A Phase Ib Clinical Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of SH3765 Tablets in Combination With Fulvestrant in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-) Advanced Breast Cancer
A Phase Ib Clinical Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of SH3765 Tablets in Combination With Fulvestrant in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-) Advanced Breast Cancer
Evaluate the efficacy and safety of the SH3765 tablet combined with fulvestrant in the treatment of patients with advanced HR-positive breast cancer
Based on the data obtained from the dose-escalation phase of the Phase I clinical trial, the safety profile of each dose cohort will be determined. The efficacy, safety, and pharmacokinetic characteristics will be further evaluated during the dose-expansion phase, thereby providing a basis for establishing the recommended dose for subsequent clinical trials.
Inclusion Criteria:
Age≥18 years, female.
Histologically confirmed HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) advanced breast cancer.
Clear clinical or radiological evidence of disease progression or intolerance prior to enrollment.
The patient has received one prior endocrine therapy regimen (as monotherapy or in combination, e.g., with a CDK4/6 inhibitor), and;a)has radiological evidence of breast cancer recurrence or progression during or within 12 months after completion of (neo)adjuvant endocrine therapy; or b) has radiological evidence of progression while receiving prior endocrine therapy as a line of treatment for locally advanced or metastatic breast cancer.
The patient must meet at least one of the following definitions:
Postmenopausal, defined as meeting at least one of the following criteria:a) age ≥ 60 years;b) age < 60 years with amenorrhea for ≥ 12 months, and follicle-stimulating hormone and plasma or serum estradiol levels within the postmenopausal range as assessed by the local laboratory, and no oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone analogue administration within 12 months; c) prior bilateral oophorectomy.Premenopausal or perimenopausal (i.e., not meeting postmenopausal criteria) and meeting the following criterion: receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprorelin) starting at least 2 weeks prior to Cycle 1 Day 1 and continuing throughout the study treatment period.
At least one measurable lesion according to RECIST version 1.1 (measurable as defined in Appendix 1; target lesions cannot be from the brain). If the subject has only one measurable lesion at baseline, that lesion must not have been previously irradiated, or there must be evidence of clear progression of the lesion after completion of radiotherapy.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
Life expectancy ≥12 weeks.
Bone marrow function meets the following requirements (without receiving blood transfusion, erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-11 (IL-11), or other corrective medications within 14 days prior to the first dose): absolute neutrophil count (ANC)≥1.5×10^9/L, platelet count (PLT)≥100×10^9/L, hemoglobin (Hb)≥90 g/L.
Liver and kidney function are essentially normal, including: total bilirubin (TBIL)≤1.5×upper limit of normal (ULN) (for subjects with Gilbert's syndrome, hepatocellular carcinoma, or liver metastases, TBIL≤3×ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×ULN (for subjects with hepatocellular carcinoma or liver metastases, ALT and AST≤5×ULN); creatinine clearance (CLcr)≥50 mL/min (calculated using the Cockcroft-Gault formula, see Appendix 7).
Coagulation function meets the following criteria: prothrombin time (PT) , activated partial thromboplastin time (APTT) and international normalized ratio (INR)≤1.5×ULN.
Female subjects of childbearing potential must have a negative pregnancy test within 7 days prior to the start of treatment. If a subject has a positive serum pregnancy test, non-pregnant status must be confirmed. Premenopausal patients who have undergone ovarian suppression via LHRH agonist should agree to use effective contraception to avoid pregnancy during the study period and for 2 years after the last dose of fulvestrant.
The subject is fully informed about this trial before its commencement and voluntarily signs and dates the informed consent form.
Exclusion Criteria:
（1）Prior treatment with an anti-tumor agent targeting PRMT5, or prior treatment with fulvestrant.
(2) Received more than one line of chemotherapy for inoperable locally advanced or metastatic disease. Neoadjuvant and adjuvant chemotherapy are not considered lines of chemotherapy for advanced breast cancer.
(3) Received anti-tumor therapies including chemotherapy or immunotherapy within 3 weeks prior to the first study drug administration, except for the following: mitomycin and nitrosoureas within 6 weeks prior to the first study drug administration; oral fluoropyrimidines (e.g., S-1, capecitabine) within 2 weeks prior to the first study drug administration. Received radiotherapy, small-molecule targeted therapy, immunotherapy, or endocrine therapy within 2 weeks prior to the first study drug administration. Use of traditional Chinese medicines/herbal medicines with anti-cancer activity as described in their labeling is permitted prior to study entry, provided such agents are discontinued before initiation of study treatment.
(4) Received other unmarketed investigational medicinal products or treatments within 4 weeks prior to the first study drug administration, or is concurrently participating in another clinical study, except where the patient is enrolled in an observational, non-interventional clinical study, or is in the follow-up phase after completion of treatment in an interventional clinical study.
(5) Underwent major organ surgical procedures (excluding needle biopsy) within 28 days prior to the first study drug administration, experienced significant traumatic injury, or requires elective surgery during the trial period.
(6) Received a live vaccine (including live attenuated vaccines) within 28 days prior to the first study drug administration.
(7) Use of systemic glucocorticoids (prednisone >10 mg/day or equivalent dose of other glucocorticoids) or other immunosuppressive agents within 14 days prior to study drug administration, except for the following: topical, ocular, intra-articular, intranasal, or inhaled glucocorticoids; short-term use of glucocorticoids for prophylactic purposes (e.g., prevention of contrast agent allergy).
(8)Have received medications known to prolong the QT interval (see Appendix 4 for details) within 14 days or 5 half-lives (whichever is longer) prior to study drug administration.
(9) Receipt of medications known as strong inhibitors or inducers of CYP3A4, or inhibitors of P-gp (see Appendices 5 and 6 for details) within 7 days prior to study drug administration.
(10)Presence of brain metastases, except for subjects with stable brain metastases, defined as follows: imaging evidence of stable or reduced lesions after local treatment, or clinical signs and symptoms stable for at least 4 weeks.
(11)Any clinical evidence suggesting severe or uncontrolled systemic diseases, including but not limited to: active bleeding diathesis; uncontrolled pleural effusion or ascites; uncontrolled diabetes mellitus; other severe psychiatric, neurological, cardiovascular, or respiratory system diseases.
(12)Presence of severe cardiovascular diseases, including but not limited to: ventricular arrhythmias requiring clinical intervention; acute coronary syndrome, congestive heart failure, stroke, or other Grade 3 or higher cardiovascular events within 6 months; New York Heart Association (NYHA) Functional Classification ≥ Class II (see Appendix 3 for details) or left ventricular ejection fraction (LVEF) <50%; clinically significant QTcF prolongation (male QTcF >450 msec or female QTcF >470 msec); clinically uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg despite optimal antihypertensive therapy), and deemed by the investigator as unsuitable for participation in the study.
(13)An active infection requiring systemic anti-infective therapy is present within 1 week prior to study drug administration and has not resolved, unless, in the investigator's judgment, conditions such as fever due to the tumor do not interfere with study drug administration, in which case the subject may be enrolled.
(14)The subject has hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection. Antiviral therapy (excluding interferon) is permitted. Subjects with HBsAg positive but HBV-DNA ≤ the upper limit of normal (ULN) of the assay, or HCV antibody positive but HCV-RNA ≤ ULN of the assay, or HIV antibody positive but HIV-RNA ≤ ULN of the assay and with a normal CD4+ T cell count may be enrolled.
(15)A previous or current history of other types of malignancies is exclusionary, except under the following circumstances: (i) cured cervical carcinoma in situ or non-melanoma skin cancer; (ii) a second primary cancer that has been curatively treated with no recurrence for five years; (iii) the investigator expects that both primary cancers may benefit from this study; (iv) the investigator has clearly determined the origin of the metastatic lesion as a specific primary tumor.
(16)Receipt of an autologous hematopoietic stem cell transplant within 90 days prior to study drug administration is exclusionary.
(17) Subjets who had receive allogeneic hematopoietic stem cell transplantation or solid organ transplantation (except corneal transplant).
(18) According to CTCAE 5.0, adverse reactions from previous anti-tumor therapy have not yet returned to ≤ grade 1 (except for toxicities which are judged by researchers to be safe, such as hair loss).
(19) Occurrence of any CTCAE Grade 3 or 4 gastrointestinal bleeding within 3 months prior to study drug administration.
(20) Presence of poorly controlled nausea and vomiting, chronic gastrointestinal disease, inability to swallow the study drug formulation, or prior extensive bowel resection that may interfere with adequate absorption of the investigational product.
(21) History of hypersensitivity to the same class of the investigational drug or to its excipients (microcrystalline cellulose, lactose, croscarmellose sodium, magnesium stearate).
(22) Pregnant or lactating women. (23) Known alcohol and/or drug dependence, or any other condition deemed by the investigator to affect the safety or compliance of the study treatment.