GenSci145 単剤療法または併用療法による、PIK3CA 変異を有する局所進行または転移性固形腫瘍患者を対象とした臨床試験。

Inclusion Criteria:

I. General inclusion criteria for all participants

1. Participants should be able to understand and voluntarily sign a written ICF (before participating in any trial-related procedures of this study).

2. Participants are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other specified study procedures.

3. At the time of signing the ICF: aged between 18 and 75 years (inclusive). If the legal age of consent in the jurisdiction in which the study is taking place is > 18 years, then the legal age of consent should be reached.

4. Central or local test results are required to confirm the presence of eligible PIK3CA mutations in tumor tissue or blood samples. Eligible PIK3CA mutations include: R88Q, G106A/D/R/S/V, K111N/R/E, G118D, N345D/H/I/K/S/T/Y, C420R, E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, E545A/D/G/K/L/Q/R/V, Q546E/H/K/L/P/R, T1025A/I/S, M1043I/T/V, N1044H/I/K/S/T/Y, H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, or other pathogenic PIK3CA mutations.

5. Fresh tumor tissue (preferred) or archived tumor tissue sections are required (participants planning to be enrolled in Part 1 Dose Level 1 or Dose Level 2 who cannot provide tumor samples or provide insufficient samples can be screened after communicating with the sponsor).

6. At least one measurable lesion as assessed according to RECIST v1.1.

7. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 (refer to Appendix 1 for details).

8. Life expectancy ≥ 3 months.

9. Has adequate hematologic and organ function within 7 days prior to the first dose of GenSci145 as follows:

   Hematology:Neutrophil count ≥ 1,500/µL (1.5 × 109/L);Hemoglobin ≥ 9 g/dL;Platelet count ≥ 100,000/µL (100 × 109/L); Liver function:Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) (TBIL ≤ 3 × ULN for patients with Gilbert's syndrome); AST and ALT ≤ 2.5 × ULN; for participants with documented liver metastases: AST and/or ALT ≤ 5.0 × ULN; Renal function:Creatinine clearance rate (CLcr) ≥ 60 mL/min (Calculated by using the Cockcroft-Gault formula, refer to Appendix 3 for details); Glucose metabolism:•Fasting blood glucose ≤ 140 mg/dL (7.7 mmol/L);HbA1c ≤ 7.0%;Fasting blood amylase ≤ 2.0 × ULN;Fasting blood lipase ≤ 1.0 × ULN; Coagulation function:•International normalized ratio or prothrombin time (PT) ≤ 1.5 × ULN, or PT within the therapeutic range of intended anticoagulant treatment if the participant is receiving anticoagulant therapy;Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, or aPTT within the therapeutic range of intended anticoagulant treatment if the participant is receiving anticoagulant therapy;

10. Women of childbearing potential (WOCBP) must be willing to use adequate contraception from signing the ICF until at least 30 days after the last dose of study treatment (or extended to 2 years if in combination with fulvestrant in accordance with the local prescribing information) and have a negative serum human chorionic gonadotropin (HCG) test within 7 days prior to the first dose of GenSci145.

11. Men able to father a child must be willing to use adequate contraception from signing the ICF until at least 30 days after the last dose.

II. Inclusion criteria only applicable to specific study part/cohort

Part 1:

1. Participants with histologically or cytologically confirmed locally advanced or metastatic solid tumors;
2. Participants with progressive disease following standard of care, or for whom, in the opinion of the investigator, no effective standard treatment regimen is available.

Part 2:

1. Female participants with histologically or cytologically confirmed HR+/HER2- locally advanced or metastatic breast cancer [HR+ in this protocol is defined as estrogen receptor (ER) positive and/or progesterone receptor (PR) positive (positive nuclear staining in ≥ 10% tumor cells); HER2- is defined as immunohistochemistry (IHC) 0, 1+, or IHC 2+ and in situ hybridization (ISH) negative];
2. Participants with progressive disease following standard of care, or for whom, in the opinion of the investigator, no effective standard treatment regimen is available.

Part 3 (Doublet), Part 4 Cohort A:

1. Female participants with histologically or cytologically confirmed HR+/HER2- locally advanced or metastatic breast cancer;

2. Participants who meet any of the following:

   1. Participants with progressive disease during (neo)adjuvant endocrine therapy or within 12 months after completing the therapy and have not received any endocrine therapy for metastatic disease;
   2. Progressive disease more than 12 months after completing adjuvant endocrine therapy, followed by progression again after one line of endocrine therapy (for metastatic disease);
   3. Newly diagnosed advanced breast cancer with disease progresses following first-line endocrine therapy;

3. Have received ≤ 1 line of chemotherapy or antibody-drug conjugate therapy in the advanced stage;

4. Prior use of CDK4/6 inhibitors that meets any of the following:

   1. Received a CDK4/6 inhibitor in the advanced stage and experienced progressive disease while on treatment or used a CDK4/6 inhibitor in the (neo)adjuvant setting and experienced progressive disease while on treatment; or within 12 months after the end of treatment;
   2. Discontinuation of treatment due to intolerance to adverse reactions (e.g., hyperglycemia, rash, etc.);
   3. If no prior use of CDK4/6 inhibitors, a plausible explanation (e.g., drug unavailability) is required.

Part 3 (Triplet), Part 4 Cohort C:

1. Female participants with histologically or cytologically confirmed HR+/HER2- locally advanced or metastatic breast cancer;
2. Progression while on or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen; if a CDK4/6 inhibitor is included in the (neo)adjuvant setting, the progression event must have occurred > 12 months after completing (neo)adjuvant therapy with CDK4/6 inhibitors.

Part 4 Cohort B:

1. Female participants with histologically or cytologically confirmed HR+/HER2- locally advanced or metastatic breast cancer with brain metastases. The diagnostic and treatment requirements are the same as those for Part 3 (doublet) and Part 4 Cohort A;
2. No immediate CNS-specific treatment (e.g., radiation therapy or surgery) is required, as evaluated by the investigator.

III. Additional inclusion criteria applicable only to participants with breast cancer participating in combination therapy

Female participants with breast cancer participating in combination therapy should meet one of the following:

1)Postmenopausal, defined as:

1. Have undergone bilateral oophorectomy ≥14 days and have recovered to baseline status; or

2. Age ≥ 60 years; or

3. Age < 60 years, and amenorrheic for ≥ 12 months, and the levels of follicle-stimulating hormone (FSH) and estradiol (E2) within the local reference range and consistent with menopause criteria when no oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone agonist/antagonist are used.

   Premenopausal or perimenopause (perimenopausal is defined as age ≥ 50 and < 60 years with amenorrhea for less than 12 months or FSH and/or E2 not in the postmenopausal range): ovarian function suppression with a luteinizing hormone-releasing hormone agonist such as goserelin or leuprorelin beginning ≥ 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of the study is require.

   Exclusion Criteria:

   1. Any active malignancy ≤ 2 years prior to the first dose of GenSci145, except for the cancer under study and any locally recurrent cancers that have been cured (e.g., resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical carcinoma in situ, or breast carcinoma in situ)
   2. Symptomatic, treatment-naïve, or progressing central nervous system (CNS) metastases; CNS metastases that have been treated with CNS treatment (e.g., surgery/radiotherapy) is allowed if all of the following conditions are met:
   1. The disease is stable for at least 3 months, with no progressive disease as confirmed by imaging examination within 4 weeks prior to the first dose of the study treatment, and all neurological symptoms have recovered to baseline;
   2. Treatment with radiation, surgery, or steroids has been discontinued for at least 4 weeks prior to the first dose of study treatment.

   3.History of metastases to meninges, spinal cord compression, or leptomeningeal disease.

   4.Prior history of acute pancreatitis (within the past 1 year) or chronic pancreatitis, or imaging evidence of metastases to pancreas.

   5.Stroke, transient ischemic attack, or other clinically significant cerebrovascular events within 6 months prior to the first dose of GenSci145.

   6.Active infections requiring IV antibiotics or other uncontrolled intercurrent illnesses requiring hospitalization. Participants with minor infections, such as periodontal infection or urinary tract infection that may be treated with a short course of oral antibiotics, are allowed to be enrolled.

   7.Type I diabetes mellitus, or history of gestational diabetes, or type II diabetes mellitus that is uncontrolled as evaluated by the Investigator.

   8.Uncontrolled hypertension (defined as blood pressure ≥ 150/90 mmHg despite optimal medical intervention).

   9.Clinically significant cardiac disorder, including but not limited to:

   1)A history of myocardial infarction or unstable angina within 6 months prior to the first dose of GenSci145; 2)New York Heart Association (NYHA) Class III or higher within 4 weeks prior to the first dose of GenSci145 ; 3)Left ventricular ejection fraction < 50% as evaluated by cardiac echocardiography within 4 weeks prior to the first dose of GenSci145; 4)Mean QT interval corrected by Fridericia's method (QTcF) > 450 ms, based on 3 consecutive resting 12-lead ECGs collected at screening; 5)Any factors that increase the risk of torsades de pointes (e.g., persistent hypokalemia despite standard treatment, family history of long QT syndrome); 6)Any clinically significant abnormalities in heart rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, grade 2/3 atrioventricular block).

   10.Interstitial pneumonitis, drug-induced pneumonitis, radiation pneumonitis requiring glucocorticoids, or other significant pulmonary disorder affecting lung function.

   11.Gastrointestinal diseases that may interfere with the oral absorption of GenSci145 as evaluated by the investigator, such as peptic ulcer, uncontrolled nausea and vomiting, malabsorption syndrome, history of small intestinal resection, active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), etc.

   12.Serous effusion that is not well controlled, including pleural effusion, ascites, and pericardial effusion (participants can be enrolled if it is controlled and stable for ≥ 2 weeks after treatment).

   13.Prior treatment with PI3K, mTOR, or AKT inhibitors. 14.Prior treatment with fulvestrant (excluding Phase Ia and Part 4 Cohort D). 15.Inoculation of live attenuated vaccines within 4 weeks prior to the first dose of GenSci145.

   16.Treatment with the following anti-tumor therapies prior to the first dose of GenSci145:

   1. Herbal medicines or Chinese patent medicines with anti-tumor activity within 2 weeks;
   2. Endocrine therapy with anti-tumor indications within 2 weeks or 5 half-lives (whichever is shorter);
   3. Radiotherapy within 4 weeks;
   4. Chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin; 14 days or 5 half-lives for oral fluorouracil agents, whichever is longer);
   5. Small molecule targeted agents, biologics, or immunotherapy within 4 weeks or 5 half-lives (whichever is shorter).

   17.Patients who have undergone major surgery within 4 weeks prior to the first dose of GenSci145, have not adequately recovered from the surgery, or are expected to undergo major surgery during the study.

   18.Participants who have received strong or moderate inducers or inhibitors of cytochrome P450 family 3 subfamily A (CYP3A) enzyme , or received strong inducers or inhibitors of CYP2C8 enzyme and CYP2C9 enzyme, or received sensitive substrates of CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2B6 enzyme , or medications with a known risk of QT/QTc interval prolongation within 5 half-lives or 14 days (whichever is longer) prior to the first dose of GenSci145.

   19.Current or recent treatment with systemic glucocorticoids or not fully recovered from side effects of systemic glucocorticoids (topical drugs, such as topical administration for rash, aerosol inhalation for chronic obstructive pulmonary disease, eye drops, and intra-articular local injection are allowed).

   20.Prior history of organ transplantation or allogeneic stem cell transplantation.

   21.Unable to swallow oral medications (e.g., tablets, capsules) without chewing, breaking, crushing, opening, or otherwise altering the form of the product.

   22.Positive hepatitis B test [defined as hepatitis B surface antigen (HBsAg) positive, further testing with hepatitis B virus DNA (HBV DNA) is required, and participants with a result above the assey upper limit of normal will be excluded]; positive hepatitis C virus antibody (HCV Ab) [further testing with hepatitis C virus RNA (HCV RNA) is required, and participants with a result above the assay upper limit of normal will be excluded]; or positive human immunodeficiency virus antibody (HIV Ab).

   23.Persistent toxicity of grade ≥ 2 from prior anti-tumor therapy as per CTCAE v6.0, except for alopecia, stable Grade 2 peripheral neuropathy, or adequately controlled endocrine toxicities.

   24.Known serious allergy to GenSci145 and/or any of its excipients. Participants with hypersensitivity to fulvestrant or palbociclib will also be excluded if entering the combination therapy group (applicable to Part 3 triplet combination and Part 4 Cohort C).

   25.Pregnant or breastfeeding women, or women who plan to breastfeed during the study or within 30 days after the last dose of GenSci145 (may be extended to 2 years if in combination with fulvestrant as per local prescribing information).

   26.Participation in other clinical studies within 4 weeks prior to the first dose (except for observational non-interventional studies or during the follow-up period in interventional studies).

   27.Any other condition that, in the investigator's opinion, would make the participant unsuitable for the study.