Selinexor for Glioblastoma

No longer recruiting at 17 trial locations

Overseen By Eric Sbar VP of Clinical Development, DO

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Karyopharm Therapeutics Inc

Must not be taking: Nitrosoureas, Bevacizumab

Disqualifiers: Pregnancy, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, selinexor, combined with other treatments for glioblastoma, a type of brain cancer. The study aims to determine the best dose and evaluate the effectiveness of these combinations for both newly diagnosed and recurrent glioblastoma. Participants will receive different combinations of selinexor with standard care treatments, such as radiation therapy, temozolomide (a chemotherapy drug), or other drugs, depending on their specific cancer type. Suitable candidates for this study include those with glioblastoma who have either not started treatment or have experienced a recurrence after initial treatment. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in glioblastoma 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, there are restrictions on certain prior treatments, such as chemotherapy and investigational agents, which must be stopped at least 4 weeks before starting the study treatment.

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

Research has shown that selinexor, whether used alone or with other treatments, is under study for safety in treating glioblastoma, a type of brain cancer. In earlier studies, common side effects of selinexor included nausea, tiredness, and leukopenia (a decrease in white blood cells). These side effects varied in intensity depending on the dose.

When combined with bevacizumab, a treatment already approved for recurring glioblastoma, past data indicate that selinexor has a known safety profile. Bevacizumab can lead to high blood pressure and bleeding but is generally considered safe when used correctly.

For selinexor combined with tumor treating fields (TTField), which use electric fields to stop cancer cells from dividing, studies are ongoing to better understand safety. However, TTField has been used in glioblastoma treatment before and usually causes mild skin irritation where the device is placed.

Studies are also examining how well patients tolerate the combination of selinexor with radiation therapy. Radiation therapy is a standard treatment but can cause tiredness and skin changes at the treatment site.

For the combination of selinexor, temozolomide, and radiation, previous studies focused on identifying the safest dose. Temozolomide is a chemotherapy drug that can cause nausea and low blood cell counts but is commonly used in glioblastoma care.

Lastly, selinexor with lomustine or carmustine, both chemotherapy drugs, has been used in other brain tumor treatments. These drugs can cause similar side effects like nausea and low blood counts, but they are generally manageable.

Overall, these treatments are under study to ensure safety while aiming to effectively treat glioblastoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about selinexor because it offers a fresh approach to treating glioblastoma, a challenging brain cancer. Unlike traditional treatments, which often involve chemotherapy and radiation, selinexor works by selectively inhibiting nuclear export. This means it helps keep tumor-suppressing proteins inside the cell nucleus, potentially stopping cancer cells from growing or spreading. Additionally, selinexor is being tested in combination with other therapies like bevacizumab and tumor-treating fields (TTFields), which could enhance its effectiveness. This innovative mechanism and its versatility in combination therapies make selinexor a promising candidate in the fight against glioblastoma.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research has shown that selinexor may help treat glioblastoma, a type of brain cancer. Studies have found that selinexor can control the disease and even shrink tumors in some cases. In this trial, participants will receive selinexor combined with various treatments. For example, one arm will test selinexor with bevacizumab, a drug that cuts off the blood supply to tumors, to see if they work better together. Other arms will explore selinexor with radiation or chemotherapy. Early research suggests that selinexor may slow tumor growth and help patients live longer. These findings support testing selinexor with different treatments for glioblastoma in this trial. ^{1 2 3 5 6}

Who Is on the Research Team?

Andrew B Lassman, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

Inclusion Criteria

Glioblastoma that is newly diagnosed or relapsed after 1 to 2 line of systemic therapy is eligible for this study

Renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥30 milliliter per minute (mL/min)

Limited to supratentorial disease for Arm E only.

Exclusion Criteria

Participants who are receiving any other investigational agents and /or have had prior therapy including:

For Arms A and B only: Participants who have previously received RT to the brain, Participants who received chemotherapy for the treatment of their glioma, Participants who are being treated with implanted Gliadel wafers

For Arm C: Prior nitrosoureas

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Finding

Participants receive selinexor in combination with standard of care to determine the maximum tolerated dose

Up to 42 days

Weekly visits for dose escalation

Phase 1b Dose Expansion

Participants continue to receive selinexor at the recommended phase 2 dose to further evaluate safety and efficacy

Up to 15.41 months

Bi-weekly visits for monitoring

Phase 2 Randomized Efficacy Exploration

Participants are randomized to different treatment arms to evaluate the efficacy of selinexor in combination with various therapies

Up to 20 months

Monthly visits for efficacy assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Carmustine
• Lomustine (CCNU)
• Selinexor
• Standard Fractionated Radiation therapy (RT)
• Temozolomide (TMZ)
• TTField

How Is the Trial Designed?

Group I: Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy Experimental Treatment 3 Interventions

Participants with nGBM mMGMT will receive 40-80 mg of selinexor oral tablet QW across dose level -1, 1, 2, 2a, 2b and 3a and 75 mg/m\^2 of temozolomide oral capsule QD in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 60 mg (dose level 2a) or 80 mg (dose level 2b and 3a) of selinexor oral tablet on Day 1 and 15 in a 28-day Cycle 2, followed by 150 mg/m\^2 (started from Cycle 3) and increase to 200 mg/m\^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycle 4 to 8 during adjuvant therapy period. Participants will continue selinexor weekly per dose level assigned until PD.

Group II: Phase 1: Arm A: Selinexor+Radiation Therapy Experimental Treatment 2 Interventions

Participants with nGBM uMGMT will receive 60 to 80 milligram (mg) of selinexor oral tablet once weekly (QW) across dose level -1, 1, 2, and 3 in combination with 2 Gray (Gy) radiation therapy (RT) daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 80 mg of selinexor oral tablet on Day 1 and 15 in a 28-day Cycle 2 and subsequently will continue at 80 mg QW until progressive disease (PD) during adjuvant therapy period.

Group III: Arm E: Selinexor+TTField Experimental Treatment 2 Interventions

Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and will receive scalp application of 200 kilohertz (kHz) of transducer array ≥18 hours/day daily for each cycle in 28 day cycle for all cycles.

Group IV: Arm D: Selinexor+Bevacizumab Experimental Treatment 2 Interventions

Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and 10 mg/kg of Bevacizumab intravenous (IV) infusion every 2 weeks (Q2W) in 28-day cycle for all cycles.

Group V: Arm C: Selinexor+Lomustine/Carmustine Experimental Treatment 3 Interventions

Participants with rGBM uMGMT or mMGMT will receive 40-80 mg of selinexor oral tablet QW across dose level -1, 1, 2, 2a, and 3 and 90-110 mg/m\^2 of lomustine or 150-200 mg/m\^2 of carmustine (substituted if lomustine is not available) capsule on Day 1 of each cycle across dose level -1, 1, 2, 2a, and 3 in a 42-day cycle for all cycles.

Group VI: Arm B Control: Temozolomide+Radiation Therapy Active Control 2 Interventions

Participants with nGBM mMGMT will receive 75 mg/m\^2 of temozolomide oral capsule QD in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 150 mg/m\^2 (started from Cycle 3) and increase to 200 mg/m\^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 during adjuvant therapy period.

Group VII: Arm A Control: Temozolomide+Radiation Therapy Active Control 2 Interventions

Participants with nGBM uMGMT will receive 75 milligram per meter square (mg/m\^2) of temozolomide oral capsule once daily (QD) in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 150 mg/m\^2 (started from Cycle 3) and increase to 200 mg/m\^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 cycles during adjuvant therapy period.

Group VIII: Arm C Control: Lomustine/Carmustine Active Control 2 Interventions

Participants with rGBM uMGMT or mMGMT will receive 110 mg/m\^2 of lomustine or 200 mg/m\^2 of Carmustine (substituted if lomustine is not available) capsule on Day 1 of each cycle in a 42-day cycle for all cycles.

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

Who Is Running the Clinical Trial?

Karyopharm Therapeutics Inc

Lead Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

The study determined that the maximum tolerated dose of temozolomide (TMZ) when combined with a fixed dose of BCNU is 80 mg/m2, with myelosuppression identified as the dose-limiting toxicity at 90 mg/m2.

In a cohort of 24 patients with malignant gliomas, the combination treatment showed a median overall survival of 132 weeks for anaplastic astrocytomas and 69 weeks for glioblastomas, indicating potential efficacy but also highlighting challenges with long-term treatment due to hematologic toxicity.

NCBI (Pubmed)

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. Raizer, JJ., Malkin, MG., Kleber, M., et al.[2018]

In a pilot study involving 29 patients with newly diagnosed anaplastic astrocytoma, the combination of carmustine and temozolomide with radiotherapy showed significant hematologic and pulmonary toxicities, leading to dose reductions in over 70% of patients in one treatment arm.

Due to the poor tolerance of the combination therapy, future studies will focus on comparing single-agent carmustine versus single-agent temozolomide, indicating a shift towards safer treatment options for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors. Chang, SM., Seiferheld, W., Curran, W., et al.[2018]

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., 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]

In a study of 40 patients with inoperable glioblastoma multiforme, the combination of carmustine (BCNU) and temozolomide showed a promising objective response rate of 42.5%, indicating its potential effectiveness as a first-line chemotherapy before and after radiotherapy.

The treatment was generally well-tolerated, with manageable grade 3-4 toxicities such as thrombocytopenia and neutropenia, and no patients discontinued treatment due to side effects, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Barrié, M., Couprie, C., Dufour, H., et al.[2022]

Cisplatin combined with other agents like vinblastine or etoposide shows promise as an effective pre-radiotherapy treatment for locally advanced non-small cell lung cancer (NSCLC), but optimal scheduling is still being researched.

In a study of 170 patients, concurrent chemotherapy with carboplatin and radiation led to increased toxicity, including significantly higher rates of neutropenia and thrombocytopenia, indicating that while this approach may improve treatment efficacy, it also raises safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. Bishop, JF.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8810630/

A Phase II Study of the Efficacy and Safety of Oral Selinexor in ... Ongoing trials are evaluating the safety and efficacy of selinexor in combination with other therapies for newly diagnosed and recurrent glioblastoma.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34728525/

A Phase II Study of the Efficacy and Safety of Oral Selinexor in ... Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma

3. asco.org asco.org/abstracts-presentations/ABSTRACT339225

A phase 1/2 study of selinexor in combination with ... The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes ... Mebendazole in recurrent glioblastoma ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.2005

Efficacy and safety of selinexor in recurrent glioblastoma. SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg ...

5. karyopharm.com karyopharm.com/wp-content/uploads/2020/11/Final-Results-of-the-KING-trial_SNO-2020.pdf

Final Results of the KING trial: Phase 2 Study of Efficacy, ... Molecular Predictors of Response to Selinexor in Recurrent. Glioblastoma (GBM). Mutations Associated with Improved Survival in Selinexor-Treated Patients. • ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05432804

NCT05432804 | Testing the Addition of an Anti-cancer ... This phase I/II trial tests the safety, side effects and best dose of selinexor given in combination with the usual chemotherapy (temozolomide)