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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diffuse Midline Glioma (DMG); Glioblastoma (GBM); High Grade Glioma (III or IV)
• Intervention / Treatment: Drug: FZ-AD005

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mengli zhou; Phone Number: 00-86-021-58953355; Email: mlzhou@fd-zj.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Sun Yat-sen University Cancer Center
      • Contact: ZHENGZHENG GUO; Phone Number: 021-58953355; Email: mlzhou@fd-zj.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily signed Informed Consent Form;
2. Age 18-70 years, both male and female;
3. 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;

4. 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);

5. 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;

6. At least one measurable lesion at baseline (RANO 2.0 )
7. 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);
8. 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;
9. Estimated life expectancy ≥12 weeks;
10. Normal coagulation function, with no risk of active bleeding;
11. Cardiopulmonary function: Left ventricular ejection fraction (LVEF) ≥50%; pulse oxygen saturation (SpO2) ≥95% on room air at rest, with no dyspnea at rest;

12. 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);

13. All acute toxicities from prior antitumor therapy or surgical procedures must have resolved to baseline severity or NCI CTCAE Version 6.0 Grade ≤1;
14. 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;
15. Good compliance.

Exclusion Criteria:

1. Prior treatment with other anti-DLL3 targeted antibody therapies or other DLL3-directed treatments, or ADC drugs containing DXd payload;
2. 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;
3. Subjects with any contraindications to magnetic resonance imaging (MRI) (e.g., cardiac pacemaker, non-removable metal implants, etc.);
4. History of other malignancies within the past 3 years (except for specific low-risk tumors that have been radically treated);

5. 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);

6. Receipt of live vaccine within 4 weeks prior to first dose;
7. 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);
8. 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;
9. Extracranial metastases or diffuse leptomeningeal disease confirmed by imaging (MRI)/cerebrospinal fluid (CSF) cytology;
10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage despite appropriate intervention;
11. 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;

12. 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;

13. Other serious systemic diseases, including but not limited to diabetes mellitus not effectively controlled;
14. Subjects with poorly healing wounds, ulcers, or fractures;
15. Patients who underwent major surgery or serious trauma within 4 weeks prior to first dose;
16. 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;
17. 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;
18. Active tuberculosis, active syphilis, history of immunodeficiency, positive human immunodeficiency virus (HIV) antibody, or other immunodeficiency diseases;
19. 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;
20. Definite history of mental illness;
21. Known history of psychoactive substance abuse, alcoholism, or drug addiction;
22. Pregnant or lactating women;
23. Uncontrolled seizures (seizure within 14 days prior to enrollment or requirement for increased antiepileptic drug dosage);
24. Clinically significant intracranial hemorrhage (>Grade 1 acute/subacute hemorrhage);
25. Any other condition that the investigator considers unsuitable for participation in this clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FZ-AD005	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The dose limiting toxicity ( DLT)	To determine the dose limiting toxicities (DLTs) of FZ-AD005	21 Days (first cycle)
Maximum Tolerable Dose (MTD)	To determine the maximum tolerated dose (MTD) and/or recommended doses for expansion (RDEs). RDEs will not exceed MTD.	Screening up to study completion, assessed up to 36 months
Adverse Events (AEs）	To check the numbers of AEs happened during the course of trial.	Screening up to study completion, assessed up to 36 months
Disease control rate(DCR)	To evaluate the [Complete Response (CR) + Partial Response (PR)+ Stable Disease] of FZ-AD005 according to RANO 2.0	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti Drug Antibody (ADA)	To check the" Anti Drug Antibody" develops in participants against the FZ-AD005 through blood sample	Up to 36 months
Time to peak (Tmax)	To measure the time to reach the maximum contraction of Total Antibody, Free DXd and FZ-AD005 in study participants	Up to 18 weeks
Terminal elimination half-life (t1/2)	To measure the time of Total Antibody, Free DXd and FZ-AD005 will take to eliminate half of it's concentration from participants.	Up to 18 weeks
Maximum observed plasma concentration (Cmax)	To measure the maximum concentration participants obtained of Total Antibody, Free DXd and FZ-AD004 in their blood plasma.	Up to 18 weeks
Area under the concentration-time curve (AUC 0-∞) from time 0 to infinity	To measure the drug profile for absorption, distribution, metabolism and excretion for Total Antibody, Free DXd and FZ-AD005 in participants blood plasma	Up to 18 weeks
Time to Cmax (Tmax)	To measure the time to reach the maximum contraction of Total Antibody, Free DXd and FZ-AD005 in study participants	Up to 18 weeks
Objective Response Rate (ORR)	To evaluate the objective response rate (ORR) [Complete Response (CR) + Partial Response (PR)] of FZ-AD005 according to RANO 2.0	Up to 12 months
Progression free survival(PFS)	Progression-free survival (PFS) was defined as the interval from the first dose start date to the date of disease progression defined as documented progressive disease (PD) or death from any cause, whichever occurs first.	Up to 36 months
Duration of Response(DOR)	Duration of Response was defined as the duration of overall response measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).	Up to 36 months
Overall Survival (OS)	overall survival was defined as the time from the date of the first dose start date to the date of death due to any cause	Up to 36 months

Collaborators and Investigators

• Sponsor: Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 2, 2026
• First Submitted That Met QC Criteria: March 2, 2026
• First Posted (Actual): March 6, 2026

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma
• Other Study ID Numbers: F0041-102

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No