.
• Subjects with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with abnormal liver function.
• History of clinically significant cardiovascular disease.
• History of serious allergic reactions to the study drugs or excipients used in the protocol.
• Women who are pregnant or lactating.
• Prior use of SERD oral medications.
• Subjects who use drugs or herbal supplements known to be moderate/strong inhibitors of CYP3A 2 Weeks before the first dose.Or Subjects who use drugs or herbal supplements known to be moderate/strong inducers of CYP3A 4 weeks before the first dose.
• Other conditions that the investigator considers unsuitable for this study.