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

Phase I Study of Intra-Tumoral Injections of Autologous Ex Vivo Expanded Natural Killer Cells in Children With Recurrent High Grade Glioma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: High Grade Glioma
• Intervention / Treatment: Biological: NK cells

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lori Jewell; Phone Number: 614-722-6576; Email: Lori.Jewell@nationwidechildrens.org

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
      • Principal Investigator: Mohamed S AbdelBaki, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events from NK cells	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	36 months
Maximum tolerated dose	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	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	To determine the overall survival, defined as the percentage of patients in the study who are alive at 6 months following start of treatment	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
NK cell antitumor activity	To assess the antitumor activity based on imaging and cytology of autologous NK cell administration directly into the tumor or the resection cavity.	36 months
Assessment of the immuno-phenotype of expanded NK cells for high-grade glioma patients	NK cell phenotypes will be measured by mass cytometry (unit of measure= % of nucleated cells)	36 months
Assessment of function of expanded NK cells for high-grade glioma patients	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)	36 months
Assessment of the immune signature based profile	To determine the immune signature-based profile of each patient's tumor as assayed by the NanoString PanCancer IO360 panel	36 months
Determination of genetic changes on high-grade gliomas	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	36 months
Changes of the T-cell Receptor Repertoires	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.	36 months

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Investigators: Principal Investigator: Mohamed S AbdelBaki, MD, Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2023
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: January 31, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: STUDY00000659

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No