Selinexor + Radiation for Brain Cancer

Recruiting at 129 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational drugs, Anti-cancer agents

Disqualifiers: Uncontrolled infection, Organ transplant, others

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

Compensation: Varies

Number of Visits: 6

132 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for children and young adults with certain aggressive brain cancers, specifically diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) with a specific genetic change. The trial aims to determine the safest and most effective dose of a drug called selinexor (a CRM1-nuclear-export-inhibitor) when combined with radiation therapy to shrink tumors. Selinexor blocks a protein that aids cancer cell growth, potentially stopping their growth or killing them. Individuals recently diagnosed with DIPG or HGG, who meet specific criteria related to their tumor's genetic makeup, might be eligible to participate. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving another investigational drug or other anti-cancer agents. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently receiving other anti-cancer agents or investigational drugs.

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

Research has shown that selinexor has been tested for safety in people with brain cancer. In earlier studies, selinexor proved safe for patients with recurrent glioblastoma, a type of brain tumor. Most patients tolerated the treatment well and could use it for extended periods. Although some side effects occurred, the amount of selinexor in the brain remained manageable.

Another study combined selinexor with radiation therapy, similar to the current trial. The aim was to find the highest dose patients could handle without serious side effects. This indicates that selinexor, especially when combined with radiation, has undergone thorough safety checks in similar situations.

Overall, these studies suggest that selinexor, whether used alone or with radiation, can be a safe treatment option for people with brain cancer, though side effects may still occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about selinexor combined with radiation therapy for brain cancer because it offers a novel approach compared to current treatments. While traditional therapies typically focus on targeting cancer cells with radiation and chemotherapy, selinexor works differently by inhibiting a protein called XPO1, which helps in exporting tumor suppressor proteins out of the cell nucleus. This action can potentially slow down or stop the growth of cancer cells. By combining this with radiation therapy, there is hope for a more effective treatment that could yield better outcomes for patients with brain cancer.

What evidence suggests that the combination of selinexor and radiation therapy might be an effective treatment for brain cancer?

Studies have shown that selinexor, when used alone, can shrink tumors in some patients with brain cancer. One study found that about 28% of patients experienced tumor reduction. Some patients continued treatment for over a year, with one remaining on it for 42 months. Selinexor blocks a protein that aids cancer cell growth, potentially stopping or killing these cells. In this trial, participants will receive a combination of selinexor and radiation therapy, which uses high energy to destroy cancer cells. This combination could be promising for treating aggressive brain cancers like DIPG and HGG. ^{1 2 3 4 5}

Who Is on the Research Team?

Adam L. Green

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 21 with newly-diagnosed DIPG or HGG that have a specific genetic mutation (H3 K27M). They must be able to breathe without difficulty, not pregnant or breastfeeding, willing to use birth control if applicable, and have not received prior cancer treatment except surgery. Patients should also have normal organ function.

Inclusion Criteria

I am not breastfeeding or have agreed to stop while on the trial.

I can take care of myself but might not be able to do heavy physical work.

Serum lipase =< 1.5 x ULN

Exclusion Criteria

Patients who have received a prior solid organ transplantation

I have only had surgery and steroids for my brain cancer.

I have macular degeneration, uncontrolled glaucoma, or cataracts.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Chemoradiotherapy

Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor orally on specified days.

5-7 weeks

5 visits per week (in-person)

Maintenance

Patients receive selinexor orally on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Up to 24 cycles (28 days each)

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for the first year, every 6 months for years 2-3, and annually for years 4-5.

Up to 5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Radiation Therapy
• Selinexor

Trial Overview

The trial is testing the safety and effectiveness of Selinexor combined with standard radiation therapy on brain tumors in two phases: finding the highest dose patients can take without severe side effects (Part 1), then seeing how well this dose works against the tumors (Part 2).

How Is the Trial Designed?

Group I: Treatment (selinexor and radiation therapy) Experimental Treatment 4 Interventions

CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor PO on 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a MRI and may undergo a biopsy during screening. MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.

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+

Published Research Related to This Trial

The study successfully established a method for image-guided proton irradiation in mouse brains, allowing for precise targeting and assessment of radiation effects, which is crucial for understanding potential adverse effects in normal tissues.

Using advanced imaging and Monte Carlo simulations, the research demonstrated a clear correlation between the proton dose distribution and DNA damage in the brain, highlighting the method's potential for translational studies in proton therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-precision image-guided proton irradiation of mouse brain sub-volumes. Suckert, T., Müller, J., Beyreuther, E., et al.[2021]

Proton radiotherapy (PRT) is a feasible option for reirradiating patients with recurrent non-small cell lung cancer (NSCLC), with 93% of the 57 patients completing their treatment, but it can lead to significant toxicity, with 42% experiencing grade 3 or higher adverse effects.

The study found that higher doses to the esophagus and concurrent chemotherapy were linked to increased toxicity, and careful consideration of tumor characteristics is essential for optimizing patient outcomes in PRT for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-Institutional Prospective Study of Reirradiation with Proton Beam Radiotherapy for Locoregionally Recurrent Non-Small Cell Lung Cancer. Chao, HH., Berman, AT., Simone, CB., et al.[2022]

In a retrospective analysis of three patients who experienced treatment-related toxicities after intracranial proton therapy, it was found that the relative biological effectiveness (RBE) in the areas of toxicity was significantly higher than expected, leading to increased radiation doses and normal tissue complication probabilities (NTCP).

Multi-field optimized (MFO) treatment plans were developed that successfully reduced the dose-averaged linear energy transfer (LETd), RBE-weighted dose (DRBE), and NTCP in critical organs at risk, suggesting that these strategies could minimize toxicity without compromising the effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment-related toxicities following proton therapy for intracranial tumors. Ödén, J., Toma-Dasu, I., Witt Nyström, P., et al.[2020]

Radiotherapy (RT) for spinal ependymoma, particularly in patients with adverse features like incomplete resection or disseminated disease, resulted in a 5-year overall survival rate of 83.7% and a progression-free survival rate of 70.8% based on a study of 25 patients.

Patients with grade I ependymoma had significantly better survival outcomes compared to those with grade II/III, indicating that tumor grade is an important factor in predicting the effectiveness of RT, while the treatment was generally safe with minimal late toxicities observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of radiotherapy for spinal cord ependymoma with adverse prognostic features: a single-center study. Byun, HK., Yi, S., Yoon, HI., et al.[2019]

In a study of 192 patients with localized prostate cancer, using prostate-based IGRT (P-IGRT) resulted in significantly lower acute gastrointestinal toxicities compared to bony structure-based IGRT (B-IGRT), with rates of 3% versus 11%.

Both P-IGRT and B-IGRT showed similar prostate-specific antigen failure-free survival rates at 3 years (95.5% for P-IGRT and 92.7% for B-IGRT), indicating that P-IGRT can reduce toxicity without compromising tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decreased acute toxicities of intensity-modulated radiation therapy for localized prostate cancer with prostate-based versus bone-based image guidance. Nakamura, K., Mizowaki, T., Inokuchi, H., et al.[2018]

Motexafin gadolinium (MGd) is a novel radiation sensitizer that may improve the effectiveness of whole brain radiation therapy (WBRT) for patients with brain metastases from non-small cell lung cancer (NSCLC).

Current outcomes for NSCLC patients undergoing WBRT are poor, with median survival times only in months, highlighting the need for effective treatments like MGd to enhance therapeutic results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motexafin gadolinium injection for the treatment of brain metastases in patients with non-small cell lung cancer. Thomas, SR., Khuntia, D.[2019]

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]

Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export that targets the protein exportin-1 (CRM1/XPO1), which is overexpressed in many tumor types and plays a crucial role in regulating protein trafficking essential for cancer cell growth and survival.

Preclinical studies have shown that Selinexor exhibits significant antineoplastic activity against various human solid and hematologic cancers, highlighting its potential as a novel therapeutic intervention in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SINE (selective inhibitor of nuclear export)--translational science in a new class of anti-cancer agents. Gerecitano, J.[2023]

In a phase 1b study involving 35 patients with recurrent solid tumors, the combination of oral selinexor and weekly paclitaxel was found to have a maximum tolerated dose of 60 mg, which was well-tolerated with no dose-limiting toxicities reported.

Among patients with ovarian cancer, the treatment showed a 17% response rate and a clinical benefit rate of 58%, with a median progression-free survival of 6.8 months, indicating promising efficacy and manageable toxicity for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer. Westin, SN., Fu, S., Tsimberidou, A., et al.[2023]

In a study involving 1,084 men undergoing three-dimensional conformal radiation therapy (3DCRT) for prostate cancer, the incidence of late gastrointestinal and genitourinary toxicity remained low, with rates ranging from 3% to 12% across different dose levels.

Higher doses of radiation (78 Gy at 2 Gy/fraction) were associated with significantly increased risks of grade 2 or greater toxicity compared to lower doses (68.4 Gy to 79.2 Gy at 1.8 Gy/fraction), indicating that while 3DCRT is generally well-tolerated, careful consideration of dose is crucial for minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term toxicity following 3D conformal radiation therapy for prostate cancer from the RTOG 9406 phase I/II dose escalation study. Michalski, JM., Bae, K., Roach, M., et al.[2022]

In a phase Ib study involving 13 patients with advanced solid tumors, the combination of selinexor and carboplatin/paclitaxel showed some clinical activity, with 3 patients achieving unconfirmed partial responses and 5 patients having stable disease.

The most common treatment-related adverse events were severe blood-related issues, such as neutropenia and leukopenia, affecting 85% of patients, indicating that while the combination therapy has potential, it also carries significant risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study. Thein, KZ., Karp, DD., Tsimberidou, A., et al.[2022]

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 involving 18 patients with early-stage central lung tumors, online adaptive intensity modulated proton therapy (IMPT) significantly reduced the mean dose to the bronchial tree compared to MR-guided radiotherapy (MRgRT), suggesting a safer treatment option with lower toxicity risks.

Both non-adaptive and online adaptive IMPT showed significant reductions in the mean doses to the ipsilateral lung and heart compared to MRgRT, indicating improved dose sparing for organs-at-risk during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of MR-guided radiotherapy accumulated doses for central lung tumors with non-adaptive and online adaptive proton therapy. Rabe, M., Palacios, MA., van Sörnsen de Koste, JR., et al.[2023]

Stereotactic radiotherapy (SRT) is an effective treatment for brain metastases, showing a median survival time of 12.9 months and a 1-year overall survival rate of 53.9% based on a study of 78 patients with 122 intracranial lesions.

Combining SRT with whole brain radiotherapy (WBRT) can further improve survival, particularly in patients with controlled extracranial lesions or multiple intracranial lesions, highlighting the importance of patient condition in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of X-ray stereotactic radiotherapy on brain metastases and prognostic analysis. Wei, W., Deng, ML., Wu, SX., 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]

Motexafin gadolinium (Xcytrin) is a promising radiosensitizer that enhances the effectiveness of radiation therapy for brain tumors, potentially improving treatment outcomes for patients with brain metastases and primary brain tumors.

This agent is well tolerated by patients and shows tumor-specific uptake, suggesting it could be a valuable addition to current treatment strategies in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motexafin gadolinium: a novel radiosensitizer for brain tumors. Forouzannia, A., Richards, GM., Khuntia, D., et al.[2014]

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Objective: To learn the highest dose of selinexor that people with brain cancer can tolerate when given with temozolomide and radiation therapy. Eligibility:.

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A phase 2 study on efficacy, safety and intratumoral pharmacokinetics of oral selinexor (KPT-330) in patients with recurrent glioblastoma (GBM).

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In an ongoing Phase 2 clinical trial, single-agent oral selinexor demonstrated anti-tumor activity in patients with recurrent glioblastoma, ...

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Study Evaluating the Efficacy and Safety of Selinexor (KPT ...

This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas. Recruitment ...