Telaglenastat + Radiation Therapy + Temozolomide for Astrocytoma

Recruiting at 24 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Prior chemotherapy, Prior brain radiation, Uncontrolled illness, Active malignancy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 5.5-6.5 weeks

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must be on a stable or decreasing dose of corticosteroids and antiepileptic therapy before joining the trial.

What data supports the effectiveness of the treatment Telaglenastat + Radiation Therapy + Temozolomide for Astrocytoma?

Research shows that combining temozolomide (a chemotherapy drug) with radiation therapy can improve survival rates in patients with certain types of brain tumors, like glioblastoma. This suggests that using temozolomide with radiation might also be effective for treating astrocytoma. ^{1 2 3 4 5}

Is the combination of Telaglenastat, Radiation Therapy, and Temozolomide safe for humans?

Temozolomide (TMZ) is generally well tolerated and safe, with common side effects like fatigue, nausea, and vomiting. However, it can cause serious blood-related issues like myelodysplastic syndrome and aplastic anemia, though these are rare. When combined with radiation therapy, common side effects include neutropenia (low white blood cell count), anemia, and dizziness, but severe blood-related toxicities are uncommon. ^{6 7 8 9 10}

What makes the treatment with Telaglenastat, Radiation Therapy, and Temozolomide unique for astrocytoma?

This treatment is unique because it combines Telaglenastat, a drug that targets cancer cell metabolism, with radiation therapy and Temozolomide, a chemotherapy drug known to enhance the effects of radiation by making cancer cells more sensitive to it. This combination aims to improve treatment effectiveness by attacking the cancer from multiple angles. ^{1 11 12 13 14}

What is the purpose of this trial?

This phase 1b trial studies the side effects and best dose of telaglenastat in combination with radiation therapy and temozolomide in treating patients with IDH-mutated diffuse or anaplastic astrocytoma. Telaglenastat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving telaglenastat with radiation therapy and temozolomide may work better than surgery, radiation therapy, and temozolomide in treating patients with IDH-mutated diffuse astrocytoma or anaplastic astrocytoma.

Research Team

Sani Kizilbash, MD, MPH

Principal Investigator

Mayo Clinic Cancer Center LAO

Eligibility Criteria

This trial is for patients with IDH-mutated diffuse or anaplastic astrocytoma. They must have certain blood levels, organ function, and no evidence of tumor in the lower brain or spine. Participants need to be over 16 years old, not pregnant, willing to use contraception, and able to give consent. Those with severe illnesses or a second active cancer are excluded.

Inclusion Criteria

My cancer has a specific IDH mutation.

I am on a stable blood thinner dose without bleeding or clotting issues.

Hemoglobin > 9.0 g/dL (within 14 days prior to registration)

Exclusion Criteria

I have never used Gliadel wafers.

I am not pregnant or breastfeeding.

I have not had radiation therapy to my brain or overlapping areas of my head and neck.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive telaglenastat orally twice daily, temozolomide once daily, and undergo radiation therapy 5 days a week for up to 5.5 weeks (diffuse astrocytoma) or 6.5 weeks (anaplastic astrocytoma)

5.5-6.5 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months

Treatment Details

Interventions

• Radiation Therapy
• Telaglenastat Hydrochloride
• Temozolomide

Trial Overview The trial tests telaglenastat combined with radiation therapy and temozolomide chemotherapy on patients with specific types of brain tumors (astrocytomas). It aims to find the best dose of telaglenastat that's effective when used alongside standard treatments like surgery and radiation.

Participant Groups

Group I: Treatment (telaglenastat, temozolomide, RT) Experimental Treatment 4 Interventions

Patients receive telaglenastat PO BID 7 days a week, temozolomide PO QD 7 days a week, and undergo RT 5 days a week for up to 5.5 weeks (diffuse astrocytoma) or 6.5 weeks (anaplastic astrocytoma) in the absence of disease progression or unacceptable toxicity.

Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

In a study of 67 patients with low-grade pituitary tumors, the combination of temozolomide (TMZ) and radiotherapy showed a significantly higher total effective rate (91.89%) compared to radiotherapy alone (70.00%).

The combined treatment resulted in greater reductions in serum levels of prolactin, insulin-like growth factor-1, and growth hormone, indicating enhanced efficacy in managing hormone levels associated with pituitary tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors. Cui, J., Shen, J., Ru, X., et al.[2022]

In a study of 27 patients with newly diagnosed high-grade gliomas, the combination of temozolomide (TMZ) and radiation therapy (RT) demonstrated promising efficacy, with a median overall survival of 19 months and a one-year survival rate of 81.2%.

The treatment was well tolerated with no drug toxicity-related mortality, indicating a favorable safety profile, especially in patients under 50 years old and those who had debulking surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The outcomes of concomitant radiation plus temozolomide followed by adjuvant temozolomide for newly diagnosed high grade gliomas: the preliminary results of single center prospective study. Shawky, H., Abo Hamar, AH., Galal, S., et al.[2020]

In a study of 165 glioblastoma patients, the extent of tumor resection was the only factor associated with longer survival, indicating that surgical removal of the tumor is crucial for improving outcomes.

The use of Gliadel wafers significantly increased the risk of adverse events, especially in patients with recurrent tumors, with those receiving eight wafers facing a 3-fold higher risk of adverse events and a 5.6-fold higher risk of site-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. De Bonis, P., Anile, C., Pompucci, A., et al.[2018]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

In a study of 9 patients with brain metastases from lung adenocarcinoma, the combination of intensity-modulated radiation therapy (IMRT) and temozolomide (TMZ) resulted in a high objective response rate of 77.8%, with one complete response and six partial responses, confirming the efficacy of this treatment approach.

Patients receiving the combination treatment experienced fewer severe adverse effects compared to those who only received IMRT, with no grade ≥3 hematologic toxicities reported, and an improvement in quality of life was noted, indicating that the addition of TMZ is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. Li, J., Chai, X., Cao, Y., et al.[2020]

Temozolomide (TMZ) can cause severe drug-induced toxic hepatitis, as demonstrated in a case where a patient developed significant liver issues after 5 weeks of treatment for glioblastoma, highlighting the importance of monitoring liver function during therapy.

To prevent serious complications, including potentially life-threatening conditions, it is crucial to monitor liver enzyme levels twice weekly during TMZ treatment and to discontinue the drug immediately if hepatitis is suspected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced liver damage. A case report. Becker, F., Hecht, M., Schmidtner, J., et al.[2021]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a retrospective study of 62 patients with anaplastic glioma, the combination of temozolomide (TMZ) and radiation therapy (RT) did not show a significant improvement in progression-free survival compared to RT alone, with median times of 14.8 months for TMZ-RT and 16.7 months for RT alone.

However, patients receiving TMZ-RT had a longer median overall survival of 34.1 months compared to 27.4 months for those treated with RT alone, suggesting a potential benefit of the combination therapy that warrants further investigation through prospective randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined temozolomide and radiation as an initial treatment for anaplastic glioma. Tham, CK., See, SJ., Tan, SH., et al.[2018]

The combination of Gliadel wafers with concurrent radio-chemotherapy using temozolomide (TMZ) in 24 patients with glioblastoma multiforme resulted in a median overall survival of 19.2 months and a median progression-free survival of 12.3 months, indicating a potential benefit of this treatment approach.

While the treatment was generally well tolerated, 10 patients experienced significant toxicity leading to premature discontinuation of TMZ, highlighting the need for careful monitoring of hematological and digestive side effects during this multimodal therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. Miglierini, P., Bouchekoua, M., Rousseau, B., et al.[2018]

The combination of temozolomide and radiation therapy is safe and well tolerated in patients with newly diagnosed glioblastoma, with only mild to moderate nonhematologic toxicities observed during treatment.

Patients treated with this regimen had a median survival of 16 months, with 58% surviving at one year and 31% at two years, indicating that this treatment may effectively prolong survival, especially in younger patients and those who had surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. Stupp, R., Dietrich, PY., Ostermann Kraljevic, S., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. [2018]

2. Egypt pubmed.ncbi.nlm.nih.gov

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors. [2022]

3. Ireland pubmed.ncbi.nlm.nih.gov

Comparative evaluation of radiochemotherapy with temozolomide versus standard-of-care postoperative radiation alone in patients with WHO grade III astrocytic tumors. [2018]

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

In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide. [2018]

5. England pubmed.ncbi.nlm.nih.gov

The outcomes of concomitant radiation plus temozolomide followed by adjuvant temozolomide for newly diagnosed high grade gliomas: the preliminary results of single center prospective study. [2020]

6. Austria pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. [2020]

10. Germany pubmed.ncbi.nlm.nih.gov

Temozolomide-induced liver damage. A case report. [2021]

11. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

12. Australia pubmed.ncbi.nlm.nih.gov

Combined temozolomide and radiation as an initial treatment for anaplastic glioma. [2018]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. [2018]

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

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. [2022]