The main objective of this clinical study is to evaluate the safety and tolerability of NK-92/5.28.z and to determine the maximum tolerated dose or maximum feasible dose (MFD). Recommended phase 2 doses both for intraoperative injections only (RP2Diio) and repetitive injections (RP2Dri) will be determined. Frequent side effects and target organs of toxicity and their severity, duration and reversibility will be determined. Furthermore, pharmacokinetics and pharmacodynamics will be examined. In addition, potential signs of anti-tumor activity of NK-92/5.28.z cells will be analyzed. In the separate "CAR2BRAIN-Check" and "CAR2BRAIN-CheckR" cohorts, combination therapy of NK-92/5.28.z with the anti-PD-1 antibody Ezabenlimab (BI 754091) will be tested.
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.
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.
Age ≥ 18 years
Anti-angiogenic therapy e.g. with bevacizumab in the last four weeks prior to study entry
Previous anti-PD-1 or anti-PD-L1 directed checkpoint inhibitor therapy (only "CAR2BRAIN-Check" cohort)
Coagulation disorder (INR>1.4 or PTT>50sec) or anticoagulation in therapeutic dosage
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.
Single group
NK-92/5.28.z
Biological/VaccineIntracranial application of NK-92/5.28.z, 1x10E7-1x10E8
Ezabenlimab
DrugIntravenous infusion of Ezabenlimab 240mg q 3 weeks
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
Maximum tolerated dose (MTD) or maximum feasible dose (MFD) for NK-92/5.28.z
Period of detectability of NK-92/5.28.z cells in blood and cerebrospinal fluid (CSF) during the first 24 weeks after NK-92/5.28.z application with qPCR.
qPCR detection of NK-92/5.28.z in blood or CSF
Cytokine profile in the blood and the cerebrospinal fluid.
NK-92- and/or CAR 5.28.z-directed immune response.
Objective response rate.
Progression-free survival.
Overall survival.
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Johann Wolfgang Goethe University Hospital
Lead sponsor
DRK Blutspendedienst Baden-Württemberg-Hessen gGmbH
Collaborator
Georg-Speyer-Haus
Collaborator
LOEWE Center Frankfurt Cancer Institute
Collaborator
German Cancer Research Center
Collaborator
