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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating glioblastoma or gliosarcoma, aggressive brain tumors. It combines chemotherapy drugs, including Carmustine and Temozolomide, with a special stem cell technique that may protect healthy cells while targeting cancerous ones. Participants should have recently undergone surgery to remove most of their tumor and must not have certain genetic markers, such as IDH1 or IDH2 mutations, in their tumor. The study aims to determine if these treatments can more effectively stop tumor growth and improve outcomes. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatments in this trial have varying safety levels in humans. The FDA has approved Carmustine for treating glioblastoma, indicating its safety for similar conditions. Studies indicate it is usually well-tolerated, though some patients might experience side effects like low blood cell counts or lung issues.

O6-benzylguanine has been tested and found generally safe, with no significant toxicity in participants. However, it can enhance the effects of other drugs, necessitating careful monitoring.

The P140K-MGMT gene therapy has been used safely in complex studies, and earlier trials showed it does not cause major blood-related problems. This suggests a promising safety profile, though additional data would be beneficial.

Temozolomide, another FDA-approved treatment for brain cancer like glioblastoma, is generally safe for adults. However, older patients might experience a significant drop in white blood cells. Its widespread use supports its safety record.

Overall, past research has shown these treatments to be generally safe, but participants should be aware of possible side effects and discuss any concerns with their doctors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for glioblastoma, which typically involves surgery, radiation, and chemotherapy drugs like temozolomide, the stem cell rescue therapy offers a novel approach. Researchers are excited about this treatment because it uses stem cell mobilization after radiation therapy to potentially enhance the body’s ability to recover and target cancer cells more effectively. This therapy also incorporates P140K-MGMT, which may improve the effectiveness of chemotherapy drugs such as carmustine and O6-benzylguanine, by protecting healthy cells and allowing higher doses to be used against cancer cells. This innovative combination of stem cell technology and enhanced chemotherapy holds promise for improving patient outcomes in a condition known for its aggressive nature.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

In this trial, participants will receive stem cell mobilization after radiation therapy. Previous studies have shown that temozolomide significantly improves survival in patients with glioblastoma when combined with radiation therapy. Research indicates that carmustine can also be beneficial, with some studies showing it can extend life by a few months. O6-benzylguanine may enhance carmustine's effectiveness by making tumor cells more responsive to treatment. Early findings suggest that using P140K MGMT-modified stem cells might protect healthy cells during chemotherapy, allowing for higher doses to target the tumor. This approach could potentially lead to better treatment outcomes. ^{4 5 6 7 8}

Who Is on the Research Team?

Leland Metheny, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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]

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]

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]

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 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 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]

Citations

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The efficacy of carmustine wafers for older patients with ... The present case-control study shows that carmustine wafers can prolong survival by 3.2 months, which is similar for younger patients with GBM in previous ...

2. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/1471-2407-10-30

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity ... The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months.

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Carmustine as a Supplementary Therapeutic Option for ... Previous research assessing the effectiveness of carmustine wafer has found a significant increase in overall survival (OS) by 2–4 months in ...

4. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT00046878

Carmustine and O(6)-Benzylguanine in Treating Patients ... O(6)-benzylguanine may increase the effectiveness of carmustine by making tumor cells more sensitive to the drug. PURPOSE: Phase II trial to study the ...

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Efficacy and safety of carmustine wafers, followed by ... The primary endpoint was the 2-year overall survival rate in glioblastoma patients with protocol treatment. Results. From October 2015 to April ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/18940042/

Safety profile of carmustine wafers in malignant glioma Carmustine (1,3-bis [2-chloroethyl]-1-nitrosourea, or BCNU) wafers are approved for recurrent glioblastoma and newly diagnosed malignant glioma (MG).

7. surgicalneurologyint.com surgicalneurologyint.com/surgicalint-articles/safety-and-efficacy-of-carmustine-bcnu-wafers-for-metastatic-brain-tumors/

Safety and efficacy of carmustine (BCNU) wafers for ... BCNU wafers are a safe and a potentially efficacious adjunct to surgery and radiation for improving local disease control in metastatic brain tumors.

8. mayoclinic.org mayoclinic.org/drugs-supplements/carmustine-intravenous-route/description/drg-20067151

Carmustine (intravenous route) - Side effects & uses Carmustine injection is used alone or together with other medicines to treat certain type of brain tumors (eg, glioblastoma, brainstem glioma, medulloblastoma, ...