C71
Conditions
Interventions
Group 1: Intracranial application of NK-92/5.28.z (HER2.taNK), 1x10E7-1x10E8 in combination with Ezabenlimab
Sponsors
Goethe-Universität Frankfurt am Main
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1.) Recurrent or refractory HER2-positive glioblastoma or its variant gliosarcoma in which relapse surgery (partial or total) or 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 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
Exclusion criteria: 1.) Anti-angiogenic therapy e.g. with bevacizumab (Avastin). 2.) Previous anti-PD-1 or anti-PD-L1 directed checkpoint inhibitor therapy (only “CAR2BRAIN-CheckR” cohort). 3.) Coagulation disorder (INR>1.4 or PTT>50sec) or anticoagulation at 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1.) To evaluate the safety and tolerability of NK-92/5.28.z cells expressing a transgenic chimeric antigen receptor (CAR) targeting HER2 alone and in combination with Ezabenlimab 2.) Determination of the maximum tolerated dose (MTD) or maximum feasible dose (MFD) for NK-92/5.28.z 3.) Determination of recommended phase 2 doses both for intraoperative injections only (RP2Diio) and repetitive injections (RP2Dri) for NK-92/5.28.z 4.) Assessment of pharmacokinetics and pharmacodynamics | — |
Secondary
| Measure | Time frame |
|---|---|
| 1.) Lack of NK-92- and/or CAR 5.28.z-directed humoral immune response 2.) Immunological, radiological or histological signs of efficacy and tumor penetrating ability of NK-92/5.28.z alone and in combination with Ezabenlimab 3.) Objective response rate 4.) Progression-free survival 5.) Overall survival | — |
Countries
Germany
Contacts
Public ContactMichael Burger
Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main
Outcome results
None listed