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

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.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma Multiforme; Supratentorial Gliosarcoma; Glioblastoma Multiforme, Adult; Supratentorial Glioblastoma
• Intervention / Treatment: Biological: P140K-MGMT; Drug: O6-benzylguanine; Drug: temozolomide; Drug: Filgrastim; Drug: carmustine; Radiation: Photon Based Radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Melissa Bratley, RN; Phone Number: 1-800-641-2422; Email: CTUreferral@uhhospitals.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
      • Contact: Leland Metheny, MD; Phone Number: 216-844-0130; Email: Leland.metheny@uhhospitals.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with histologically confirmed, newly diagnosed, supratentorial glioblastoma or gliosarcoma who have undergone tumor resection are eligible up to 35 days postoperatively. Participants with primarily infratentorial disease, or with multifocal, or leptomeningeal dissemination of disease will be excluded. In general, participants will not have > 1 cm residual measurable or evaluable disease after surgical tumor resection.
• Participant must have unmethylated MGMT
• Absence of IDH1 or IDH2 mutation on tumor tissue by a CLIA-approved immunohistochemistry or DNA sequencing test on local testing.
• Participants aged 18 years or older.
• ECOG performance status 0-1or Karnofsky ≥ 70.
• Life expectancy of at least 12 weeks.
• No plan for hypofractionated radiation therapy

• Adequate hematologic and hepatic function:

  • CBC/differential obtained within 28 days prior to registration:

    • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 Note: the use of G-CSF or other intervention to achieve Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 is acceptable)
    • Platelets ≥ 50,000 cells/mm3 (Note: the use of transfusion or other intervention to achieve Platelets ≥ 50,000 cells/mm3 is acceptable)
    • Hemoglobin ≥ 9.0 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥9.0 g/dl is acceptable)

  • Adequate hepatic function within 28 days prior to registration:

    • Bilirubin ≤ 3 ULN
    • ALT and AST ≤ 3 x ULN
• Participants of child-bearing potential must agree to use single barrier contraception from time of trial entry to completion of the last cycle of chemotherapy.
• Must be willing and able to understand and provide informed consent.
• Participant must be considered to be clinically stable.
• The participant will be identified as a candidate for an autologous transplant via an evaluation by a transplant physician per standard of care.
• No evidence of active infection.
• Participant must have the ability to understand and willingness to sign an informed consent document.

Exclusion Criteria:

• Any known medical or hereditary condition associated with immunosuppression; or other medical illness, which may jeopardize participant safety.
• Pregnant or lactating women. There is data to indicate that BCNU and TMZ is teratogenic and carcinogenic. Thus, its use in pregnant women would confer unnecessary risk to the fetus.
• Participants with a corrected DLCO or FEV1 < 50% of predicted.
• Participants with known diagnosis heart failure or cardiac insufficiency and an LVEF of < 40%.
• Inability to undergo repeated MRI evaluation; or allergy or intolerance of Gadoliniumcontaining contrast agent.
• Active illicit drug use or diagnosis of active alcoholism.
• Prior diagnosis of any malignant disease with the exception of non-melanomatous skin cancer, or carcinoma in situ of the cervix, bladder, prostate, or breast, unless the participant has been disease-free/in remission for ≥2 years prior to date of study enrollment.
• Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness.
• Serologic status reflecting active hepatitis B or C infection. Individuals that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive individuals will be excluded).

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: stem cell mobilization after radiation therapy; 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.

Biological: P140K-MGMT; 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; Drug: O6-benzylguanine; O6BG is a low molecular-weight purine analog which selectively and irreversibly inactivates the DNA-repair enzyme, O6- alkylguanine DNA-alkyltransferase.; Other Names: BG; Drug: temozolomide; 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; Other Names: TMZ; Drug: Filgrastim; 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.; Other Names: G-CSF,Granulocyte-Colony Stimulating Factor; Drug: carmustine; BCNU is a lipid soluble agent which has alkylating properties, plus an isocyanate metabolite which interferes with DNA and RNA synthesis.; Other Names: BCNU,bis-chloronitrosourea; Radiation: Photon Based Radiotherapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	proportion of participants experiencing a grade 3 or higher AE/SAE	Up to 30 days post-treatment
Overall Survival	Median overall survival in months.	Up to 15 years post-treatment
Percent of participants able to complete treatment	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.	10 years after start of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myelosuppression	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.	5 years
Detection of P140K transduced BG and TMZ resistant cells	% of patients with detectable P-140K-MGMT	5 years
Enrichment of P140K-MGMT	What % of patients have enrichment of P140K-MGMT.	5 years
Tumor Response using imaging	Tumor response assessed via iRANO criteria	5 years
PFS using imaging	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	5 years

Collaborators and Investigators

• Sponsor: Leland Metheny
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Leland Metheny, MD, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2023
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: September 13, 2021
• First Posted (Actual): September 22, 2021

Study Record Updates

• Last Update Posted (Actual): September 10, 2026
• Last Update Submitted That Met QC Criteria: September 8, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Biological Factors; Carbohydrates; Dacarbazine; Triazenes; Imidazoles; Amides; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Granulocyte Colony-Stimulating Factor; Nitrosourea Compounds; Urea; Nitroso Compounds; Temozolomide; Carmustine; O(6)-benzylguanine; Filgrastim
• Other Study ID Numbers: CASE5320; 1U01CA236215-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie or influence the results observed from the study.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Investigators who provide a methodologically sound proposal for use of requested data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

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