Inclusion Criteria:
* 1\. Voluntarily participate in the study after being fully informed, sign the written ICF, and agree to comply with the procedures specified in the protocol.
* 2\. Male or female aged ≥18 years at the time of signing the ICF.
* 3\. Subjects with pathologically confirmed locally advanced or metastatic solid tumors.
* 4\. Subjects confirmed to be KRASG12D mutation-positive in tumor tissue samples. Subjects may use historical results from local laboratories (within 2 years before signing the ICF).
Note: Test results must be provided by a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) or an equivalent certification, a third-party laboratory recognized by the investigator, or the pathology department of grade A tertiary hospital.
* 5\. Requirements for tumor type are as follows:
1. Phase Ib: Subjects with locally advanced or metastatic solid tumors who have documented radiologically disease progression, and are intolerant to standard treatment, or have no standard treatment, or have failed to standard treatment.
2. Phase II Cohort 1: Subjects with locally advanced or metastatic PDAC who have previously received gemcitabine- or nab-paclitaxel-based chemotherapy regimens or FOLFIRINOX/mFOLFIRINOX standard treatment and failed to standard treatment (have received at least first-line standard therapy and failed to standard treatment);
3. Phase II Cohort 2: Subjects with locally advanced or metastatic solid tumors who have documented radiologically disease progression and are intolerant to standard treatment, or have no standard treatment, or have failed to standard treatment (Selected tumor types will be determined based on prior study results).
* 6\. Presence of at least 1 measurable lesion assessable by computed - tomography (CT) or magnetic resonance imaging (MRI) according to RECIST Version 1.1. For lesions previously treated with radiotherapy or other local treatments, radiological confirmation of disease progression is required before they can be considered measurable lesions.
* 7\. ECOG performance status score of 0 or 1.
* 8\. Life expectancy of at least 3 months (assessed by the investigator).
* 9\. Laboratory tests within 7 days before the first dose confirm adequate bone marrow, liver, kidney, and coagulation function reserves, and no blood transfusion or blood products have been received within 14 days before the relevant tests:
1. Platelets ≥100×10⁹/L, and no platelet transfusion or thrombopoietin (TPO) treatment has been received within 14 days before the screening blood routine test.
2. Hemoglobin ≥90 g/L, and no blood transfusion, red blood cell transfusion, or erythropoietin (EPO) treatment has been received within 14 days before the screening blood routine test.
3. Neutrophil count ≥1.5×10⁹/L, and no colony-stimulating factor (CSF) has been used within 14 days before the screening blood routine test.
4. Creatinine clearance (Clcr) estimated by the Cockcroft-Gault (C-G) formula ≥60 mL/min, or estimated glomerular filtration rate (eGFR) estimated by the Modification of Diet in Renal Disease (MDRD) equation ≥60 mL/min.
5. Urine protein negative or weakly positive (±); or urine protein 1+, but urine protein-to-creatinine ratio (UPCR) in random morning urine \<0.5 or 24-hour urine protein quantification \<0.5 g/24 h.
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×Upper Limit of Normal (ULN) (≤5×ULN if liver metastasis exists). g) Total bilirubin ≤1.5×ULN (≤3×ULN is allowed for subjects with Gilbert's syndrome).
7. Prothrombin time and activated partial thromboplastin time ≤1.5×ULN, International Normalized Ratio (INR) ≤1.5. For subjects receiving anticoagulant therapy, INR \<3.0 or within the target range of anticoagulant therapy (if applicable).
* 10\. Female subjects of childbearing potential must agree to abstain from sexual intercourse or use effective contraceptive methods from the time of signing the ICF until 6 months after the last dose of study drug. Acceptable contraceptive methods include: oral, injectable, or implantable hormonal contraception; intrauterine device or intrauterine system; male condom with spermicide or occlusive cap (diaphragm or cervical/vaginal cap).
* 11\. Male subjects must agree to abstain from sexual intercourse, undergo sterilization surgery, or use effective contraceptive methods from the time of signing the ICF until 6 months after the last dose of study drug.
Note: Effective contraceptive methods include: use of a male condom, with the female partner also using hormonal contraception or an intrauterine device (used for at least 4 weeks before administration); use of a male condom, with the female partner also using a diaphragm with spermicide or a cervical/vaginal cap.
Exclusion Criteria:
* 1\. Previous treatment with KRASG12D inhibitors. Note: Except for subjects in Phase Ib, who may have received previous treatment with KRASG12D inhibitors.
* 2\. Previous treatment with focal adhesion kinase (FAK) inhibitors.
* 3\. Received any anti-cancer drug treatment (including cytotoxic therapy, targeted therapy, biological therapy, or hormonal therapy other than alternative therapy) or other investigational drug treatment and radiotherapy within 14 days before the first dose.
* 4\. Have other KRAS mutations (excluding KRASG12D mutation), and have other positive mutation sites with available marketed targeted drugs.
* 5\. Subjects with known spinal cord compression symptoms, unstable or symptomatic/progressive central nervous system (CNS) metastasis, or meningeal metastasis. Subjects with a history of brain metastasis who are clinically and radiologically stable (i.e., no progression of CNS disease confirmed by two consecutive brain MRI or CT scans (if MRI is not suitable) with an interval of at least 4 weeks) may be enrolled (if the subject has previously received radiotherapy for brain metastasis, the MRI or CT scan must be performed at least 4 weeks after the last brain radiotherapy). For subjects who have received corticosteroid treatment, corticosteroids must have been discontinued for at least 2 weeks before the first dose of study drug. For subjects receiving anti-epileptic treatment, their medication dose must have been stable for at least 2 weeks.
* 6\. Any of the following cardiovascular conditions:
1. Congestive heart failure with New York Heart Association (NYHA) functional class II or higher.
2. Severe arrhythmia and left bundle branch block requiring drug treatment.
3. Acute myocardial infarction, severe or unstable angina pectoris, coronary or peripheral artery bypass surgery within 6 months before the first dose.
4. Left ventricular ejection fraction (LVEF) \<50%.
5. Prolonged corrected QT interval (QTcF) by Fridericia's formula at rest, with an average QTc interval \>480 ms measured by three consecutive ECGs, or risk factors for torsades de pointes, such as clinically significant hypokalemia, family history of long QT syndrome, or familial arrhythmia (e.g., Pre-excitation Syndrome) as judged by the investigator.
6. Uncontrolled hypertension (defined as systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg after standardized antihypertensive drug treatment).
7. Deep vein thrombosis (other than implantable venous access port or catheter-related thrombosis) or pulmonary embolism within 6 months prior to the first dose of study treatment.
* 7\. Subjects with stroke or other severe cerebrovascular diseases (e.g., acute cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) within 12 months prior to the first dose of study treatment.
* 8\. Subjects with interstitial lung disease or any active infection requiring systemic treatment within 14 days prior to the first dose of study treatment, including but not limited to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
* 9\. Subjects with active autoimmune diseases (e.g., autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease) requiring systemic treatment (including disease-modifying drugs, corticosteroids, or immunosuppressants) within the past 2 years. Hashimoto's thyroiditis, vitiligo, and psoriasis that do not require systemic treatment are excluded. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
* 10.The investigator judges that the subject has a history or evidence of substance abuse, or has medical, psychological, or social conditions that may interfere with study participation or evaluation of study results.
Note: The following conditions are not recommended for enrollment, including but not limited to: 1) Presence of pleural effusion, pericardial effusion, or ascites that is poorly controlled and requires clinical management; 2) Active bleeding such as hemoptysis or gastrointestinal bleeding during the screening period, subjects with only a small amount of blood in sputum are allowed to enroll; 3) Received live vaccines or attenuated live vaccines within 28 days prior to the first dose of study treatment.
* 11.Subjects with gastrointestinal (GI) disorders that may significantly impair the oral administration, absorption, or metabolism of the study drug, including dysphagia, refractory nausea and vomiting, malabsorption syndrome, gastrectomy or small bowel resection that impairs the oral absorption or metabolism of the study drug, symptomatic inflammatory bowel disease, and partial or complete intestinal obstruction.
Note: Subjects with clinical or radiological evidence of intestinal obstruction, or those who developed intestinal obstruction within the previous 3 months with unresolved underlying cause are not recommended for enrollment.
* 12.The subject has not recovered from the toxicity of previous anti-tumor treatment (except for alopecia and pigmentation), defined as not recovered to NCI CTCAE v5.0 ≤Grade 1 (≤Grade 2 for peripheral neuropathy).
* 13.The subject has undergone major surgery within 4 weeks prior to the first dose of study drug or has not fully recovered from previous surgical treatment. For percutaneous liver biopsy and other needle biopsies, a 14-day washout period is required before the first dose of study treatment.
Note: Subjects expected to undergo major surgery or those who need to interrupt study medication for scheduled surgery during the study treatment, should also be excluded.
* 14.The subject has received or plans to receive within 2 weeks before the first dose of study drug treatment:
1. Drugs that are known to be narrow therapeutic window substrates of CYP3A.
2. Drugs that are known to be strong inducers or inhibitors of CYP3A4.
3. Drugs that are known to be strong inhibitors of P-glycoprotein.
4. Drugs known/potentially causing QTc interval prolongation or torsades de pointes (e.g., antiarrhythmic drugs).
Note: For details, refer to Appendix 9 in Section 10.9.
* 15.Pregnant or lactating women.
* 16.Positive for hepatitis B surface antigen (HBsAg) with hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥2500 copies/mL or 500 IU/mL, positive for hepatitis C virus (HCV) antibody with HCV ribonucleic acid (HCV RNA) above the lower limit of detection, or positive for human immunodeficiency virus (HIV) antibody.
* 17.A history of other malignant tumors within 5 years before the first dose, except for cured basal cell carcinoma of the skin, carcinoma in situ (e.g., carcinoma in situ of the breast, squamous cell carcinoma in situ of the skin, cervical carcinoma in situ).
* 18.Known allergy (such as life-threatening hypersensitivity reaction) or other intolerances to IN10018, RNK08954 or their pharmaceutical excipients; or subjects with severe allergic diathesis.
