Stem Cell Rescue Therapy for Glioblastoma

(hSTAR GBM Trial)

Recruiting at 1 trial location

Overseen By Melissa Bratley, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Leland Metheny

Disqualifiers: Immunosuppression, HIV, Pregnancy, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you should not have had prior chemotherapy for glioblastoma and that post-operative steroids should be tapered to a certain level before enrollment.

What data supports the effectiveness of the drug combination used in the Stem Cell Rescue Therapy for Glioblastoma?

Research shows that temozolomide (TMZ) has high response rates in treating certain brain tumors, and combining carmustine (BCNU) with O6-benzylguanine (BG) has been studied for its activity in treating resistant malignant gliomas. These findings suggest potential effectiveness in glioblastoma treatment. ^{1 2 3 4 5}

Is Stem Cell Rescue Therapy for Glioblastoma safe for humans?

Research shows that treatments involving carmustine (BCNU) and temozolomide (TMZ) can cause myelosuppression (a decrease in bone marrow activity leading to fewer blood cells) as a significant side effect. The combination of these drugs has been tested in humans, and while it is feasible, it may lead to blood-related toxicities, especially with long-term use. ^{4 6 7 8 9}

What makes the Stem Cell Rescue Therapy for Glioblastoma unique?

This treatment is unique because it combines gene therapy with chemotherapy, using a modified gene (MGMT-P140K) to protect healthy cells from the toxic effects of chemotherapy drugs like Carmustine and Temozolomide, allowing for higher doses to be used against the tumor while reducing side effects. ^{4 8 10 11 12}

What is the purpose of this trial?

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.

Research Team

Leland Metheny, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults aged 18-70 with newly diagnosed, supratentorial glioblastoma or gliosarcoma who've had a significant portion of their tumor surgically removed. They should have an expected survival of at least 12 weeks, be in good physical condition (ECOG 0-1 or Karnofsky ≥70), and not have received prior chemotherapy for GBM. Participants must not have certain genetic mutations (unmethylated MGMT without IDH1/IDH2 mutation) and should be stable enough to undergo an autologous transplant.

Inclusion Criteria

Negative screening for Hepatitis B, C, and HIV

Patient must be considered clinically stable

I can provide 10 slides or a sample of my tumor for testing.

Exclusion Criteria

I have been cancer-free or in remission for at least 2 years.

Inability to undergo repeated MRI evaluation or allergy to Gadolinium-containing contrast agent

Active illicit drug use or diagnosis of alcoholism

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive 6 weeks of standard of care radiotherapy

6 weeks

Stem Cell Mobilization

Participants undergo stem cell mobilization after radiation therapy

2-4 weeks

Chemotherapy

Participants receive chemotherapy with O6-benzylguanine, temozolomide, and carmustine

Variable, based on dose escalation

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Carmustine
• Filgrastim
• O6-benzylguanine
• P140K-MGMT
• Photon Based Radiotherapy
• Temozolomide

Trial Overview The study tests the effectiveness of P140K MGMT hematopoietic stem cells combined with O6-benzylguanine, temozolomide, and carmustine chemotherapy on patients post-surgery. It aims to make bone marrow more resistant to chemo so higher doses can target tumor cells while sparing the bone marrow.

Participant Groups

Group I: stem cell mobilization after radiation therapy Experimental Treatment 6 Interventions

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.

Carmustine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as BiCNU for:

• Brain tumors
• Multiple myeloma
• Hodgkin's disease
• Non-Hodgkin's lymphoma

Approved in European Union as Carmubris for:

• Brain tumors
• Multiple myeloma
• Hodgkin's disease
• Non-Hodgkin's lymphoma

Approved in Canada as BCNU for:

• Brain tumors
• Multiple myeloma
• Hodgkin's disease
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Leland Metheny

Lead Sponsor

Trials

6

Recruited

80+

Andrew Sloan, MD

Lead Sponsor

Trials

2

Recruited

90+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

The novel compound EPIC-0307 enhances the effectiveness of temozolomide (TMZ) in treating glioblastoma by inhibiting DNA damage repair proteins and reducing the expression of MGMT, a key factor in TMZ resistance.

EPIC-0307 works by disrupting the PRADX-EZH2 interaction, which leads to increased expression of tumor suppressor genes and promotes cell cycle arrest and apoptosis in GBM cells, thereby restoring sensitivity to TMZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EPIC-0307-mediated selective disruption of PRADX-EZH2 interaction and enhancement of temozolomide sensitivity to glioblastoma via inhibiting DNA repair and MGMT. Xin, L., Tan, Y., Zhu, Y., et al.[2023]

In a phase II trial involving 32 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a 25% objective response rate, indicating its potential as an effective second-line treatment after PCV chemotherapy.

TMZ was generally well tolerated, with hematological side effects being the most common, and a median time to progression of 8 months for those who responded, suggesting it could be a viable option for patients who do not respond to initial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. van den Bent, MJ., Chinot, O., Boogerd, W., et al.[2020]

In a study using human glial tumor xenografts in athymic mice, the combination of the AGT inhibitor dBG with BCNU or TMZ allowed for higher doses of these drugs to be used, resulting in significant tumor growth delays, especially in tumors with high AGT activity.

TMZ was found to be less toxic and more effective than BCNU against certain glioblastoma xenografts, and the combination of TMZ with dBG enhanced its efficacy, particularly in tumors with higher AGT levels, indicating that targeting AGT can improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. Kokkinakis, DM., Bocangel, DB., Schold, SC., et al.[2018]

In a phase II trial involving 18 patients with nitrosourea-resistant malignant glioma, the combination of O(6)-benzylguanine (O(6)-BG) and carmustine (BCNU) did not result in any partial or complete tumor responses, indicating limited efficacy of this treatment regimen.

While no tumor regression was observed, five patients experienced stable disease for varying durations (up to 18 weeks), but the treatment was associated with significant hematopoietic toxicity, affecting 12 patients with grade 3 or higher side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. Quinn, JA., Pluda, J., Dolan, ME., et al.[2021]

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., et al.[2018]

In a phase I trial involving 23 patients with recurrent or progressive malignant glioma, the maximum-tolerated dose (MTD) of carmustine (BCNU) combined with O(6)-benzylguanine (O(6)-BG) was determined to be 40 mg/m², administered at 6-week intervals.

The study demonstrated that O(6)-BG effectively inhibits the DNA repair protein AGT, which is responsible for resistance to alkylnitrosourea therapy, paving the way for further investigation in a phase II trial for treating nitrosourea-resistant malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. Friedman, HS., Pluda, J., Quinn, JA., et al.[2017]

Transplanting bone marrow cells that express the MGMT-P140K mutant significantly protects against the toxic effects of the combination therapy of O(6)-benzylguanine (BG) and BCNU in mice, improving blood counts and survival rates.

The MGMT-P140K-transduced cells allowed for a more intense BG and BCNU treatment regimen, resulting in substantial delays in tumor growth, extending the doubling time of glioma xenografts by over 40 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic expression of O(6)-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O(6)-benzylguanine and 1,3-bis-(2-chloroethyl)-1-nitrosourea. Kreklau, EL., Pollok, KE., Bailey, BJ., et al.[2020]

The study determined that the maximum tolerated dose of temozolomide (TMZ) when combined with a fixed dose of BCNU is 80 mg/m2, with myelosuppression identified as the dose-limiting toxicity at 90 mg/m2.

In a cohort of 24 patients with malignant gliomas, the combination treatment showed a median overall survival of 132 weeks for anaplastic astrocytomas and 69 weeks for glioblastomas, indicating potential efficacy but also highlighting challenges with long-term treatment due to hematologic toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy. Raizer, JJ., Malkin, MG., Kleber, M., et al.[2018]

In a study involving four dogs, the combination of BCNU and temozolomide (TMZ) was successfully used as a reduced-intensity conditioning regimen, allowing for stable engraftment of gene-modified hematopoietic stem cells (HSCs) without significant blood cell loss.

The modified HSCs provided effective chemoprotection during TMZ treatment, suggesting that this approach could enhance the safety and efficacy of chemotherapy for patients with glioblastoma and other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo selection of autologous MGMT gene-modified cells following reduced-intensity conditioning with BCNU and temozolomide in the dog model. Gori, JL., Beard, BC., Ironside, C., et al.[2021]

The combination of the MGMT inhibitor O6-benzylguanine with either the CDK 4/6 inhibitor LY2835219 or the TGF-βRI inhibitor LY2157299 significantly enhances the sensitivity of temozolomide-resistant glioblastoma cells in vitro, suggesting a potential strategy to overcome treatment resistance.

Importantly, these drug combinations did not affect normal human neurons and astrocytes, indicating a level of safety for surrounding healthy brain tissue while targeting resistant cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells. Das, A., Henderson, FC., Alshareef, M., et al.[2021]

In a clinical trial involving 7 newly diagnosed glioblastoma patients with MGMT(hi) tumors, gene therapy allowed for a significant increase in the number of tolerated O6-benzylguanine (O6BG) and temozolomide (TMZ) chemotherapy cycles, averaging 4.4 cycles per patient compared to 1.7 cycles in historical controls.

The study demonstrated promising outcomes with a median progression-free survival of 9 months and overall survival of 20 months, suggesting that gene therapy could enhance chemotherapy tolerance and effectiveness in treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. Adair, JE., Johnston, SK., Mrugala, MM., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]

2. England pubmed.ncbi.nlm.nih.gov

EPIC-0307-mediated selective disruption of PRADX-EZH2 interaction and enhancement of temozolomide sensitivity to glioblastoma via inhibiting DNA repair and MGMT. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Hematopoietic expression of O(6)-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O(6)-benzylguanine and 1,3-bis-(2-chloroethyl)-1-nitrosourea. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy. [2018]

10. England pubmed.ncbi.nlm.nih.gov

In vivo selection of autologous MGMT gene-modified cells following reduced-intensity conditioning with BCNU and temozolomide in the dog model. [2021]

11. Italy pubmed.ncbi.nlm.nih.gov

MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. [2021]