Selinexor + Chemotherapy + Radiation for Brain Cancer

Overseen By Theresa Cooley Zgela, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Temozolomide, Selinexor

Must not be taking: Investigational agents

Disqualifiers: Prior brain radiation, Chemotherapy, Severe liver dysfunction, HIV, others

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

Compensation: Varies

Number of Visits: 7

11 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Glioblastoma is a type of brain cancer. Treatments include radiation, chemotherapy, and surgery. But survival rates are poor. Researchers think that the drug selinexor, when combined with chemotherapy and radiation, might help. Objective: To learn the highest dose of selinexor that people with brain cancer can tolerate when given with temozolomide and radiation therapy. Eligibility: People ages 18 and older with brain cancer that has not been treated with chemotherapy or radiation. Design: Participants will be screened under another protocol. Before participants start treatment, they will have tests: Neurological and physical evaluations Blood and urine tests Possible computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain if they have not had one in 3 weeks. Participants will lie in a machine that takes pictures of the body. They may have a dye injected into a vein. Surveys about their well-being Participants will have radiation to the brain for up to 6 weeks. This will usually be given once a day, Monday through Friday. Starting the second day of radiation, participants will take selinexor by mouth once a week. They will take it in weeks 1, 2, 4, and 5. The timing may be changed. Starting the first day of radiation, participants will take temozolomide by mouth once a day until they complete radiation. Participants will have blood tests once per week during treatment. Participants will have a follow-up visit 1 month after they complete treatment. Then they will have visits at least every 2 months for the first 2 years, then at least every 3 months for another year. Visits will include MRIs and blood tests.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Temozolomide when used with radiation therapy for brain cancer?

Research shows that Temozolomide, when combined with radiation therapy, has increased survival rates in patients with malignant gliomas, a type of brain cancer. This combination has shown promising results as a first-line treatment for high-grade gliomas. ^{1 2 3 4 5}

Is the combination of Selinexor, chemotherapy, and radiation therapy safe for humans?

Research shows that combining temozolomide (a chemotherapy drug) with whole-brain radiotherapy has been studied for safety in patients with brain metastases, indicating it is generally safe for human use in this context. ^{6 7 8 9 10}

What makes the Selinexor + Chemotherapy + Radiation treatment unique for brain cancer?

This treatment is unique because it combines Selinexor, a drug that blocks the export of tumor-suppressing proteins from the cell nucleus, with Temozolomide, which can penetrate the blood-brain barrier and enhance the effects of radiation therapy. This combination aims to improve the effectiveness of radiation therapy while potentially preserving quality of life by targeting cancer cells more precisely. ^{6 9 11 12 13}

Research Team

Kevin A Camphausen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with newly diagnosed glioblastoma or gliosarcoma who haven't had chemo or radiation, can undergo radiotherapy and temozolomide treatment, have a certain level of physical function (KPS >70), and agree to use contraception. Excluded are those with uncontrolled infections, severe liver issues, pregnant/nursing women, HIV patients, prior brain RT or chemotherapy for glioma.

Inclusion Criteria

My diagnosis is glioblastoma or gliosarcoma (grade IV astrocytoma).

I am eligible for specific radiation therapy and temozolomide treatment.

Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment and for one month after treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

Exclusion Criteria

I do not have HIV due to potential treatment complications.

I can take oral medication without issues like vomiting or severe diarrhea.

I haven't had significant bleeding or coagulation issues in the last month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Radiation and Chemotherapy

Participants receive radiation therapy and temozolomide daily, with selinexor administered weekly

6 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

11 weeks

1 visit (in-person) at 1 month, then every 2 months for 2 years, then every 3 months for another year

Treatment Details

Interventions

• Radiation Therapy
• Selinexor
• Temozolomide

Trial Overview The trial is testing the highest dose of Selinexor that's tolerable when combined with Temozolomide and generic Radiation Therapy in treating new cases of brain cancer. Participants will receive daily radiation for up to 6 weeks while taking oral Selinexor weekly and Temozolomide daily during this period.

Participant Groups

Group I: 1/Experimental Therapy - Selinexor with Temozolomide and Radiation Experimental Treatment 7 Interventions

Selinexor with temozolomide and radiation

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 study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

Intensity-modulated radiotherapy (IMRT) effectively reduces radiation exposure to healthy tissues, minimizing side effects and enhancing treatment efficiency by allowing for smaller or more frequent doses.

Chemoradiotherapy, particularly using cisplatin and cetuximab, has become a standard treatment for tumors, especially in cases beyond early-stage disease, highlighting its role in improving cancer care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oncological treatment modalities in head and neck cancer]. Saarilahti, K., Lindholm, P.[2018]

In a study of 128 patients with high-grade gliomas, the combination of radiotherapy and temozolomide showed favorable outcomes, with only 9% experiencing grade 3 hematological toxicity and no grade 4 toxicity reported, indicating a manageable safety profile.

Statistical analysis revealed that factors such as age, tumor histology, and the use of temozolomide were linked to improved 2-year overall survival, supporting the efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas. Corsa, P., Parisi, S., Raguso, A., et al.[2022]

Current treatments for brain tumors are often inadequate, leading to ongoing research into the use of concurrent chemotherapy and radiotherapy to improve patient outcomes.

Trials are exploring new agents that can effectively cross the blood-brain barrier and minimize overlapping toxicities, which may enhance the safety and efficacy of combined therapies for brain tumor patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent chemotherapy and radiotherapy in patients with brain tumors. Glantz, MJ., Kim, L., Choy, H., et al.[2005]

In a randomized trial involving 20 patients with multiple brain metastases, stereotactic radiotherapy (SRT) was found to significantly preserve quality of life (QoL) compared to whole-brain radiotherapy (WBRT), particularly in mobility, self-care, and alopecia after 3 months.

Patients receiving SRT reported better physical and social functioning, indicating that SRT not only controls local tumors but also enhances the overall well-being of patients compared to traditional WBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life among patients with 4 to 10 brain metastases after treatment with whole-brain radiotherapy vs. stereotactic radiotherapy: a phase III, randomized, Dutch multicenter trial. Hartgerink, D., Bruynzeel, A., Eekers, D., et al.[2022]

In a study of 45 breast cancer patients undergoing stereotactic radiosurgery (SRS) for brain metastases, 22.2% developed clinically significant radionecrosis (CSRN), with a striking 39.1% of those receiving trastuzumab emtansine (T-DM1) experiencing this complication compared to only 4.5% of those not receiving T-DM1.

The use of T-DM1 was linked to a 13.5-fold increase in the risk of CSRN, likely due to its targeting of reactive astrocytes, which enhances radiation-induced damage and swelling, suggesting that caution is needed when combining T-DM1 with SRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4. Stumpf, PK., Cittelly, DM., Robin, TP., et al.[2020]

Temozolomide (TMZ) was found to effectively radiosensitize two out of three human glioblastoma multiforme (GBM) cell lines when combined with single-dose gamma-irradiation, indicating its potential to enhance the effectiveness of radiation therapy.

In a study involving three genetically characterized GBM cell lines, TMZ demonstrated an additive effect with fractionated irradiation, particularly showing a significant reduction in surviving cells in the AMC 3046 cell line, suggesting that TMZ can improve treatment outcomes for certain GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. van Nifterik, KA., van den Berg, J., Stalpers, LJ., et al.[2018]

Combining CyberKnife stereotactic radiosurgery (SRS) with a dose-dense regimen of temozolomide (TMZ) significantly improved median survival (12 months vs. 7 months) and 6-month progression-free survival (66.7% vs. 18%) in patients with recurrent glioblastoma multiforme (GBM).

While the combination treatment showed better outcomes, over 40% of patients experienced grade 3 hematological toxicity, indicating a need for careful monitoring of side effects in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of CyberKnife re-irradiation and "dose dense" temozolomide for recurrent gliomas. Conti, A., Pontoriero, A., Arpa, D., et al.[2022]

Combining brain radiotherapy (RT) with temozolomide (TMZ) significantly improves the objective response rate (ORR) in patients with brain metastases, with an odds ratio of 2.27, indicating a better response to treatment compared to RT alone.

However, this combination treatment does not lead to a significant improvement in overall survival (OS) or progression-free survival (PFS), and it is associated with increased adverse effects, such as severe nausea and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. Zhao, Q., Qin, Q., Sun, J., et al.[2018]

References

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

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

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

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. [2018]

3. Finland pubmed.ncbi.nlm.nih.gov

[Oncological treatment modalities in head and neck cancer]. [2018]

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

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas. [2022]

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

Concurrent chemotherapy and radiotherapy in patients with brain tumors. [2005]

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

Quality of life among patients with 4 to 10 brain metastases after treatment with whole-brain radiotherapy vs. stereotactic radiotherapy: a phase III, randomized, Dutch multicenter trial. [2022]

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

Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4. [2020]

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

Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. [2018]

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

Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. [2018]

10. India pubmed.ncbi.nlm.nih.gov

Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases. [2018]

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

Chemosensitized radiosurgery for recurrent brain metastases. [2021]

12. Austria pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of CyberKnife re-irradiation and "dose dense" temozolomide for recurrent gliomas. [2022]

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

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. [2018]