A Phase 2 Study of Sirolimus for Injection (Albumin-bound) in Patients With Progressive or Symptomatic Epithelioid Hemangioendothelioma

This is a non-randomized, open label, single arm Phase 2 trial with histologically-confirmed progressive and/or symptomatic epithelioid hemangioendothelioma requiring systemic treatment. Nab-sirolimus 100 mg/m2 will be administered as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary objective is to determine ORR evaluated by investigator based on RECIST V1.1 of nab-sirolimus in patients with EHE who require systemic treatment.

Inclusion criteria

1.Aged ≥ 18 years old; Histologically confirmed progressive or symptomatic epithelioid hemangioendothelioma (EHE) unsuitable for curative surgery, and deemed by the investigator to require systemic therapy.

[Referencing the 2021 ESMO Expert Consensus for investigator judgment: Patients with serous cavity effusion and/or obvious systemic symptoms shall initiate systemic therapy as early as possible. Patients with metastatic disease accompanied by documented disease progression, aggravated symptoms and/or organ dysfunction are eligible for systemic therapy.] 2.At least one measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).

3.Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2. 4.Estimated survival time > 3 months. 5.Adequate major organ function prior to treatment (no blood transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) or similar agents administered within 14 days before screening tests), meeting the following criteria:

• Hematology:

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count ≥ 100 × 10⁹/L; Hemoglobin ≥ 90 g/L.

• Renal function: Serum creatinine ≤ 1.5 × upper limit of normal (ULN).
• Hepatic function:

Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with liver metastasis, biliary obstruction or confirmed Gilbert's syndrome); Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastasis).

• Coagulation function:

International normalized ratio (INR) and prothrombin time (PT) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. 6.Fasting serum triglycerides < 300 mg/dL (3.42 mmol/L); fasting serum cholesterol < 350 mg/dL (9.07 mmol/L).

7.Glycated hemoglobin (HbA1c) < 8%. 8.Participants of childbearing potential (female or male partners with female partners of childbearing potential) and participants with non-surgical sterilization must use effective contraception [e.g., intrauterine device (IUD), oral contraceptives, condoms] throughout the study treatment period and for 6 months after the end of study treatment. Females of childbearing potential without surgical sterilization must have a negative serum pregnancy test within 7 days prior to enrollment and shall not be breastfeeding.

9.Participants must be fully informed of the study prior to trial participation and voluntarily sign the written informed consent form (ICF).

Exclusion criteria

• Received any anti-tumor therapies including mTOR inhibitors (e.g., sirolimus, everolimus), chemotherapy, radiotherapy, biotherapy, endocrine therapy, targeted therapy and immunotherapy within 4 weeks prior to the first dose of study drug, except for the following:

• Nitrosoureas (e.g., carmustine, lomustine) or mitomycin C: within 6 weeks prior to the first dose of study drug;
• Oral fluoropyrimidines and small-molecule targeted agents: within 2 weeks prior to the first dose of study drug or within 5 known half-lives of the drug, whichever is longer;
• Traditional Chinese medicines with anti-tumor indications: within 2 weeks prior to the first dose of study drug.
• Received any other unapproved investigational product within 4 weeks prior to the first dose of study drug.
• Underwent major surgical procedures within 4 weeks prior to the first dose of study drug, or have not fully recovered from any previous invasive procedures.
• Received systemic glucocorticoids (prednisone > 10 mg/day or equivalent dose of similar agents) or other immunosuppressants within 2 weeks prior to the first dose of study drug. Exceptions: topical, ophthalmic, intra-articular, intranasal and inhaled glucocorticoids; short-term glucocorticoid use for prophylaxis (e.g., prevention of contrast medium allergy).
• Had an infection requiring systemic (oral or intravenous) anti-infective therapy within 2 weeks prior to enrollment (uncomplicated urinary tract infection or upper respiratory tract infection is excluded).
• Received live vaccines, live attenuated vaccines or COVID-19 vaccines within 4 weeks prior to the first dose of study drug.
• Used strong inhibitors or inducers of hepatic metabolic enzyme CYP3A4 within 2 weeks prior to the first dose of study drug, or continued to take such agents.
• Have a history of other malignant tumors within 5 years prior to enrollment, except for: cured basal cell carcinoma, squamous cell skin carcinoma, superficial bladder cancer, in situ prostate cancer, cervical carcinoma in situ, breast carcinoma in situ, or other locally curable cancers with continuous disease-free survival for 5 years.
• Have a history of severe cardiovascular diseases, including severe cardiac rhythm or conduction abnormalities (e.g., ventricular arrhythmias requiring clinical intervention, second- or third-degree atrioventricular block); myocardial infarction, unstable angina, heart failure, NYHA Class II or higher heart failure, or a history of coronary artery bypass grafting within 6 months prior to the first dose; left ventricular ejection fraction (LVEF) < 50% at screening; QTcF > 450 msec in male participants or QTcF > 470 msec in female participants.
• Adverse events from prior anti-tumor therapies have not recovered to Grade ≤ 1 per CTCAE Version 6.0 (alopecia and other toxicities judged by the investigator to pose no safety risk are excluded).
• Have clinically symptomatic central nervous system (CNS) metastases or leptomeningeal metastases, or have evidence of uncontrolled CNS/leptomeningeal metastases, and are deemed ineligible for enrollment by the investigator.
• Have uncontrolled serous cavity effusions (e.g., pleural effusion, ascites, pericardial effusion) requiring frequent drainage or medical intervention within 14 days prior to the first dose. Additional intervention needed within 2 weeks after prior management is not allowed (excluding cytological examination of effusion samples).
• Currently have interstitial lung disease / non-infectious pneumonia requiring intervention, or interstitial lung disease cannot be ruled out by imaging examinations at screening.
• Have known hypersensitivity or intolerance to any component of the study drug or its excipients.
• Have a history of autoimmune diseases (excluding tuberous sclerosis), immunodeficiency diseases including positive HIV test, other acquired or congenital immunodeficiency disorders, or a history of organ transplantation.
• Have active hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection or active syphilis infection.

• Active HBV infection: Hepatitis B surface antigen (HBsAg) positive with HBV-DNA titer ≥ 1 × 10³ IU/mL. Participants with positive HBsAg and peripheral blood HBV-DNA < 1 × 10³ IU/mL may be enrolled if the investigator confirms chronic hepatitis B is stable and will not increase participant risks.
• Active HCV infection: Anti-HCV positive and HCV RNA positive.
• Active syphilis infection: Positive syphilis serology (RPR or TRUST) or syphilis infection requiring systemic treatment.
• Have concomitant diseases that may seriously compromise participant safety or interfere with study completion (e.g., uncontrolled hypertension and/or hyperglycemia, active gastrointestinal bleeding), or are otherwise considered ineligible for this trial by the investigator.