Zemetostat With Anlotinib in Patients With Recurrent/Metastatic Head and Neck Soft Tissue Sarcoma

Lab values

• 1\. Patients previously treated with anlotinib or EZH1/2 / EZH2 inhibitors. 2. Re-irradiation to the head-and-neck region (including cervical, supraclavicular and infraclavicular lymph nodes) within 6 months prior to enrollment.
  • 3\. Tumor encasement, invasion or infiltration of major blood vessels; tumor invasion into skin or mucosal cavities; or ulcerated/bleeding tumor lesions.
  • 4\. Known hypersensitivity to anlotinib, zemetostat, or any of their excipients. 5. Concurrent use of known moderate- or strong-inducers / inhibitors of CYP3A4 / CYP3A5, or P-gp inhibitors.
  • 6\. Uncontrolled hypertension despite anti-hypertensive medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg).
  • 7\. Any condition impairing oral drug ingestion, or any condition altering drug disposition (absorption, distribution, metabolism or excretion) in vivo.
  • 8\. Coagulopathy (INR \> 2.0, PT \> 16 s); bleeding diathesis; or receiving thrombolytic or anticoagulant therapy. Prophylactic low-dose aspirin and low-molecular-weight heparin are permitted.
  • 9\. Clinically significant bleeding events or definite bleeding diathesis within 3 months before enrollment, such as hemoptysis ≥2.5 mL/day, gastrointestinal hemorrhage, high-risk esophageal-gastric varices, hemorrhagic gastric ulcer, vasculitis, etc. If baseline fecal occult blood is positive, repeat testing is required. If persistently positive, gastroscopy shall be performed. Patients with severe esophageal-gastric varices identified on gastroscopy are excluded (exception: patients who underwent gastroscopy within the preceding 3 months to rule out such findings).
  • 10\. Known inherited or acquired bleeding or thrombotic predisposition (e.g., hemophilia, coagulation disorders, thrombocytopenia).
  • 11\. Receiving concurrent anti-neoplastic therapy. 12. Participation in other investigational drug / therapeutic clinical trials within 4 weeks before the first study drug dose.
  • 13\. Positive human immunodeficiency virus (HIV) antibody or \*Treponema pallidum\* antibody.
  • 14\. Active hepatitis B or hepatitis C infection:
  • For subjects positive for HBsAg or HBcAb: HBV-DNA level above the upper limit of normal.
  • For subjects positive for HCV antibody: HCV-RNA level above the upper limit of normal.
  • 15\. Symptomatic large-volume pleural effusion or ascites requiring clinical intervention.
  • 16\. Active pulmonary disease (interstitial pneumonia, pneumonia, obstructive pulmonary disease, asthma) or history of active pulmonary tuberculosis.
  • 17\. Any uncontrolled clinical medical conditions, including but not limited to:
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  • Persistent or active severe infection;
  • Poorly controlled diabetes mellitus;
  • Cardiac disease (New York Heart Association Grade III/IV congestive heart failure or cardiac conduction block).
  • 18\. Any of the following events occurring within 6 months prior to first study drug administration: deep-vein thrombosis or pulmonary embolism; myocardial infarction; severe or unstable arrhythmia or angina pectoris; percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting; cerebrovascular accident, transient ischemic attack, cerebral embolism.
  • 19\. Prior stem-cell transplantation or solid-organ transplantation. 20. History of untreatable substance abuse involving psychotropic agents, or history of psychiatric disorders.
  • 21\. Other severe, acute or chronic medical illnesses or laboratory abnormalities that, in the investigator's opinion, may increase study-related risks or confound interpretation of study results.
  • 22\. Poor compliance as judged by the investigator, or other conditions rendering the subject unsuitable for study participation.
  • 23\. History of other malignant malignancies within the past 5 years.

• 1\. Aged 18-75 years, regardless of gender. 2. Patients with histopathologically confirmed head-and-neck soft-tissue sarcoma that is recurrent/metastatic after surgery with no curative-intent treatment (surgery/radiotherapy) options, or locally advanced unresectable disease; with measurable lesions (≥10 mm on spiral CT scan, meeting RECIST 1.1 criteria).
  • 3\. Have previously received at least one cycle of doxorubicin-containing chemotherapy, with radiologically confirmed disease progression or judged by the investigator to derive no further clinical benefit from prior therapy. Prior chemotherapy must have been completed at least 4 weeks before the first study drug administration, and all treatment-related toxicities must have resolved to baseline or to Grade 1 or lower per CTCAE Version 5.0.
  • 4\. Malignant tumors with immunohistochemically-verified deficiency of the SWI/SNF (BAF) complex (including ARID1A, ARID1B, SMARCA2 (BRM), SMARCA4 (BRG1), SMARCB1 (INI1), etc.).
  • 5\. Accessible evaluable tumor tissue (paraffin-embedded specimen obtained within the past 2 years or fresh tumor tissue).
  • 6\. ECOG performance status of 0 or 1. 7. Expected survival ≥12 weeks. 8. Adequate major organ function within 2 weeks prior to treatment initiation, as defined below: i. Bone marrow: hemoglobin ≥100 g/L without transfusion or colony-stimulating factor support; white blood cell count ≥4.0 × 10⁹/L or absolute neutrophil count ≥2.0 × 10⁹/L; platelet count ≥100 × 10⁹/L.
• Liver: total serum bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN.
• Kidney: serum creatinine \<1.5 × ULN \*\*or\*\* creatinine clearance ≥60 mL/min; blood urea nitrogen ≤200 mg/L.
• Urine protein: negative on dipstick; if dipstick shows 1+ protein, 24-hour total urinary protein must be \<500 mg.
• Blood glucose: within normal range; or patients with diabetes on stable anti-diabetic therapy with well-controlled glycemia.
• Cardiac function: no myocardial infarction within 1 year; no unstable angina; no symptomatic severe arrhythmia; no cardiac insufficiency.
  • 9\. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to the first study drug dose. Fertile men and women with child-bearing potential must use highly effective contraceptive measures throughout the study (e.g., oral contraceptives, intrauterine device, sexual abstinence, or barrier contraception combined with spermicide), and continue contraception for 12 months after treatment completion.
  • 10\. Subjects voluntarily participate in this study, provide written informed consent, demonstrate good compliance, and are willing to complete follow-up assessments.
  • 11\. Patients for whom the investigator judges study treatment may confer clinical benefit.