Brain Metastasis, Glioblastoma (GBM), Glioblastoma Multiforme (GBM), Malignant Meningioma, Malignant Solid Brain Tumors
Conditions
Keywords
Malignant Solid Brain Tumors, Immunotherapy, Natural Killer Cell, NK Cell
Brief summary
This is a multi-center, open-label investigator-initiated trial (IIT) designed to evaluate the safety, tolerability, and feasibility of combined intracranial and intravenous administration of ex vivo expanded and activated natural killer (NK) cells in adult patients with malignant solid brain tumors who have failed standard treatment modalities. The primary objective is to determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) of the combined NK cell therapy. Secondary objectives include preliminary assessment of anti-tumor activity as measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR) per RANO criteria, and evaluation of the immunological effects of NK cell infusion in the tumor microenvironment and peripheral blood.
Interventions
Intrathecal Administration Combined with Intravenous Infusion of Autologous NK Cells 1. Intracranial/Intrathecal Injection: NK cells are administered into the cerebrospinal fluid via a surgically implanted intracranial Ommaya reservoir or lumbar puncture. This approach successfully bypasses the blood-brain barrier, allowing NK cells to act directly on tumor lesions in the central nervous system. 2. Intravenous Infusion: Following intracranial/intrathecal injection, the patient receives an intravenous infusion of NK cells.
Sponsors
Peking University Third Hospital
Henan Academy of Innovations in Medical Science
Zhengzhou Second Hospital
Qinhuangdao Runze Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 Dose escalation design
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, age 18-70 years old (both ends included) 2. At least one evaluable lesion with previous biopsy or pathohistologic confirmation of malignant central nervous system tumor, with imaging suggestive of continued progression or recurrence after comprehensive treatment 3. Karnofsky Performance Status (KPS) ≥ 60% 4. Life expectancy \> 4 weeks, and must be able to undergo an MRI with contrast 5. Patients who completed radiotherapy or systemic therapies (including temozolomide/bevacizumab or other agents) for at least 4 weeks prior to enrollment. All prior treatment-related toxicities should be defined as ≤ grade 1 (except for toxicities such as alopecia or leukoplakia) according to the Common Terminology Standard for Adverse Events (CTCAE 6.0) 6. Dexamethasone dose ≤ 4 mg/day or equivalent corticosteroid dose, or no dexamethasone administered 7. Must have adequate organ and marrow function as defined below: * White blood cell count (WBC) ≥ 3 x 10\^9/L * Absolute neutrophil count (ANC) \> 1 x 10\^9/L * Hemoglobin (Hb) ≥ 90 g/L * Platelet (PLT) ≥ 80×10\^9/L * Albumin transaminase (ALT) \& albumin transaminase (AST) \< 1.5 × institutional upper limit of normal (ULN) * Serum creatinine (Cr) \< 1.5 x institutional ULN * Total bilirubin \< 1.5 x institutional ULN * PT \& PTT ≤ 1.25 x institutional ULN 8. No obvious hereditary diseases 9. Normal cardiac function with left ventricular ejection fraction \>55% 10. No bleeding and coagulation disorders 11. Absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to NK cell infusion and/or there aren't any indications of meningitis 12. Fertile women must have had a pregnancy test with a negative result within 7 days prior to the start of treatment, and subjects are willing to use contraception (hormonal or barrier method of birth control or abstinence) during the clinical trial and for 6 months after the last cell infusion; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately 13. Signed, written informed consent
Exclusion criteria
1. Active hepatitis B or C virus, HIV infection, or other untreated active infection 2. Pregnant and lactating women 3. Participants with organ failure 4. Participants with a chronic disease requiring immunologic or hormonal therapy 5. Participants with an allergy to immunotherapy and related cells 6. Participants with uncontrolled intercurrent illness 7. Participants with psychiatric illness/social situations that would limit compliance with study requirements 8. Participants with a history of organ transplantation or who are awaiting organ transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) | 3 months following NK cells administration | Defined as the incidence of ≥ Grade 3-4 adverse events related to NK cells according to common terminology criteria for adverse events (CTCAE) v6.0. |
| Incidence of Dose-Limiting Toxicities (DLTs) | 28 days following initial treatment with NK cells | Defined as events attributable to NK cells infusion within 28 days post-infusion. Grade 3 or higher cytokine release syndrome (CRS) lasting more than 2 weeks, according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria; Any NK cells-related AE requiring intubation; Grade 4 non-hematologic toxicities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 3 months following NK cells administration | According to modified RANO criteria, ORR is defined as proportion of subjects with confirmed CR and PR. |
| Duration of response (DOR) | 3 months following NK cells administration | According to modified RANO criteria, DOR is defined as time from the date when a response of confirmed CR/PR is first met to the date of confirmed disease progression or death. |
Countries
China
Contacts
CONTACTChenlong YANG, M.D., Ph.D.
Outcome results
None listed