Inclusion Criteria:
-1. Patients aged 18 to 75 years (calculated as of the date of signing the informed consent), regardless of gender.
2\. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 3. Histologically confirmed advanced or metastatic Ewing sarcoma, with at least one measurable lesion that has not been treated locally (according to RECIST v1.1, this measurable lesion must have a maximum diameter of ≥ 10 mm on spiral CT scans or a short diameter of ≥ 15 mm for enlarged lymph nodes).
4\. The primary tumor or locally recurrent tumor cannot be completely resected through surgery or other local treatments (e.g., stereotactic radiosurgery, argon-helium knife, ultrasound-guided focused ultrasound, etc.); first-line chemotherapy (VAC/IE) has failed, leading to distant metastasis, and the metastatic tumors cannot be completely resected through surgery or other local treatments; or the patient refuses surgery or other local treatments.
5\. Expected survival of ≥ 12 weeks. 6. Basic normal function of major organs, with severe abnormalities in blood, heart, lung, liver, kidney, bone marrow functions, or immune deficiency diseases meeting protocol requirements:
1. Complete Blood Count (CBC): (No blood transfusion, use of Granulocyte-Colony Stimulating Factor \[G-CSF\], or corrective therapy within 14 days prior to screening)
\- Hemoglobin ≥ 90 g/L;
* Neutrophil count ≥ 1.5 × 10\^9/L;
* Platelet count ≥ 75 × 10\^9/L;
2. Biochemical Tests: (No albumin infusion within 14 days)
* Albumin ≥ 29 g/L;
* Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN);
* Total bilirubin (TBIL) ≤ 1.5 times ULN;
* Creatinine (Cr) ≤ 1.5 times ULN or Cr clearance \> 50 mL/min (Cockcroft-Gault formula):
* Male: Cr clearance = ((140 - age) × weight) / (72 × blood Cr)
* Female: Cr clearance = ((140 - age) × weight) / (72 × blood Cr) × 0.85
* Weight in kg; blood Cr in mg/mL;
* Urinary protein \< 2+ (if urinary protein ≥ 2+, a 24-hour urine protein quantification can be performed, with \< 1.0 g in 24 hours allowing for inclusion);
3. Coagulation Function: Activated partial thromboplastin time (APTT) and International Normalized Ratio (INR) ≤ 1.5 × ULN (patients on stable doses of anticoagulants like low molecular weight heparin or warfarin, with INR within the expected therapeutic range, can be screened);
4. Thyroid Function: Thyroid-Stimulating Hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be evaluated, with normal levels allowing for inclusion;
5. Echocardiogram: Left ventricular ejection fraction (LVEF) ≥ 60%. 7. Non-surgically sterile or premenopausal female patients must use a medically approved contraceptive method (such as an intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 6 months after the end of study treatment; non-surgically sterile premenopausal females must have a negative serum or urine HCG test within 7 days prior to study enrollment and must not be breastfeeding; male patients with female partners of childbearing potential should use effective contraception during the study and for 6 months after the last dose of fluzoparib, liposomal irinotecan, or temozolomide.
8\. Understanding the study procedures and methods, voluntarily participating in this trial, and signing the informed consent form in writing, with a full understanding of the trial content, process, and potential adverse reactions.
Exclusion Criteria:
* 1\. Plans to receive any other anti-tumor treatments during this trial. 2. Received radiotherapy for Ewing sarcoma within 4 weeks prior to the first administration of the study drug, or received other investigational drugs or cell therapies.
3\. Presence of intracranial tumor lesions diagnosed by imaging. 4. History of other active malignancies within the past 5 years, or currently having other active malignancies aside from Ewing sarcoma. Curatively treated localized tumors, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate in situ carcinoma, cervical in situ carcinoma, and breast in situ carcinoma, are allowed.
5\. Presence of clinically symptomatic ascites requiring paracentesis or drainage, or having undergone paracentesis within the last 3 months; only those with small amounts of ascites detected by imaging but without clinical symptoms are excluded; uncontrolled or moderate to severe pleural effusion or pericardial effusion; evidence of intraperitoneal free air that cannot be explained by paracentesis or recent surgical procedures.
6\. History of epilepsy, or having experienced diseases that can induce seizures (including transient ischemic attacks, strokes-not just isolated imaging findings of cerebral ischemia without clinical history, or head trauma with loss of consciousness requiring hospitalization) within 12 months prior to the first administration of the study drug.
7\. Previous treatment with PARP inhibitors, irinotecan, temozolomide, including but not limited to fluzoparib.
8\. History of allergic reactions, including severe drug allergies or drug hypersensitivity; known allergies or intolerances to fluzoparib, liposomal irinotecan, temozolomide, or their excipients.
9\. Severe infections (CTCAE grade \> 2) occurring within 4 weeks prior to the first administration of the study drug, such as severe pneumonia requiring hospitalization, bacteremia, or infections with complications; baseline chest imaging indicating active pulmonary inflammation, presence of infection symptoms and signs within 2 weeks before the first administration of the study drug, or requiring oral or intravenous antibiotic treatment (excluding prophylactic use of antibiotics).
10\. Cannot discontinue the use of medications that may affect P-glycoprotein (P-gp) during the study period.
11\. Use of strong or moderate inhibitors or inducers of hepatic drug-metabolizing enzyme CYP3A4 within 14 days prior to the first administration of the study drug.
12\. Presence of factors that impair swallowing, chronic diarrhea, bowel obstruction, or other factors affecting drug intake and absorption.
13\. History of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), or having had other malignancies within 5 years prior to the first administration of this study (with the exception of completely resolved in situ cancers and malignancies determined by the investigator to have slow progression).
14\. Co-infection with other viral infections (anti-HCV positive, anti-HIV positive, HBsAg positive) or syphilis infection.
15\. History of immune deficiency (including positive human immunodeficiency virus \[HIV\] test, other acquired or congenital immune deficiencies) or history of organ transplantation.
16\. Known history of abuse of psychotropic substances, alcoholism, or drug abuse.
17\. Any condition judged by the investigator to pose a significant risk to patient safety or to affect the patient's ability to complete the study (such as poorly controlled hypertension, severe diabetes, thyroid disease, and psychiatric disorders) or any other situation.
