Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Gliosarcoma

Disease Attributes

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

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.

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.

Given CB-NK-TGF-betaR2-/NR3C1- intratumorally

Cord Blood-derived Expanded Allogeneic Natural Killer Cells

Resection

Shiao-Pei Weathers, MD

Shiao-Pei S. Weathers, MD

Shiao-Pei S Weathers, MD

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.

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.

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

A Phase I Clinical Trial With a Window-of-Opportunity Component of Engineered NK Cells Containing Deleted TGF-ßR2 and NR3C1 in Recurrent Glioblastoma

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Temozolomide

Lenograstim

Carmustine

O(6)-benzylguanine

polysaccharide-K

Adjuvants, Immunologic

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Participants at University Hospitals-Seidman Cancer Center (UH-SCC) will receive stem cell mobilization after 6 weeks of standard of care (SOC) radiotherapy. Followed by SOC chemotherapy.

Ex Vivo Cultured P140K MGMT CD34+ Cells. The transduced cells are a biological product and production is detailed in the Cellular Therapy Lab standard operating procedures and IND 14099

P140K-MGMT

O6BG is a low molecular-weight purine analog which selectively and irreversibly inactivates the DNA-repair enzyme, O6- alkylguanine DNA-alkyltransferase.

O6-benzylguanine

Standard of care, photon-based radiotherapy (60Gy in 30 fractions) will be performed in both arms without concomitant TMZ between to 6 weeks post-operatively. Radiotherapy will be performed at UH-SCC.

Photon Based Radiotherapy

Temozolomide is not directly active but undergoes rapid non-enzymatic conversion at physiologic pHto the reactive compoundMTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylationof DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine

temozolomide

Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology. Endogenous filgrastim is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells, which regulates the production of neutrophils within the bone marrow.

Filgrastim

BCNU is a lipid soluble agent which has alkylating properties, plus an isocyanate metabolite which interferes with DNA and RNA synthesis.

carmustine

Melissa Bratley, RN

Leland Metheny, MD

This phase II trial studies the effect of P140K MGMT hematopoietic stem cells, O6-benzylguanine, temozolomide, and carmustine in treating participants with supratentorial glioblastoma or gliosarcoma who have recently had surgery to remove most or all of the brain tumor (resected). Chemotherapy drugs, such as 6-benzylguanine, temozolomide, and carmustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing. Placing P140K MGMT, a gene that has been created in the laboratory into bone marrow making the bone more resistant to chemotherapy, allowing intra-patient dose escalation which kills more tumor cells while allowing bone marrow to survive.

hSTAR GBM (Hematopoetic Stem Cell (HPC) Rescue for GBM)

Phase II Trial O6-benzylguanine(BG) and Temozolomide(TMZ) Therapy of Glioblastoma Multiforme (GBM) With Infusion of Autologous P140K MGMT+Hematopoietic Progenitors to Protect Hematopoiesis

Individual participant data that underlie or influence the results observed from the study.

To evaluate and compare the feasibility of introducing and expressing P140K MGMT cDNA using a lentiviral-based provirus in autologous hematopoietic stem cells harvested from newly diagnosed IDH-1 WT GBM with unmethylated MGMT promoter using two different sequences of stem cell mobilization.

1. What percent of patients who enter trial can complete treatment.

proportion of participants experiencing a grade 3 or higher AE/SAE

To determine what proportion of patients who receive P140K MGMT transduced CD34 cells tolerate BG and dose escalated TMZ without myelosuppression.

We will report % of patients who suffer grade I-5 SAES related to myelosuppression.

% of patients with detectable P-140K-MGMT

What % of patients have enrichment of P140K-MGMT.

Tumor response assessed via iRANO criteria

PFS measured from the date of initial histological diagnosis to progression (as defined above), death, last contact, or last tumor assessment before the start of further anti-tumor therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Engineered NK Cells Containing Deleted TGF-BetaR2 and NR3C1 for the Treatment of Recurrent Glioblastoma	NCT04991870	Recurrent Glios... Recurrent Supra... Supratentorial ...	Cord Blood-deri... Resection	18 Years -	M.D. Anderson Cancer Center
hSTAR GBM (Hematopoetic Stem Cell (HPC) Rescue for GBM)	NCT05052957	Glioblastoma Mu... Glioblastoma Mu... Supratentorial ... Supratentorial ...	P140K-MGMT O6-benzylguanin... Photon Based Ra... temozolomide Filgrastim carmustine	18 Years - 75 Years	Case Comprehensive Cancer Center
hSTAR GBM (Hematopoetic Stem Cell (HPC) Rescue for GBM)	NCT05052957	Glioblastoma Mu... Glioblastoma Mu... Supratentorial ... Supratentorial ...	P140K-MGMT O6-benzylguanin... Photon Based Ra... temozolomide Filgrastim carmustine	18 Years - 75 Years	Case Comprehensive Cancer Center

Spots Global Cancer Trial Database for supratentorial gliosarcoma