Intracranial Injection of NK-92/5.28.z Cells in Combination With Intravenous Ezabenlimab in Patients With Recurrent HER2-positive Glioblastoma (CAR2BRAIN)

March 26, 2024 updated by: Michael Burger, Johann Wolfgang Goethe University Hospital

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

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" cohort, combination therapy of NK-92/5.28.z with the anti-PD-1 antibody Ezabenlimab (BI 754091) will be tested.

Study Overview

Status

Active, not recruiting

Conditions

Study Type

Interventional

Enrollment (Estimated)

42

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

      • Frankfurt, Germany, 60528
        • Johann W. Goethe University Hospital, Department of Neurosurgery
      • Frankfurt, Germany, 60528
        • Johann W. Goethe University Hospital, Senckenberg Institute of Neurooncology
    • Baden-Württemberg
      • Mannheim, Baden-Württemberg, Germany, 68167
        • Neurochirurgische Klinik, Universitätsmedizin Mannheim
    • Rheinland-Pfalz
      • Mainz, Rheinland-Pfalz, Germany, 55131
        • Neurochirurgische Klinik, Universitätsmedizin Mainz

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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-Check" cohort) is being planned. Those patients with planned biopsy may be included into the "CAR2BRAIN-Check" 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.
    • Suspected tumor relapse is located in the wall of an already existing resection cavity.
    • This resection cavity has a volume of at least 2.5 ml or is connected to a ventricle or has a broad connection to the surface of the brain.
    • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NK-92/5.28.z + Ezabenlimab
Intracranial application of NK-92/5.28.z, 1x10E7-1x10E8; intravenous infusion of Ezabenlimab 240mg q 3 weeks
Intracranial application of NK-92/5.28.z, 1x10E7-1x10E8
Intravenous infusion of Ezabenlimab 240mg q 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
Time Frame: 24 weeks
24 weeks
Maximum tolerated dose (MTD) or maximum feasible dose (MFD) for NK-92/5.28.z
Time Frame: 24 weeks
24 weeks
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.
Time Frame: 24 weeks
qPCR detection of NK-92/5.28.z in blood or CSF
24 weeks
Cytokine profile in the blood and the cerebrospinal fluid.
Time Frame: 24 weeks
24 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
NK-92- and/or CAR 5.28.z-directed immune response.
Time Frame: 24 weeks
24 weeks
Objective response rate.
Time Frame: 24 weeks
24 weeks
Progression-free survival.
Time Frame: 24 weeks
24 weeks
Overall survival.
Time Frame: 24 weeks
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2017

Primary Completion (Estimated)

December 31, 2025

Study Completion (Estimated)

June 30, 2026

Study Registration Dates

First Submitted

November 30, 2017

First Submitted That Met QC Criteria

December 19, 2017

First Posted (Actual)

December 27, 2017

Study Record Updates

Last Update Posted (Estimated)

March 27, 2024

Last Update Submitted That Met QC Criteria

March 26, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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