PNOC028: Intra-Tumoral Injections of Natural Killer Cells for Recurrent Malignant Brain Tumors

Sponsor

Sabine Mueller, MD, PhD (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05887882

Collaborator

Rally Foundation (Other), Washington University School of Medicine (Other), Nationwide Children's Hospital (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial tests the safety, side effects, and best dose of ex vivo expanded natural killer cells in treating patients with cancerous (malignant) tumors affecting the upper part of the brain (supratentorial) that have come back (recurrent) or that are growing, spreading, or getting worse (progressive). Natural killer (NK) cells are immune cells that recognize and get rid of abnormal cells in the body, including tumor cells and cells infected by viruses. NK cells have been shown to kill different types of cancer, including brain tumors in laboratory settings. Giving NK cells from unrelated donors who are screened for optimal cell qualities and determined to be safe and healthy may be effective in treating supratentorial malignant brain tumors in children and young adults.

Condition or Disease	Intervention/Treatment	Phase
Pediatric Brain Tumor Recurrent Pediatric Brain Tumor Pediatric Supratentorial Neoplasm	Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells Procedure: Implantation	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To determine the safety and tolerability of natural killer (NK) cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via an Ommaya reservoir in patients with recurrent or progressive supratentorial malignant brain tumors.
To determine the recommended phase 2 dose (RP2D) for natural killer (NK) cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via an Ommaya reservoir in patients with recurrent or progressive supratentorial malignant brain tumors.

EXPLORATORY OBJECTIVES:

To determine the 6 months overall survival (OS), defined as the percentage of patients in the study who are alive at 6 months following start of treatment.
To determine the persistence, immuno-phenotype and function of adoptively-transferred expanded NK cells, and correlate the findings with the overall response.
To determine the immune signature-based profile of each patient's tumor. IV. To determine changes in the T-cell receptor (TCR) repertoire diversity before and after Transforming growth factor beta imprinted (TGFβi) NK cell treatment.
To evaluate the effect of systemic steroids on the persistence and efficacy of TGFβi NK cells.
To assess Quality of Life (QOL) and cognitive measures in children and young adults with recurrent or progressive supratentorial malignant brain tumors.

OUTLINE: This is a dose-escalation study.

Participants undergo placement of an Ommaya reservoir and receive universal donor expanded TGF-beta-imprinted NK cells (TGFBi NK cells) intratumorally via Ommaya reservoir in 4-week cycles. Infusions via Ommaya will occur once weekly for three weeks followed by one week of rest. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles. Participants will be followed for 5 years after completion of treatment, or until removal from study or death, whichever comes first.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Intra-Tumoral Injections of Ex Vivo Expanded Natural Killer Cells in Children and Young Adults With Recurrent or Progressive Supratentorial Malignant Brain Tumors

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 31, 2027

Anticipated Study Completion Date :

Jul 31, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Level 2 (3x10^6/m^2) - Starting Dose Enrolled patients must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. Starting dose of 3x10^6/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.	Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion. Other Names: UD TGFβi NK cells UD TGFβi NK cell product Procedure: Implantation Undergo placement of Ommaya reservoir
Experimental: Dose Level 3 (3x10^7/m^2) If no safety or toxicity events are demonstrated by the starting dose cohort, enrolled patients in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10^7/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.	Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion. Other Names: UD TGFβi NK cells UD TGFβi NK cell product Procedure: Implantation Undergo placement of Ommaya reservoir
Experimental: Dose Level 4 (3x10^8/m^2) If no safety or toxicity events are demonstrated by the previous dose cohort, enrolled patients in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10^8/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.	Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion. Other Names: UD TGFβi NK cells UD TGFβi NK cell product Procedure: Implantation Undergo placement of Ommaya reservoir

Arm

Intervention/Treatment

Experimental: Dose Level 2 (3x10^6/m^2) - Starting Dose

Enrolled patients must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. Starting dose of 3x10^6/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.

Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells

The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion.

Other Names:

UD TGFβi NK cells

UD TGFβi NK cell product

Procedure: Implantation

Undergo placement of Ommaya reservoir

Experimental: Dose Level 3 (3x10^7/m^2)

If no safety or toxicity events are demonstrated by the starting dose cohort, enrolled patients in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10^7/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.

Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells

The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion.

Other Names:

UD TGFβi NK cells

UD TGFβi NK cell product

Procedure: Implantation

Undergo placement of Ommaya reservoir

Experimental: Dose Level 4 (3x10^8/m^2)

If no safety or toxicity events are demonstrated by the previous dose cohort, enrolled patients in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10^8/m^2 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement, and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If patients have stable or improved disease, patients may continue to receive therapy for a total of 12 cycles.

Biological: Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells

The TGFβi NK cell product will be manufactured in the Cell Therapy Laboratory at Nationwide Children's Hospital and given via infusion.

Other Names:

UD TGFβi NK cells

UD TGFβi NK cell product

Procedure: Implantation

Undergo placement of Ommaya reservoir

Outcome Measures

Primary Outcome Measures

Proportion of participants with treatment-emergent adverse events [From initiation of study treatment until 30 days from the end of therapy, approximately 1 year]
Adverse events and clinically significant laboratory abnormalities (meeting grade 3, 4, or 5 criteria according to NCI CTCAE) will be summarized by maximum intensity and relationship to study drug(s). Grade 1 and 2 adverse events will be summarized if related to study therapy. Descriptive statistics will be utilized to display the data on toxicity seen. Toxicities will be summarized by tabulation in terms of type, grade and attribution for each dose level of each group of patients studied at the end of the trial.
Recommended Phase II dose (RP2D) [From initiation of study treatment until 30 days from the end of therapy, approximately 1 year]
RP2D is defined as the dose level at which fewer than one-third of participants experience a dose limiting toxicity (DLT)

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 39 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants must have a histologically-confirmed recurrent or progressive, non-metastatic supratentorial World Health Organization (WHO) Grade III/IV malignant brain tumor. Including, but not limited to: anaplastic ependymoma, embryonal tumor, primitive neuroectodermal tumor, atypical teratoid rhabdoid tumor (ATRT) , anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma, glioblastoma multiforme, gliosarcoma, or malignant glioma (NOS), WHO Grade II ependymoma.
Participants 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.
Given the lack of a standard of care treatment for children with recurrent or progressive grade III/IV malignant brain tumors, participants must have completed first-line treatment with radiation and/or chemotherapy prior to participating in this trial.
All participants must be >= 1 year of age and < 39 years of age at the time of entry into the study. The first 3 participants must be >= 8 years of age and < 39 years of age at the time of entry into the study.
Performance Score: Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants <=16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Must have recovered from the acute toxic effects of prior therapy (i.e., NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5, grade 1 or less)

An interval of at least 12 weeks must have elapsed since the completion of radiation therapy.
At least 6 weeks since the completion of any cytotoxic chemotherapy regimen.
At least 12 weeks since the completion of any immunotherapies or cell therapies.
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.
For patients who have received prior bevacizumab, at least 6 weeks is required.

Organ Function Requirements:
Adequate Bone Marrow Function Defined as:

Peripheral absolute neutrophil count (ANC) >750/mm^3.
Platelet count >75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).

Adequate Renal Function Defined as:

A serum creatinine > 1.5 x upper limit normal (ULN) based on age/gender.

Adequate Liver Function Defined as:

Total bilirubin < 1.5 x upper limit of normal (ULN) for age; in presence of Gilbert's syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN.
Alanine aminotransferase (ALT) < 3 x ULN.
Aspartate aminotransferase (AST) < 3 x ULN.

Adequate Neurologic Function Defined as:

Participants with seizure disorder may be enrolled if seizures are well-controlled. Patients on non-enzyme inducing anticonvulsants may be excluded pending interaction(s) with study drug.
Signs and symptoms of neurologic deficit must be stable for > 1 week prior to enrollment.

The effects of Transforming growth factor beta resistant (TGFβi) natural killer (NK) cells on the developing human fetus are unknown. For this reason and because TGFβi NK cells as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 6 months after completion of TGFβi NK cells administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.

Exclusion Criteria:

Participants with evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease, Cerebral spinal fluid (CSF) dissemination or extra-neural disease.
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 TGFβi NK cells.
Participants undergoing needle biopsies only (open biopsies are the minimum requirement for enrollment).
Participants who are receiving any other investigational agents.
Women of childbearing potential must not be pregnant or breast-feeding.
Participants on chronic corticosteroid therapy (except for replacement therapy).
Evidence of active uncontrolled infection or unstable or severe intercurrent medical conditions.
Any medical condition that precludes surgery.
Prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) > 1.5 x ULN.
Participants 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.
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 Study Chairs.
Participants 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.
History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the participants ability to participate or inability to obtain informed consent because of psychiatric or complicating medical problems.