Intracranial NK-92 cell injections plus IV ezabenlimab for recurrent HER2‑positive glioblastoma

Multicenter, Open Label, Phase I Study of Intracranial Injection of NK-92/5.28.z Cells in Patients With Recurrent HER2-positive Glioblastoma

This trial will test whether injecting engineered NK-92 immune cells into the brain together with intravenous ezabenlimab is safe and shows signs of benefit in adults with recurrent HER2‑positive glioblastoma.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 42 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Johann Wolfgang Goethe University Hospital (Academic / other)
• Drugs / interventions: bevacizumab, chemotherapy, radiation, methotrexate, Ezabenlimab
• Locations: 5 sites (Heidelberg, Baden-Wurttemberg and 4 other locations)
• Trial ID: NCT03383978 on ClinicalTrials.gov

What this trial studies

This Phase 1 dose‑finding trial delivers NK-92/5.28.z cells directly into the brain at the time of relapse surgery (or by biopsy in a specific cohort) and combines repeated injections with the anti‑PD‑1 antibody ezabenlimab in parallel cohorts. The main goals are to determine safety, the maximum tolerated or feasible dose, and recommended Phase 2 dosing for single intraoperative and repetitive injection schedules. Investigators will monitor adverse events, target organs of toxicity, pharmacokinetics and pharmacodynamics, and look for early signs of anti‑tumor activity. Separate CAR2BRAIN-Check and CAR2BRAIN-CheckR cohorts test the combination with ezabenlimab versus the NK-92 approach alone.

Who should consider this trial

Good fit: Adults (≥18 years) with recurrent or refractory HER2‑positive glioblastoma or gliosarcoma who are candidates for relapse surgery (or planned biopsy for the CheckR cohort), have received prior standard radiotherapy and alkylating chemotherapy when applicable, and have adequate life expectancy and organ function are eligible.

Not a fit: Patients without HER2 expression, those who cannot undergo the required surgery or biopsy, or those with very limited life expectancy or significant organ dysfunction are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could provide a new targeted immunotherapy option that may slow or shrink recurrent HER2‑positive glioblastoma while defining a tolerable dosing strategy.

How similar studies have performed: Early‑phase work with engineered NK cells and CAR-based immunotherapies has shown limited and mixed signals in glioblastoma, so combining intracranial NK‑92 cells with PD‑1 blockade remains largely experimental.

Eligibility criteria

Inclusion Criteria:

1. Recurrent or refractory HER2-positive glioblastoma or its variant gliosarcoma in which relapse surgery (partial or total) or a biopsy (biopsy only for the "CAR2BRAIN-CheckR" cohort) is being planned. Those patients with planned biopsy may be included into the "CAR2BRAIN-CheckR" cohort, if all of the following conditions apply:

   * Biopsy is necessary (as determined by the treating physician) to rule out the differential diagnosis of pseudoprogression prior to relapse surgery.
   * Patients must be candidates for relapse surgery, which must be postponable for four weeks.
2. Prior therapy must include the standard of care for glioblastoma (radiotherapy and alkylating chemotherapy, or at least a part thereof if the therapy was terminated prematurely due to therapy failure or poor tolerance). For patients with non-methylated MGMT-Promotor, prior alkylating chemotherapy is dispensable.
3. Age ≥ 18 years
4. Life expectancy ≥ 3 months
5. Bilirubin ≤ 3x normal, AST ≤ 5x normal, ALT ≤ 5x normal, serum creatinine ≤ 2x upper limit of normal for age, leukocyte count ≥ 3/nl, thrombocyte count ≥ 100/nl and Hb ≥ 8.0 g/dl
6. Blood oxygenation of ≥ 90% as measured by pulse oximetry on room air
7. Women must have a negative serum pregnancy test within 72h prior to the start of the first NK-92/5.28.z cell injection.
8. Sexually active patients must be willing to utilize effective birth control methods throughout the study and for 24 weeks after the last NK-92/5.28.z cell injection. This includes two different forms of effective contraception (e.g. hormonal contraceptive and condom, IUD/IUS and condom) or sterilization.
9. Patients should have been off other antineoplastic therapy for two weeks prior to entry in this study. Temozolomide will be allowed up to 48h preinjection. At the time of inclusion, dexamethasone up to a total dose of 4 mg per day will be allowed if medically indicated.
10. Informed consent explained to and signed by patient; patient given copy of informed consent.
11. Karnofsky performance score of ≥ 70%

Exclusion criteria:

1. Anti-angiogenic therapy e.g. with bevacizumab in the last four weeks prior to study entry
2. Previous anti-PD-1 or anti-PD-L1 directed checkpoint inhibitor therapy (only "CAR2BRAIN-Check" cohort)
3. Coagulation disorder (INR\>1.4 or PTT\>50sec) or anticoagulation in therapeutic dosage
4. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. However, patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
5. Patients with Type I diabetes mellitus not on a stable dose of insulin regimen
6. Psoriatic arthritis (however, patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are permitted provided that they meet all of the following conditions:

   * Rash must cover less than 10% of body surface area
   * Disease is well controlled at baseline and only requiring low potency topical steroids
   * No acute exacerbations of underlying condition within the previous 12 months (not requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids))
7. Patients with clinical or laboratory signs for immunodeficiency or under immunosuppressive medication other than corticosteroids
8. Severe intercurrent infection
9. Known HIV, HBV (defined by detection of HBsAg) or HCV positivity (defined by detection of HCV-IgG)
10. Chronic heart failure NYHA ≥III
11. Patients with a prior solid organ transplantation or allogenic haematopoietic stem cell transplantation
12. Patients unable to undergo MRI
13. Pregnancy or breastfeeding
14. Drug or alcohol abuse
15. Severe psychiatric disorder which might interfere with the study treatment or examination
16. Simultaneous participation in another interventional clinical trial. If a subject participated in a trial testing another IMP, such IMP should have been terminated at least 30 days before inclusion of the subject.

Where this trial is running

Heidelberg, Baden-Wurttemberg and 4 other locations

• Neurochirurgische Klinik, Universitätsklinikum Heidelberg — Heidelberg, Baden-Wurttemberg, Germany (Recruiting)
• Neurochirurgische Klinik, Universitätsmedizin Mannheim — Mannheim, Baden-Wurttemberg, Germany (Recruiting)
• Neurochirurgische Klinik, Universitätsmedizin Mainz — Mainz, Rhineland-Palatinate, Germany (Recruiting)
• Johann W. Goethe University Hospital, Department of Neurosurgery — Frankfurt, Germany (Recruiting)
• Johann W. Goethe University Hospital, Senckenberg Institute of Neurooncology — Frankfurt, Germany (Recruiting)

Study contacts

• Principal investigator: Michael C Burger, PD Dr. med. — Johann W. Goethe University Hospital, Frankfurt am Main, Germany
• Study coordinator: Michael C Burger, PD Dr. med.

Conditions Glioblastoma