Stem Cell Rescue Therapy for Glioblastoma

(hSTAR GBM Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Leland Metheny, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Leland Metheny

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

No Placebo Group

Prior Safety Data

Trial Summary

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.

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}

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

I am between 18 and 75 years old.

Negative screening for Hepatitis B, C, and HIV

Patient must be considered clinically stable

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

Trial 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 (Alkylating agents)
• Filgrastim (Corticosteroid)
• O6-benzylguanine (Alkylating agents)
• P140K-MGMT (Virus Therapy)
• Photon Based Radiotherapy (Radiation)
• Temozolomide (Alkylating agents)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

NIH-Clinical Center Bethesda, MD

University Hospitals Cleveland Medical Center Cleveland, OH

Who Is Running the Clinical Trial?

Leland Metheny Lead Sponsor

Andrew Sloan, MD Lead Sponsor

National Cancer Institute (NCI) Collaborator

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] Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy.

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] Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA damage repair factors are important for the TMZ response in patients. Here, we reported a novel compound, called EPIC-0307, that increased TMZ sensitivity by inhibiting specific DNA damage repair proteins and MGMT expression.

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] Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy.

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] Bis-2-chloroethylnitrosourea (BCNU) or temozolomide (TMZ) were tested alone or in combination with the AGT inhibitors O6-benzyl-2'-deoxyguanosine (dBG) or O6-benzylguanine (BG) against human glial tumor xenografts growing s.c. in athymic mice. Four glioblastoma (SWB77, SWB40, SWB39, and D-54) and one anaplastic oligodendroglioma (SWB61) xenografts having O6-alkylguanine-DNA alkyltransferase (AGT) activities of 75, 45, 10, 45 fmol/mg protein.

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] We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas.

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

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018] To investigate the efficacy and safety of temozolomide (TMZ) and lomustine (CCNU) in malignant brain gliomas.

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] The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma.

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] The major mechanism of tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is the DNA repair protein O(6)-methylguanine DNA methyltransferase (MGMT). This repair system can be temporarily inhibited by the free base O(6)-benzylguanine (BG), which depletes cellular MGMT activity and sensitizes tumor cells and xenografts to BCNU. In clinical studies, the combination of BG and BCNU enhanced the myeloid toxicity of BCNU, thereby reducing the maximum tolerated dose. We have shown previously that retroviral expression of the P140K mutant of MGMT (MGMT-P140K) in murine and human hematopoietic cells produces significant resistance of bone marrow cells to low-dose, combination BG and BCNU treatment in vivo. In the current study, we investigated the ability of bone marrow transplantation with MGMT-P140K-transduced hematopoietic cells to protect against an intensive antitumor treatment regimen of combination BG and BCNU in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The donor marrow cells underwent in vivo BG and BCNU selection before transplantation, allowing infusion of a highly selected population of transduced cells. Tolerance to the intensive BG and BCNU treatment was markedly improved in secondary MGMT-P140K-transplanted mice (n = 19) compared to untransplanted mice (n = 15), as indicated by blood counts and survival rate. The dose-intensified BG and BCNU therapy produced significant growth delays of glioma xenografts in MGMT-P140K-transplanted mice, extending the tumor doubling time by >40 days. These results demonstrate that MGMT-P140K-transduced bone marrow protects against BG and BCNU combination therapy in vivo and allows dose-intensified treatment of tumor xenografts.

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] We conducted a study to determine the dose-limiting toxicity of an extended dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's ability to deplete O6-alkylguanine-DNA-alkyltransferase and the synergistic activity of these two agents. Patients with malignant gliomas who had undergone radiation therapy were eligible. Patients were treated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ was started at 50 mg/m2 and increased in 10-mg/m2 increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of starting TMZ. A standard phase 1 dose-escalation scheme was used with 3 patients per cohort. Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were treated. The dose-limiting toxicity was myelosuppression at 90 mg/m2 of TMZ. The total number of cycles given was 73 (median number was 2). Six patients (25%) required a dose reduction in BCNU, and six were removed from study for hematologic toxicity after cycle 1; three patients overlapped. The median time to progression and overall survival were, respectively, 82 and 132 weeks for anaplastic astrocytomas and 14 and 69 weeks for glioblastomas. We conclude that the combination of BCNU and the extended dosing schedule of TMZ is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80 mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2. This is the recommended dose for phase 2, but myelosuppression after cycle 1 suggests that long-term treatment may be difficult.

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] Chemotherapy with 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ) is commonly used for the treatment of glioblastoma multiforme (GBM) and other cancers. In preparation for a clinical gene therapy study in patients with glioblastoma, we wished to study whether these reagents could be used as a reduced-intensity conditioning regimen for autologous transplantation of gene-modified cells. We used an MGMT(P140K)-expressing lentivirus vector to modify dog CD34(+) cells and tested in four dogs whether these autologous cells engraft and provide chemoprotection after transplantation. Treatment with O(6)-benzylguanine (O6BG)/TMZ after transplantation resulted in gene marking levels up to 75%, without significant hematopoietic cytopenia, which is consistent with hematopoietic chemoprotection. Retrovirus integration analysis showed that multiple clones contribute to hematopoiesis. These studies demonstrate the ability to achieve stable engraftment of MGMT(P140K)-modified autologous hematopoietic stem cells (HSCs) after a novel reduced-intensity conditioning protocol using a combination of BCNU and TMZ. Furthermore, we show that MGMT(P140K)-HSC engraftment provides chemoprotection during TMZ dose escalation. Clinically, chemoconditioning with BCNU and TMZ should facilitate engraftment of MGMT(P140K)-modified cells while providing antitumor activity for patients with poor prognosis glioblastoma or alkylating agent-sensitive tumors, thereby supporting dose-intensified chemotherapy regimens.

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] Label="BACKGROUND" NlmCategory="BACKGROUND">Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-βRI inhibitor) seeking to overcome GB treatment resistance.

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

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. [2021] Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.