Inclusion Criteria:
* 1.Signed Informed Consent Form 2.Age ≥ 18 years at time of signing Informed Consent Form 3.Ability to comply with the study protocol, in the investigator's judgment 4.Histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma.
5.The disease must have progressed after previous chemotherapy given in a neoadjuvant, adjuvant (only if distant metastases occurred within 6 months of completing adjuvant therapy), 1st line therapy of locally advanced, or metastatic setting.
6.Availability of a representative tumor specimen that is suitable for pathological evaluation and biomarker expression analysis.
* A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in approximately 8-10 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report within 4 weeks of randomization.
* If fewer than 8 slides are obtained, but there are enough slides for E-cadherin testing by local lab of each site patients are still eligible.
7.ECOG Performance status (PS) of 0 or 1 within 7 days prior to initiation of study treatment.
8.At least one measurable lesion per RECIST v1.1 9.Adequate hematologic and organ function, defined by the following laboratory test results, obtained within 7 days prior to initiation of study treatment:
* ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support
* Lymphocyte count ≥ 0.5 × 109/L (500/μL)
* Platelet count ≥ 100 × 109/L (100,000/μL) without transfusion
* Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion, but must not have been transfused within 2 weeks prior to screening
* Fasting glucose \< 6.1.mmol/L and HbA1c \< 5.7%
* AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN).
* Total bilirubin ≤ 1.5 × ULN with the following exception:
Patients with known Gilbert disease: total bilirubin ≤ 3 × ULN
* Serum creatinine ≤ 1.5 × ULN or Creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula)
* Albumin ≥ 25 g/L (2.5 g/dL)
* For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 × ULN
* For patients receiving therapeutic anticoagulation: stable anticoagulant regimen 10.Negative HIV test at screening 11.For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below: Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of \< 1% per year during the treatment period and for at least 1 week after the final dose of study treatment. Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of non-hormonal contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
12.For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for at least 1 week after the final dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
Exclusion Criteria:
* 1.Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway.
2.Prior treatment with any RAS inhibitor or BRCA inhibitor. 3.Known hypersensitivity to any of the components of study treatments. 4.Histology consistent with small cell carcinoma, Neuroendocrine carcinoma, or mixed carcinoma.
5.Type 2 diabetes requires ongoing systemic treatment at the time of study entry;or pre-diabetes, or any history of Type 1 diabetes；or any other type of diabetes.
6.Inability or unwillingness to swallow pills 7.Malabsorption syndrome or other condition that would interfere with enteral absorption 8.Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
* Measurable disease outside the CNS
* No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for ≥ 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases
* Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic assessments
* Screening CNS radiographic assessments ≥ 4 weeks since completion of radiotherapy
* No history of intracranial hemorrhage or spinal cord hemorrhage 9.Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved, and has prior approval from the Medical Monitor.
10.Serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1 11.Any concurrent ocular or intraocular condition excluding cataracts (e.g. , diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition.
12.Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye 13.Requirement for daily supplemental oxygen 14.Symptomatic active lung disease, including pneumonitis 15.History of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazines) are considered to have active disease and are therefore ineligible.
16.Any active bowel inflammation (including diverticulitis) 17.Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study 18.Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed.
19.Clinically significant and active liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis 20.Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, or infectious disease) or any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that renders the patient at high risk from treatment complications 21.Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before study treatment 22.Investigational drug(s) within 4 weeks before study treatment 23.Prior radiotherapy to ≥ 25% of bone marrow, or hematopoietic stem cell or bone marrow transplantation 24.Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and Grade ≤ 2 peripheral neuropathy 25.History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer 26.History of or active clinically significant cardiovascular dysfunction, including the following:
* History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment
* History of myocardial infarction within 6 months prior to first dose of study treatment
* New York Heart Association Class III or IV cardiac disease or congestive heart failure requiring medication
* Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication
* Coronary heart disease that is symptomatic or unstable angina
* Congenital long QT syndrome or QT interval corrected through use of Fridericia's formula \> 470 ms demonstrated by at least two ECGs \> 30 minutes apart, or family history of sudden unexplained death or long QT syndrome 27.Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) 28.Chronic corticosteroid therapy of ≥ 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease 29.Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors within 1 week or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment 30.Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of study treatment.
Women of childbearing potential (including those who have had a tubal ligation) must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment or negative urine pregnancy test if serum pregnancy test is not available.
31.Major surgical procedure, or significant traumatic injury, within 28 days prior to Day 1 of Cycle 1 or anticipation of the need for major surgery during the course of study treatment 32.Minor surgical procedures \<7 days prior to first dose of study treatment. Patients must have sufficiently recovered from surgery, including adequate wound healing.
