SM-1 Combined With Temozolomide in Subjects With Refractory or Recurrent High-Grade Gliomas

Obitazidine Fumarate Enteric-coated Pellet Capsules (SM-1) in Combination With Temozolomide in Subjects With Refractory or Recurrent Gliomas: Phase I Trial

The aim of this clinical trial is to evaluate the safety, preliminary effectiveness, and pharmacokinetic profiles of SM-1 (Obitrexate Fumarate Enteric-coated Pellet Capsules) combined with temozolomide, and conduct systematic dose exploration for the treatment of refractory or recurrent high-grade gliomas in adult patients. The core focus is to screen the optimal clinical dose regimen of SM-1, fully monitor adverse reactions, and preliminarily observe the anti-tumor efficacy of the combination regimen. The main questions it aims to answer are:

• What is the safety profile and tolerability of different dose cohorts of SM-1 in combination with temozolomide in patients with refractory or recurrent high-grade gliomas?
• What are the pharmacokinetic characteristics of SM-1 across different dose levels, supporting accurate dose optimization for subsequent clinical medication?
• Can the optimized SM-1 combined regimen exert preliminary anti-tumor effectiveness in patients with refractory or recurrent high-grade gliomas, and confirm the recommended Phase II dose? Researchers will enroll eligible patients and assign them to different gradient dose groups of SM-1 for dose-escalation exploration, match with standardized temozolomide combination therapy, comprehensively collect full-cycle safety data, and preliminarily evaluate the clinical anti-tumor efficacy of different dose combinations to determine the optimal safe and effective therapeutic dose for subsequent large-scale clinical trials.

Inclusion Criteria:

1. Voluntarily sign the informed consent form.

2. Age ≥ 18 years, with no restriction on gender.

3. Patients with pathologically confirmed recurrent high-grade glioma (including grade III and IV, excluding brainstem tumors) after standard therapy.

   Definition of recurrence: confirmed recurrence by re-biopsy or surgery, or definite recurrence by MRI with at least one measurable intracranial tumor lesion per the RANO criteria (see Appendix 1 for details).

4. At least 4 weeks have elapsed between major surgery (excluding puncture/biopsy) and the first dose of study drug.

5. At least 3 months have elapsed between the last radiotherapy session and enrollment.

6. Expected survival > 3 months.

7. KPS score ≥ 60.

8. Stable or tapering dose of corticosteroids for at least 5 days prior to dosing.

   Adequate organ function, meeting all of the following criteria:

9. Hepatic function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (upper limit of normal), or ≤ 5 × ULN in case of liver metastasis; total bilirubin ≤ 1.5 × ULN.

   Renal function: Creatinine clearance ≥ 60 mL/min (calculated by the Cockcroft-Gault equation).

   Hematological function: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L, hemoglobin ≥ 9.0 g/dL.

   Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% as measured by echocardiogram.

10. Patients must use effective contraception from the start of screening until 6 months after the end of the study. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study drug.

11. Patients are fully informed of the study procedures, contents, and potential adverse reactions, and are willing and able to complete the study in accordance with the clinical trial protocol.

Exclusion Criteria:

1. Received any anti-cancer therapy within 28 days prior to the first dose of study drug, including radiotherapy, biological agents (antibodies, immunomodulators, cytokines, etc.), chemotherapeutic agents (subjects who received nitrosourea drugs within 42 days prior to the first dose are excluded), or traditional Chinese medicines with anti-tumor indications; or participation in any clinical study treatment within ≤28 days prior to the first dose of study drug.
2. History of immunodeficiency, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.
3. Conditions affecting oral drug absorption, such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.
4. Patients with a clear bleeding tendency, e.g., gastrointestinal bleeding, hemorrhagic gastric ulcer; history of melena or hematemesis within 2 months prior to dosing; or at risk of visceral hemorrhage.
5. Received hematopoietic cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or erythropoietin) within 7 days prior to the first dose of study drug.
6. Unresolved toxicity from prior anti-tumor therapy, i.e., not returned to baseline or Grade 0-1 per NCI CTCAE Version 5.0 (except alopecia).
7. Known hypersensitivity to study drugs (SM-1 and temozolomide), their excipients, or dacarbazine.
8. Known history of psychoactive substance abuse, alcoholism, or drug addiction.
9. Hepatitis B surface antigen (HBsAg)-positive subjects with peripheral blood hepatitis B virus deoxyribonucleic acid (HBV-DNA) titer above the upper limit of normal at the study center; subjects with positive hepatitis C virus (HCV) antibody must undergo further HCV RNA testing, with positive HCV RNA quantification; positive human immunodeficiency virus (HIV) or syphilis test results.
10. History of any of the following diseases within 6 months prior to the first dose of study drug: severe or unstable angina pectoris, myocardial infarction, coronary artery revascularization, congestive heart failure, cerebrovascular events (including transient ischemic attack), etc.
11. History of pulmonary embolism within 6 months prior to the first dose of study drug; history of thrombosis, pulmonary embolism, or deep vein thrombosis (except when controlled by anticoagulant therapy, with subjects on a stable dose for ≥2 weeks).
12. Any clinically significant infection, i.e., any acute viral, bacterial, or fungal infection requiring specific treatment (anti-infective therapy must be completed ≥7 days prior to study initiation).
13. Any unhealed wounds, fractures, or ulcers within 28 days prior to the first dose of study drug; other serious uncontrolled conditions, including uncontrolled diabetes (glycosylated hemoglobin ≥9% within 28 days prior to enrollment in patients with a history of diabetes) or clinical symptoms of unstable congestive heart failure.
14. ≥Grade 2 peripheral neuropathy within 14 days prior to enrollment.
15. Patients on antiepileptic medications (except those with stable dose levels for ≥14 days prior to the first dose of study drug) or with grand mal seizures not effectively controlled by medication.
16. History of other malignancies, unless progression-free for ≥5 years with low risk of recurrence as judged by the investigator, or patients with carcinoma in situ.
17. History of torsade de pointes or congenital long QT syndrome.
18. Hypertensive patients with poorly controlled blood pressure, or blood pressure readings during screening with systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg.
19. ≥Grade 2 arrhythmia per NCI CTCAE Version 5.0, symptomatic bradycardia, or QTcF >450 ms in males and >470 ms in females (QT interval corrected using Fridericia's formula: QTcF = QT/RR^0.33).
20. Severe electrolyte imbalance as judged by the investigator.
21. Pregnant or lactating women.
22. Patients with life-threatening diseases or psychiatric disorders that may increase the risk of study drug administration or interfere with the interpretation of study results, or conditions that may reduce compliance with study procedures, or patients whom the investigator deems unsuitable for inclusion.