A Phase I, Open-Label, Single/Multiple Dose, Dose-escalation Study to Evaluate the Safety, Tolerability and Antitumor Activity of TX103 CAR-T Cell Injection (TX103) in Subjects With Recurrent or Progressive Grade 4 Glioma.
This is a phase I, open-Label, single/multiple dose, dose-escalation study to evaluate the safety, tolerability and antitumor activity of anti-B7-H3 CAR-T cell injection (TX103) in subjects with recurrent or progressive Grade 4 Glioma.The study also plan to explore the Maximum Tolerated Dose (MTD) and determine the Recommended Phase II Dose (RP2D) of the CAR-T cell therapy.
• Subjects must voluntarily participate in the study and sign a written informed consent document; subjects should be willing and able to follow and complete study procedures.
• Male or female subjects aged 18 to 75 years (both inclusive).
• Subject must have histologically diagnosed grade 4 glioma, such as glioblastoma, grade 4 astrocytoma, diffuse hemispheric glioma, according to 2021 WHO Classification of Tumors of the CNS. Subjects must have had experienced disease recurrence or progression\* after surgery combined with Stupp regimen (concurrent radiotherapy and temozolomide (TMZ) followed by adjuvant TMZ) and are not candidate for re-resection. For subjects harboring specific gene mutations, such as NTRK gene fusion or BRAF V600E mutation, they must have also progressed on corresponding mutation-directed therapies before enrollment.
• \* Disease recurrence or progression must be confirmed by radiographic or histopathological diagnosis.
• Subjects with confirmed B7-H3 positive\* (≥30%) tumor expression by immunohistochemistry (IHC) in either primary or recurrent tumor tissue.
• \*B7-H3 positive rate is defined as the percentage of B7-H3 positive tumor cells in non-necrotic tumor tissue.
• Subjects with KPS score of ≥60.
• Subjects should have adequate venous access for collection of peripheral blood mononuclear cells (PBMCs).
• Subjects with left ventricular ejection fraction (LVEF) ≥ 40% within one month prior to the first dose.
• Subjects with oxygen saturation ≥95% under the resting state.
• Subjects with adequate organ function, as indicated by laboratory test results that meet the following criteria:
‣ Hematological function: Absolute neutrophil count (ANC) ≥1.5×109/L, hemoglobin (Hb) ≥90g/L, platelet count (PLT) ≥100×109/L, absolute lymphocytes count (ALC) ≥0.15×109/L. Blood transfusion, granulocyte (macrophage) colony stimulating factor, recombinant human erythropoietin, recombinant human thrombopoietin, platelet receptor agonist, recombinant human interleukin-11, and other supportive treatments are prohibited within 14 days before the test.
⁃ Liver function: Total bilirubin (TBIL) ≤ 1.5 × ULN, patients with Gilbert's syndrome (persistent or recurrent hyperbilirubinemia, presenting as unconjugated bilirubin in the absence of evidence of hemolysis or liver pathology) Except for elevated erythrocytes; alanine aminotransferases (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN.
⁃ Renal function: serum creatinine (Scr) ≤1.5×ULN.
⁃ Coagulation function (in the absence of anticoagulant therapy): prothrombin time (PT) or activated partial thromboplastin time (APTT) or international normalized ratio (INR) ≤ 1.5×ULN.
⁃ Female subjects of childbearing potential must have a negative serum pregnancy test at screening and if a positive urine test or a negative result cannot be confirmed by urine test.
⁃ Women of childbearing potential (which refer to women who have not been surgically sterilized and pre-menopausal women) should use highly effective and reliable method of contraception (refer to Section 5.3 for contraception method) from the start of the study until 6 months after the last dose of the study drug; sexually active male subjects, if no vas deferens for ligation, consent must be given to the use of highly effective and reliable method of contraception from the start of the study until 6 months after the last dose of the study drug.