Engineered NK Cells Containing Deleted TGF-BetaR2 and NR3C1 for the Treatment of Recurrent Glioblastoma
- Conditions
- Recurrent Supratentorial GlioblastomaSupratentorial GliosarcomaRecurrent Gliosarcoma
- Interventions
- Biological: Cord Blood-derived Expanded Allogeneic Natural Killer CellsProcedure: 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: Ommaya catheter will be inserted prior to 1st injection of NK cells (at the time of screening biopsy). Participants will receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes every 4 weeks for up to 8 doses in the absence of disease progression or unacceptable toxicity. Every NK cell Injection is 10 min followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter .
GROUP 2: Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter It will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30, and 90 days.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 25
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Group 1 (CB-NK-TGF-betaR2-/NR3C1- ) Cord Blood-derived Expanded Allogeneic Natural Killer Cells Participants will receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every four weeks 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 Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity. Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection) Resection Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 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