A Phase I Study of FZ-AD005 in Patients With High-Grade Glioma (HGG)

Inclusion criteria

• Voluntarily signed Informed Consent Form;
• Age 18-70 years, both male and female;
• Patients must be able to provide tumor tissue samples (archived tumor tissue within 2 years [maximum 5 years] or fresh core needle biopsy specimen, if possible) for DLL3 testing, with positive assessment results;
• Histopathologically confirmed high-grade glioma, classified according to WHO CNS5 2021 criteria, meeting one of the following characteristics:

Group A (Post-radiotherapy maintenance phase): Diffuse midline glioma (DMG), with H3 K27 alterated by CLIA-certified laboratory; Patients must be in the maintenance treatment phase following new diagnosis and completion of standard first-line radiotherapy; Group B (Recurrent or progressive high-grade glioma): Recurrent or progressive high-grade glioma (WHO CNS5 Grade 3-4). Including but not limited to: IDH wild-type glioblastoma (GBM), IDH-mutant astrocytoma (Grade 3-4), IDH-mutant oligodendroglioma (Grade 3), etc. (Note: Recurrent or progressive DMG patients may be enrolled in this group during dose escalation phase);

• Prior treatment status:

Group A (Post-radiotherapy maintenance phase): Must have completed standard radiotherapy, with enrollment occurring within 2-6 weeks after radiotherapy completion, and no definitive evidence of progressive disease (PD) on post-radiotherapy imaging; Group B (Recurrent or progressive high-grade glioma): Must be recurrent or refractory patients who have failed standard treatment: must have received at least one prior line of standard treatment (including radiotherapy and/or chemotherapy, such as temozolomide), with an imaging evidence of PD; for patients with prior radiotherapy, disease progression must occur >12 weeks after radiotherapy, or must be histopathologically confirmed as tumor recurrence rather than necrosis/pseudoprogression by radiotherapy;

• At least one measurable lesion at baseline (RANO 2.0 )
• Karnofsky Performance Status (KPS) score ≥70 (if patient has slightly lower score solely due to stable focal neurological deficits but can maintain basic daily living with support, 60 is approval);
• If patient is receiving corticosteroids for tumor-related cerebral edema or neurological symptoms, dosage must be stable or decreasing for at least 7 days prior to baseline MRI, with dose ≤5 mg/day dexamethasone (or equivalent dose of other corticosteroids); if increased steroid dosage is required during screening to control cerebral edema due to clinical deterioration, the patient is ineligible;
• Estimated life expectancy ≥12 weeks;
• Normal coagulation function, with no risk of active bleeding;
• Cardiopulmonary function: Left ventricular ejection fraction (LVEF) ≥50%; pulse oxygen saturation (SpO2) ≥95% on room air at rest, with no dyspnea at rest;
• Bone marrow reserve and organ function must meet the following requirements:

Hematology: Absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥90 g/L (without transfusion, erythropoietin [EPO], granulocyte colony-stimulating factor [G-CSF], or other medical supportive treatment within 14 days prior to screening); Coagulation: For subjects not receiving anticoagulation therapy, prothrombin time international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5×upper limit of normal (ULN) (Note: Subjects receiving stable anticoagulation therapy are allowed if parameters are within therapeutic range and no bleeding risk); Liver: Total serum bilirubin ≤1.5×ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN; if Gilbert's syndrome (unconjugated hyperbilirubinemia) is confirmed, total bilirubin ≤3.0×ULN; AST and ALT ≤3×ULN; Kidney: Serum creatinine (Scr) ≤1.5×ULN, or creatinine clearance (Ccr) ≥50 mL/min (calculated by Cockcroft and Gault formula);

• All acute toxicities from prior antitumor therapy or surgical procedures must have resolved to baseline severity or NCI CTCAE Version 6.0 Grade ≤1;
• Within 7 days prior to enrollment, women of childbearing potential must have negative serum or urine pregnancy test; male and female subjects must agree to use effective contraception (e.g., oral contraceptives, intrauterine device, abstinence, or barrier contraception with spermicide) during study drug administration and for 6 months after the last dose;
• Good compliance.

Exclusion criteria

• Prior treatment with other anti-DLL3 targeted antibody therapies or other DLL3-directed treatments, or ADC drugs containing DXd payload;
• History of allergic reaction to exatecan or ≥Grade 3 gastrointestinal toxicity following prior exatecan use, or hypersensitivity to protein components structurally similar to FZ-AD005, or hypersensitivity to excipients of the FZ-AD005 investigational drug;
• Subjects with any contraindications to magnetic resonance imaging (MRI) (e.g., cardiac pacemaker, non-removable metal implants, etc.);
• History of other malignancies within the past 3 years (except for specific low-risk tumors that have been radically treated);
• Failure to meet the following washout period requirements prior to first dose:

Chemotherapy (non-nitrosourea), small molecule targeted therapy: ≤3 weeks (21 days) or 5 half-lives (whichever is longer); Nitrosoureas (e.g., lomustine) or mitomycin C: ≤6 weeks (42 days); Immune checkpoint inhibitors (ICI), antibody drugs (including other ADCs): ≤4 weeks (28 days) or 5 half-lives (whichever is longer); Anti-angiogenic therapy (e.g., bevacizumab): ≤5 weeks (35 days); Radiotherapy: For Treatment Group B: whole brain or involved-field radiotherapy ≤12 weeks; palliative radiotherapy (non-intracranial target lesions) ≤2 weeks (Note: For Treatment Group A subjects, standard first-line radiotherapy prior to this enrollment is not subject to this 12-week restriction, but must meet the specific window requirement for time since radiotherapy completion as stated in the inclusion criteria);

• Receipt of live vaccine within 4 weeks prior to first dose;
• Active infection requiring drug intervention within 2 weeks prior to first dose, or unexplained fever >38°C with elevated procalcitonin results between screening and first dose (subjects with tumor-related fever may be enrolled at investigator's discretion);
• Severe mass effect or risk of brain herniation, defined as: baseline MRI showing midline shift >5 mm, or signs of uncontrolled intracranial hypertension/hydrocephalus; or investigator's judgment that the patient cannot tolerate any degree of treatment-induced cerebral edema;
• Extracranial metastases or diffuse leptomeningeal disease confirmed by imaging (MRI)/cerebrospinal fluid (CSF) cytology;
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage despite appropriate intervention;
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis requiring steroid treatment, or current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be excluded by imaging at screening;
• Serious cardiovascular or cerebrovascular disease or history (including but not limited to the following):

Myocardial infarction or unstable angina within 6 months prior to first dose; Congestive heart failure with cardiac function ≥Grade II (NYHA classification); Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg); Baseline QTcF >450 ms (male) or >470 ms (female); Clinically significant arrhythmia or conduction block requiring drug treatment;

• Other serious systemic diseases, including but not limited to diabetes mellitus not effectively controlled;
• Subjects with poorly healing wounds, ulcers, or fractures;
• Patients who underwent major surgery or serious trauma within 4 weeks prior to first dose;
• Receipt of autologous organ or stem cell transplantation within 3 months prior to first dose, or allogeneic organ (except corneal transplantation) or stem cell transplantation within 6 months prior to first dose;
• Hepatitis B surface antigen (HBsAg) positive with HBV DNA >2000 IU/mL or 10⁴ copies/mL. If HBsAg positive but with low DNA, should receive antiviral treatment according to local treatment guidelines and be willing to receive antiviral treatment throughout the study period; Hepatitis C antibody positive with HCV RNA above the upper limit of normal of the study center;
• Active tuberculosis, active syphilis, history of immunodeficiency, positive human immunodeficiency virus (HIV) antibody, or other immunodeficiency diseases;
• Requirement for systemic corticosteroids (>5 mg/day dexamethasone or equivalent dose of similar drugs) or other immunosuppressants for systemic treatment within 2 weeks prior to first dose or during the study; Note: Topical and inhaled corticosteroids with minimal systemic absorption are permitted; corticosteroids ≤5 mg/day dexamethasone (or equivalent dose) for physiological replacement therapy or treatment of tumor-related symptoms are permitted, provided the subject has stable or decreasing dosage for at least 7 days prior to baseline MRI; short-term (≤7 days) corticosteroids for prophylaxis (e.g., contrast allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity due to contact allergens) are permitted;
• Definite history of mental illness;
• Known history of psychoactive substance abuse, alcoholism, or drug addiction;
• Pregnant or lactating women;
• Uncontrolled seizures (seizure within 14 days prior to enrollment or requirement for increased antiepileptic drug dosage);
• Clinically significant intracranial hemorrhage (>Grade 1 acute/subacute hemorrhage);
• Any other condition that the investigator considers unsuitable for participation in this clinical study.