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Intra-tumoral Injection of Natural Killer Cells in High-Grade Gliomas (NK HGG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04254419
Recruitment Status : Not yet recruiting
First Posted : February 5, 2020
Last Update Posted : January 13, 2022
Sponsor:
Information provided by (Responsible Party):
Nationwide Children's Hospital

Brief Summary:
Patients will receive 3 cycles of NK cell infusions over 12 weeks. Each cycle will consist of 1 infusion per week for 3 weeks, followed by a rest week (week 4). Dose will be escalated in an inter-patient stepwise fashion consisting of 4 dose levels.

Condition or disease Intervention/treatment Phase
High Grade Glioma Biological: NK cells Phase 1

Detailed Description:
Patient enrollment will follow a 3+3 design. Patients will receive 3 cycles of NK cell infusions over 12 weeks. Each cycle will consist of 1 infusion per week for 3 weeks, followed by a rest week (week 4). Dose will be escalated in an inter-patient stepwise fashion consisting of 4 dose levels until dose limiting toxicities are observed or the recommended phase II dose is determined.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Intra-Tumoral Injections of Autologous Ex Vivo Expanded Natural Killer Cells in Children With Recurrent High Grade Glioma
Estimated Study Start Date : July 2022
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: NK cell infusion

For source PBMCs from the patient, up to 3ml/kg (maximum 150ml) of heparinized peripheral blood will be drawn. NK cell product will be manufactured by a GMP facility. Once the NK cell goes through the appropriate procedures, it will undergo a lot release testing and cryopreservation by day 14 for infusion.

If NK cells fail to meet release criteria or are insufficient in number for the dose level assigned, collection of PBMCs may be repeated up to 2 additional times.

Duration of study therapy is up to 12 weeks and nine doses of NK cells.

Biological: NK cells

Natural killer cells will be taken from the patients peripheral blood cell collection. The administration of the cells will be done via an Ommaya intra-cavitary/intra-tumoral device.

Once the infusion is ready for administration patients will be admitted to the infusion unit for monitoring. NK cells will be administered through the Ommaya in approximately 2 milliliters over approximately 2 minutes; followed by 1 milliliter preservative-free normal saline flush over approximately 1 minute.





Primary Outcome Measures :
  1. Incidence of adverse events from NK cells [ Time Frame: 36 months ]
    To identify the incidence of adverse events from autologous natural killer cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via Ommaya reservoir in patients with recurrent high-grade glioma. This will be evaluated using the CTCAE version 5

  2. Maximum tolerated dose [ Time Frame: 36 months ]
    To establish the maximum tolerated dose (MTD) of autologous natural killer cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via Ommaya reservoir in patients with recurrent high-grade glioma. MTD will be the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity during cycle 1 of therapy


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 6 months ]
    To determine the overall survival, defined as the percentage of patients in the study who are alive at 6 months following start of treatment


Other Outcome Measures:
  1. NK cell antitumor activity [ Time Frame: 36 months ]
    To assess the antitumor activity based on imaging and cytology of autologous NK cell administration directly into the tumor or the resection cavity.

  2. Assessment of the immuno-phenotype of expanded NK cells for high-grade glioma patients [ Time Frame: 36 months ]
    NK cell phenotypes will be measured by mass cytometry (unit of measure= % of nucleated cells)

  3. Assessment of function of expanded NK cells for high-grade glioma patients [ Time Frame: 36 months ]
    NK cell functional potency will be measured as cytotoxicity by calcien- AM cytotoxicity assays (unit of measure= % of patietns with complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), or progressive disease (PD) with calculated 95% confidence intervals)

  4. Assessment of the immune signature based profile [ Time Frame: 36 months ]
    To determine the immune signature-based profile of each patient's tumor as assayed by the NanoString PanCancer IO360 panel

  5. Determination of genetic changes on high-grade gliomas [ Time Frame: 36 months ]
    To determine the o6-methylguanine-DNA-methyltransferase (MGMT) methylation and mutation status of BRAF V600E, ACVR1, ATRX, TP53, H3.3 G34, H3.3/ H3.1 K27 and IDH1, along with the presence or absence of 9p21 (CDKN2A) homozygous deletion as well as PDGFR amplification

  6. Changes of the T-cell Receptor Repertoires [ Time Frame: 36 months ]
    To determine changes in the TCR repertoire diversity using a Nanostring custom reagent that evaluates the VDJ sequences present before and after NK cell treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have a histologically-confirmed recurrent non-metastatic supratentorial WHO Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, and anaplastic pleomorphic xanthoastrocytoma) or WHO Grade IV malignant glioma (glioblastoma multiforme, gliosarcoma, malignant glioma NOS)
  2. Patients should be candidates for resection/open biopsy of the recurrent tumor and be deemed candidate for placement of an Ommaya reservoir placed intra-cavitary/ intra-tumoral; measurable residual tumor after surgery is not required for study entry
  3. Given the lack of a standard of care treatment for children with recurrent grade III/IV gliomas, patients must have completed first-line treatment with 54 Gy of radiation prior to participating in this trial
  4. All patients must be ≥ 3 years of age and <18 years of age at the time of study entry into the study
  5. Lansky score of 50 or greater if ≤ 16 years of age or a Karnofsky score of 50 or greater if >16 years of age
  6. Adequate bone marrow function, without transfusion or growth factors within 21 days of NK cell administration, defined as a white blood cell ≥ 2.5 x 103/microliter, hemoglobin ≥ 9 gm/dL, absolute neutrophil count ≥ 1,000 cells/microliter and platelet count of ≥ 75,000 cells/microliter
  7. Patients must be off systemic steroids (except replacement therapy) for at least 3 days prior to NK cell infusion
  8. Adequate liver function (ALT, AST and alkaline phosphatase < 2 times ULN, bilirubin < 1.5 times ULN), and adequate renal function (BUN or creatinine < 1.5 times ULN) prior to NK cell
  9. Must have recovered from the toxic effects of prior therapy (i.e., NCI-CTCEA version 5 grade 1 or less) 9a. An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy 9b. At least 6 weeks since the completion of any cytotoxic chemotherapy regimen 9c. For targeted agents only, patient should have recovered from any toxicity of the agent and have a minimum of 2 weeks since the last dose 9d. For patients who have received prior bevacizumab, at least 6 weeks is required before starting study treatment
  10. Patients of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation

Exclusion Criteria:

  1. Patients with intra- or extra-CNS metastasis
  2. Tumor involvement that would require ventricular, brainstem or posterior fossa injection or access through a ventricle or risk of ventricular penetration in order to deliver the NK cells
  3. Tumors involving both hemispheres or those involving the subependyma or suspected CSF dissemination
  4. Patients undergoing needle biopsies (Open biopsies are the minimum requirement for enrollment)
  5. Pregnant or lactating patients
  6. Patients on chronic corticosteroid therapy (except for replacement therapy)
  7. Evidence of active uncontrolled infection or unstable or severe intercurrent medical conditions. All subjects must be afebrile at baseline (i.e., < 38.0 Celsius [C])
  8. Any medical condition that precludes surgery
  9. Prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) > 1.5 x ULN
  10. Patients with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV), or an auto- immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible
  11. Evidence of bleeding diathesis or use of anticoagulant medication or any medication which may increase the risk of bleeding. If the medication can be discontinued >1 week prior to NK cell infusion then the subject may be eligible following consultation with the principal investigator (PI)
  12. Subjects with significant systemic or major illnesses including but not limited to: congestive heart failure, ischemic heart disease, kidney disease or renal failure, organ transplantation, or significant psychiatric disorder
  13. History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the subject's ability to participate or inability to obtain informed consent because of psychiatric or complicating medical problems

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04254419


Contacts
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Contact: Melinda Triplet, RN 614-722-6039 Melinda.Triplet@nationwidechildrens.org
Contact: Lori Jewell 614-722-6576 Lori.Jewell@nationwidechildrens.org

Locations
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United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Contact: Melinda Triplet, RN    614-722-6039    Melinda.Triplet@nationwidechildrens.org   
Principal Investigator: Mohamed S AbdelBaki, MD         
Sponsors and Collaborators
Nationwide Children's Hospital
Investigators
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Principal Investigator: Mohamed S AbdelBaki, MD Nationwide Children's Hospital
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Responsible Party: Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT04254419    
Other Study ID Numbers: STUDY00000659
First Posted: February 5, 2020    Key Record Dates
Last Update Posted: January 13, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue