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

Official title

An Open-Label, Multicenter, Phase I Study of FZ-AD005 Antibody-Drug Conjugate in Patients With Recurrent/Refractory High-Grade Glioma (HGG)

Overview

An Open Label, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of FZ-AD005 in Patients with HGG, especially in DMG and other Recurrent HGG.

Interventions

• Drug FZ-AD005
  Every 21 days for 1 cycle. Subjects will receive an intravenous infusion of FZ-AD005 until confirmed progression, unaccepted toxicity, or any criterion for withdrawal from the study.

Primary outcome measures

• Maximum Tolerable Dose (MTD) [Time frame: Screening up to study completion, assessed up to 36 months]
• The dose limiting toxicity ( DLT) [Time frame: 21 Days (first cycle)]
• Adverse Events (AEs） [Time frame: Screening up to study completion, assessed up to 36 months]
• Disease control rate(DCR) [Time frame: Up to 36 months]

Secondary outcome measures (10)

• Objective Response Rate (ORR) [Time frame: Up to 12 months]
• Progression free survival(PFS) [Time frame: Up to 36 months]
• Duration of Response(DOR) [Time frame: Up to 36 months]
• Overall Survival (OS) [Time frame: Up to 36 months]
• Anti Drug Antibody (ADA) [Time frame: Up to 36 months]
• Time to peak (Tmax) [Time frame: Up to 18 weeks]
• Terminal elimination half-life (t1/2) [Time frame: Up to 18 weeks]
• Maximum observed plasma concentration (Cmax) [Time frame: Up to 18 weeks]
• Area under the concentration-time curve (AUC 0-∞) from time 0 to infinity [Time frame: Up to 18 weeks]
• Time to Cmax (Tmax) [Time frame: Up to 18 weeks]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-Sen University Cancer Center — Guangzhou

Identifiers

NCT: NCT07455045 · F0041-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗