Selinexor + Temozolomide for Recurrent Glioblastoma

Recruiting at 37 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Bevacizumab, Dacarbazine

Disqualifiers: Uncontrolled illness, Pregnant, Severe COVID-19, others

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

Compensation: Varies

Number of Visits: 2

97 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests selinexor with temozolomide for patients whose brain cancer has returned. Selinexor blocks a protein that helps cancer cells grow, and temozolomide damages their DNA to kill them or stop their growth. Temozolomide is a DNA methylating drug currently used as a first-line treatment in glioblastoma therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

What data supports the effectiveness of the drug combination Selinexor and Temozolomide for treating recurrent glioblastoma?

Temozolomide has shown promise in treating recurrent glioblastoma, with studies indicating it can improve the time before the disease progresses and enhance quality of life, although it may not significantly extend overall survival. This suggests potential benefits when combined with other treatments like Selinexor. ^{1 2 3 4 5}

Is the combination of Selinexor and Temozolomide safe for humans?

Selinexor has been studied in various cancers and is generally considered safe, with common side effects including tiredness, nausea, and loss of appetite. Temozolomide has also been evaluated for safety in treating brain tumors, with known side effects like nausea and low blood cell counts. Both drugs have been used in humans with manageable side effects. ^{4 6 7 8 9}

What makes the drug combination of Selinexor and Temozolomide unique for treating recurrent glioblastoma?

Selinexor is a unique drug because it works by blocking a protein called exportin-1, which helps cancer cells grow and spread. This drug is taken orally and has shown effectiveness in various cancers, making it a novel option when combined with Temozolomide for treating recurrent glioblastoma. ^{6 7 8 9 10}

Research Team

Frances E. Chow

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

Adults with recurrent glioblastoma who've had prior temozolomide and radiotherapy can join. They must have measurable disease, adequate organ function, and a Karnofsky performance status of at least 60%. HIV-positive patients on effective therapy, those cured of hepatitis C, or with controlled hepatitis B are eligible. Pregnant women and breastfeeding mothers cannot participate; others must use contraception.

Inclusion Criteria

I can care for myself but may not be able to do active work.

I am HIV-positive, on treatment, and my viral load is undetectable.

I have received temozolomide and radiotherapy as my first treatment.

Exclusion Criteria

Patients receiving other investigational agents

Patients with uncontrolled intercurrent illness

History of hypersensitivity to dacarbazine

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose-escalation study of selinexor in combination with fixed dose temozolomide to determine the maximum tolerated dose

28 days

Multiple visits for dose escalation and monitoring

Phase II Treatment

Randomized study comparing selinexor and temozolomide combination therapy vs. temozolomide monotherapy

28-day cycles, repeated in the absence of disease progression or unacceptable toxicity

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 2 months up to 2 years

Follow-up visits every 2 months

Treatment Details

Interventions

• Selinexor
• Temozolomide

Trial Overview The trial is testing the safety and effectiveness of adding Selinexor to standard chemotherapy (Temozolomide) for recurrent brain tumors. It's assessing if this combination better controls tumor growth compared to Temozolomide alone.

Participant Groups

Group I: Group II (temozolomide, selinexor) Experimental Treatment 4 Interventions

Patients receive temozolomide PO on days 1-5 of each cycle and selinexor PO on days 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the study and blood sample collection while on study.

Group II: Group I (temozolomide) Active Control 3 Interventions

Patients receive temozolomide PO on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the study and blood sample collection while on study.

Selinexor is already approved in United States, Canada for the following indications:

Approved in United States as Xpovio for:

• Multiple myeloma
• Diffuse large B-cell lymphoma

Approved in Canada as Xpovio for:

• Multiple myeloma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Combining temozolomide with tamoxifen or hypericin significantly enhances its antitumor effects against glioblastoma multiforme by promoting cell death and inhibiting tumor growth.

In an in vivo mouse model, hypericin was particularly effective in boosting the antiglioma activity of temozolomide, suggesting that this combination therapy could be a promising approach for treating malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of glioblastoma cell killing by combination treatment with temozolomide and tamoxifen or hypericin. Gupta, V., Su, YS., Wang, W., et al.[2021]

In a study of 32 patients with recurrent high-grade gliomas who had previously failed PCV chemotherapy, temozolomide showed limited efficacy as a second-line treatment, with only 7 patients experiencing clinical improvement.

The median survival for patients treated with temozolomide was 4 months, and 28% were alive at 6 months, indicating that while it may provide some benefit, the overall response rate was low and not influenced by factors like age or previous treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide as second-line chemotherapy for relapsed gliomas. Trent, S., Kong, A., Short, SC., et al.[2019]

Temozolomide, a new chemotherapy drug, was tested on 16 patients with recurrent glioblastoma multiforme, showing a median overall survival of 6.5 months and a 1-year survival rate of 16%.

The survival outcomes with temozolomide were comparable to other studies, indicating its potential effectiveness, and suggesting the need for further randomized trials to explore its use in initial treatment and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in second-line treatment after prior nitrosurea-based chemotherapy in glioblastoma multiforme: experience from a Portuguese institution. Teixeira, MM., Garcia, I., Portela, I., et al.[2018]

In a study of 151 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma, temozolomide (TMZ) demonstrated significantly better progression-free survival (78.87%) compared to semustine (Me-CCNU) (55.88%), indicating its superior efficacy.

TMZ also had a lower rate of adverse events (29.11%) compared to Me-CCNU (45.15%), suggesting that TMZ is not only more effective but also has a better safety profile for treating these types of brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma]. Sun, J., Yang, XJ., Yang, SY.[2018]

Temozolomide is an oral chemotherapy drug recently approved in the UK for treating recurrent malignant gliomas, showing improved time to progression and quality of life, although it does not significantly extend overall survival.

The drug is generally well tolerated, with serious side effects like myelosuppression and thrombocytopenia occurring in less than 10% of patients, making it a safer option compared to standard chemotherapy protocols that have a response rate of less than 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of temozolomide in recurrent malignant gliomas. Gaya, A., Rees, J., Greenstein, A., et al.[2019]

Selinexor, an oral inhibitor of exportin 1 (XPO1), was found to be safe for patients with advanced solid tumors, with the most common side effects being mild to moderate fatigue, nausea, and anorexia, while serious toxicities were rare.

In a study of 189 patients, selinexor demonstrated some antitumor activity, with 4% of patients achieving a complete or partial response and 17% maintaining stable disease for at least 4 months, indicating its potential as a therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. Abdul Razak, AR., Mau-Soerensen, M., Gabrail, NY., et al.[2022]

Selinexor, an oral medication targeting exportin-1, showed a 6-month progression-free survival rate of up to 17% in patients with recurrent glioblastoma, indicating its potential efficacy as a monotherapy.

The treatment was generally manageable with side effects like fatigue and nausea, and at the highest dose of 80 mg weekly, it led to measurable tumor reductions in 28% of patients, with one complete response observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma. Lassman, AB., Wen, PY., van den Bent, MJ., et al.[2023]

In a phase 2 trial involving 114 patients with heavily pretreated recurrent gynecological cancers, selinexor showed a disease control rate of 30%, indicating its potential effectiveness as a treatment option for ovarian and endometrial cancers.

Common side effects included thrombocytopenia and fatigue, but these were manageable and reversible, with lower-grade adverse events observed in patients receiving a once-weekly dosing schedule compared to twice-weekly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies. Vergote, IB., Lund, B., Peen, U., et al.[2023]

Selinexor, an inhibitor of the exportin 1 (XPO1) receptor, showed significant cytotoxic activity against various solid tumors and acute lymphoblastic leukemia (ALL) xenografts in a study involving in vitro and in vivo testing, with 76% of solid tumor models and 63% of ALL models showing improved event-free survival.

The treatment resulted in objective responses in 4 out of 38 solid tumor xenografts and 25% of ALL xenografts, indicating its potential effectiveness, particularly in tumors with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Attiyeh, EF., Maris, JM., Lock, R., et al.[2023]

Selinexor, when used in combination with dexamethasone or bortezomib and dexamethasone, showed an overall response rate of 29.5% in 44 patients with relapsed or refractory myeloma, indicating its efficacy as a treatment option.

The most common side effects included fatigue and thrombocytopenia, with 56% of patients requiring dose reductions; however, these adjustments did not negatively impact progression-free survival, suggesting that selinexor can be managed safely in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Efficacy and Toxicity of Selinexor: Importance of Patient Characteristics, Dose Intensity and Post Progression Outcomes. Kastritis, E., Gavriatopoulou, M., Solia, E., et al.[2023]

References

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

Enhancement of glioblastoma cell killing by combination treatment with temozolomide and tamoxifen or hypericin. [2021]

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

Temozolomide as second-line chemotherapy for relapsed gliomas. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide in second-line treatment after prior nitrosurea-based chemotherapy in glioblastoma multiforme: experience from a Portuguese institution. [2018]

4. China pubmed.ncbi.nlm.nih.gov

[Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma]. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The use of temozolomide in recurrent malignant gliomas. [2019]

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

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. [2022]

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

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma. [2023]

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

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies. [2023]

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

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. [2023]

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

Real World Efficacy and Toxicity of Selinexor: Importance of Patient Characteristics, Dose Intensity and Post Progression Outcomes. [2023]