Engineered NK Cells Containing Deleted TGF-BetaR2 and NR3C1 for the Treatment of Recurrent Glioblastoma

Phase 1

Recruiting

• Conditions: Recurrent Supratentorial Glioblastoma; Supratentorial Gliosarcoma; Recurrent Gliosarcoma
• Interventions: Biological: Cord Blood-derived Expanded Allogeneic Natural Killer Cells; Procedure: Resection

• Registration Number: NCT04991870
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 and NR3C1 (cord blood \[CB\]-NK-TGF-betaR2-/NR3C1-) in treating patients with glioblastoma that has come back (recurrent). CB-NK-TGF-betaR2-/NR3C1- cells are genetically changed immune cells that may help to control the disease.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of escalating doses of off-the-shelf CB-NK-TGF-betaR2-/NR3C1- in patients with recurrent glioblastoma (GBM), occurrence of dose limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD). (Group 1) II. To evaluate the immunological phenotype and anti-tumor function of NK cells in resected tumor tissue after treatment with CB-NK-TGF-betaR2-/NR3C1- in the surgical expansion group. (Group 2)

SECONDARY OBJECTIVE:

I. To determine response as measured by Response Assessment in Neuro-Oncology (RANO), duration of clinical response, progression free survival (PFS), time to progression (TTP), and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Monitoring immune responses following CB-NK-TGF-betaR2-/NR3C1- dosing, in vivo persistence and expansion of CB-NK-TGF-betaR2-/NR3C1- during treatment, characterization of immune cell subpopulations in the peripheral blood, serum analysis of immune correlates, alloreactivity characterization, and anti-HLA antibody analysis, and CB-NK-TGF-betaR2-/NR3C1- trafficking in tumor microenvironments in the surgical expansion cohort.

II. Tumor tissue from surgical resection will be further analyzed for immune infiltrates, fibrosis, and tumor microenvironment.

OUTLINE: This is a dose-escalation study followed by a dose-expansion study. Patients are assigned to 1 of 2 groups.

GROUP 1: Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 8 doses in the absence of disease progression or unacceptable toxicity.

GROUP 2: Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes on days 0, 7, and 14. Patients undergo standard of care surgical resection on day 15. Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 7, 30, and 90 days.

Study Timeline

• Study First Submitted: 2021-02-24
• Study First Submitted QC: 2021-08-04
• Study First Posted: 2021-08-05
• Study Start: 2023-04-28
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-22
• Last Update Posted: 2024-08-26
• Primary Completion: 2026-01-31
• Study Completion: 2026-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)	Resection	Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes on days 0, 7, and 14. Patients undergo standard of care surgical resection on day 15. Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.
Group 1 (CB-NK-TGF-betaR2-/NR3C1- )	Cord Blood-derived Expanded Allogeneic Natural Killer Cells	Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 8 doses in the absence of disease progression or unacceptable toxicity.
Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)	Cord Blood-derived Expanded Allogeneic Natural Killer Cells	Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes on days 0, 7, and 14. Patients undergo standard of care surgical resection on day 15. Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Incidence of dose-limiting toxicities (DLTs) (Group 1)	Up to 28 days	Will determine maximum tolerated dose and safety of escalating doses of cord blood (CB)-(NK) cells patients with recurrent glioblastoma. A DLT is defined as any grade \>= 3 adverse event assessed as related to CB-NK cells by the investigator (that is, grade \>= 3 adverse drug reaction; grading according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	From definitive histological diagnosis until the time of death, assessed up to 90 days post-treatment	OS will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on OS.
Objective response rate (ORR)	Up to 90 days post-treatment	ORR will be defined as the proportion of patients with tumor size reduction (partial response and complete response, per Response Assessment in Neuro-Oncology \[RANO\] criteria). Will be calculated as the ratio of number of patients with response over number of patients treated, and 95% confidence interval of ORR will be estimated.
Progression-free survival (PFS)	From the start of treatment until the time of first disease progression or relapse (as defined by RANO criteria), or death due to disease, assessed up to 6 months post-treatment	PFS will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on PFS. The point estimate of median PFS and 6-month progression-free survival (PFS6) will be estimated.
Duration of response (DOR)	From the time of initial response until documented tumor progression per RANO criteria, assessed up to 90 days
Time to progression (TTP)	From the date of start of treatment until the tumor progression as defined by RANO, assessed up to 90 days post-treatment	TTP will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on TTP.

Trial Locations

Locations (1)

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States