Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Background:

* Although radiation has been shown to improve outcomes in patients with glioblastoma (GBM), median survival remains poor. Even with the addition of temozolomide (TMZ) to surgical resection and radiotherapy, most GBMs will recur in field or adjacent to the high dose radiation volume.
* High rates of local failure indicate that GBM cells in situ are relatively radioresistant and that the effectiveness of GBM radiotherapy would benefit from additional radiosensitization.
* Selinexor has recently been shown to enhance the radiosensitivity of glioma cells both in vitro and in vivo.

Objectives:

-Assess the safety, tolerability, and maximum tolerated dose of selinexor when combined with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma and gliosarcoma.

Eligibility:

* Men and women greater than 18 years old
* Histologically confirmed newly diagnosed glioblastoma or gliosarcoma
* Karnofsky Performance Scale (KPS) greater than or equal to 70
* Patients who have not previously been treated with chemotherapy or radiation therapy

Design:

* This is a Phase I trial to determine the safety and tolerability of selinexor in combination with external beam radiation therapy (RT) and temozolomide in patients with newly diagnosed glioblastoma or gliosarcoma using a "3 plus 3 design" and three dose escalation levels, with 3 patients per dose level (provided no dose limiting toxicity (DLT), a maximum of 21 patients will be enrolled.
* Patients will be treated with external beam radiation therapy in a standard manner with temozolomide given daily during radiation. Selinexor will be administered concurrent with the RT/temozolomide.
* We anticipate accrual of 21 evaluable patients which will take approximately 2 years. The accrual ceiling has been set to 24 patients.

• Selinexor (Drug), also known as Xpovio: Selinexor will be administered orally at an initial dose of 80 mg. The first dose will be given on day 2 of radiation and will thereafter be administered weekly on the second day of weekly radiation on weeks 1, 2, 4, and 5. If this dose level is tolerated, the dose will be escalated to 60 mg twice a week (days 1 and 4) on weeks 1,2,4,5. The third and final dose level will also be 60mg administered twice weekly for 6 weeks starting on days 1 and 4 radiation.
• Temozolomide (Drug), also known as Temodar: Temozolomide will begin on the first day or evening prior of radiation and be administered orally daily at a dose of 75 mg/m\^2 during the radiation treatment. Temozolomide will continue until the completion of radiation and then will be stopped. Beginning 1-month post-radiation therapy (RT), the adjuvant temozolomide will be given per standard of care.
• Generic Radiation therapy (RT) (Radiation): Radiation therapy (RT) will be administered daily (Monday to Friday)
• Selective serotonin receptor (5-HT3) antagonists (Other), also known as Serotonin antagonists: Anti-emetic for breakthrough nausea.
• Olanzapine (Other), also known as Zyprexa Relprevv, Zyprexa Zydis, Zyprexa: 2.5mg to 5mg once a day if weight loss is rapid.
• Salt tablets (Dietary supplement), also known as Sodium Chloride tablets: To treat hyponatremia, add salt tablets to participants diet per institutional guidelines.
• Anti-diarrheal (Other), also known as Loperamide, Imodium: Treat diarrhea with an anti-diarrheal per institutional guidelines

Primary outcomes

• Maximum Tolerated Dose (MTD) of Selinexor [7 weeks]: The MTD is the dose level at which no more than 1 of up to 6 participants experience dose limiting-toxicity (DLT) within 1 month of completion of treatment, and the dose below that at which at least 2 (of< =6) participants have DLT as a result of selinexor/radiation therapy (RT)/temozolomide.

Secondary outcomes

• Dose-limiting Toxicities of Selinexor to Concurrent Radiation Therapy and Temozolomide Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG) [Measured each week of treatment and up to 30 days post treatment; approximately 6-7 weeks with another month added on = ~ 11 weeks to monitor.]: Dose-limiting toxicities of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. CTCAE: Grade 3 is severe, and Grade 4 is life-threatening. RTOG: Grade 3 Brain/Central nervous system (CNS): neurologic findings present sufficient to require home care; Skin: confluent moist desquamation other than skin folds; Eye: severe keratitis; Ear: severe external otitis; and Grade 4 Brain/CNS is serious neurologic impairment; Skin: ulceration; Eye: loss of vision; and Ear: deafness.DLT's include all adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity.
• Dose-limiting Toxicities Effects on Quality of Life (QOL) [Measured each week of treatment and up to 30 days post treatment; approximately 6-7 weeks with another month added on = ~ 11 weeks to monitor.]: Define the dose-limiting toxicities (DLT) effects on quality of life (QOL) in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores will be summarized. DLT's include all adverse events (AE), including clinically significant abnormal findings on laboratory evaluations, regardless of severity. Evaluations completed on participants weekly or complications requiring admission to the emergency room (ER)/hospital are also included in the collection of AEs to determine if DLT.
• Dose-limiting Toxicities (DLT) Effects on Neurocognition [Measured each week of treatment and up to 30 days post treatment; approximately 6-7 weeks with another month added on = ~ 11 weeks to monitor.]: Define the dose-limiting toxicities effects on neurocognition in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. DLT's include all adverse events (AE), including clinically significant abnormal findings on laboratory evaluations, regardless of severity. Evaluations completed on participants weekly or complications requiring admission to the emergency room (ER)/hospital are also included in the collection of AE's to determine if DLT.
• Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Scale [Baseline and completion of treatment, up to 3 years]: The PROMIS depression questionnaire in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores from questionnaires rating symptoms on a scale of 1 (never) - 5 (very often several times a day) will be summarized. A score of 1 is the best outcome. A score of 5 is worst outcome. The difference between two timepoints - baseline and close of treatment is also reported.

Other outcomes

• Dose-limiting Toxicities (DLT) Effects on Quality of Life (QOL) Using the MD Anderson Symptom Inventory for Brain Tumors (MDSAI-BT) [Baseline and close of treatment, up to 3 years]: DLT effects on quality of life (QOL) using the MD Anderson Symptom Inventory for Brain Tumors (MDASI-BT) in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores from questionnaires rating symptoms on a scale of 0 (symptoms not present)-10 (as bad as you can imagine) will be summarized. A score of 0 is the best outcome. A score of 10 is the worst outcome. The difference between two timepoints - baseline and close of treatment is also reported.
• Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale [Baseline and completion of treatment, up to 3 years]: The PROMIS anxiety scale in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores from questionnaires rating symptoms on a scale of 1 (never) - 5 (always) will be summarized. A score of 1 is the best outcome. A score of 5 is the worst outcome. The difference between two timepoints - baseline and close of treatment is also reported.
• National Cancer Institute (NCI) Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [Baseline and completion of treatment, up to 3 years]: The NCI PRO-CTCAE in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores from questionnaires rating symptoms on a scale of 0 (None) - 4 (Very severe) will be summarized. A score of 0 is the best outcome. A score of 4 is the worst outcome. The difference between two timepoints - baseline and close of treatment is also reported.
• Neuro-quality of Life (QOL) Assessment Cognition Function [Baseline and completion of treatment, up to 3 years]: The Neuro-QOL assessment Cognition Function in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. A DLT is defined as a clinically significant adverse event assessed as unrelated to tumor progression, intercurrent illness or concomitant medications and meets any of the criteria such as any Grade 3 or 4 toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; and any Grade 3 or 4 toxicity per Radiation Therapy Oncology Group (RTOG) acute morbidity. QOL life scores from questionnaires rating symptoms on a scale of 5 (Never) -1 (Very often-several times a day), e.g., thinking slow, will be summarized. A score of 5 is the best outcome. A score of 1 is the worst outcome. The difference between two timepoints - baseline and close of treatment is also reported.
• Progression Free Survival (PFS) [From initiation of treatment on protocol to progression as per RANO criteria or death due to disease progression, approximately months]: PFS is defined as the time from initiation of treatment on protocol to progression as per Response Assessment in Neuro-Oncology (RANO) criteria or death due to disease progression. Progressive disease is at least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions. Clear clinical deterioration not attributable to other causes apart from tumor or attributable to changes in steroid use. Failure to return for evaluation as a result of death or deteriorating condition.
• Overall Survival (OS) [From initiation of treatment on protocol to date of death due to any cause, approximately months.]: OS is defined as the time from initiation of treatment on protocol to date of death due to any cause. For participants alive as of last follow-up, time to death will be censored at last contact date.
• Number of Participants With Serious and/or Non-Serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [Adverse events are documented from the first study intervention, Study Day 1, through 30 days after the subject received the last study drug administration, an average of 2.5 months.]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event.

Sex: All, ages: 18 Years to any

* INCLUSION CRITERIA:

  1. Histological diagnosis

     * Pathologically confirmed glioblastoma or gliosarcoma (including astrocytoma, grade IV)
  2. Patients must be eligible for definitive external beam radiotherapy and temozolomide.
  3. Age >18 years. Because no dosing or adverse event data are currently available on the use of Selinexor in combination with Temodar in patients <18 years of age, children are excluded from this study.
  4. Patients should have a Karnofsky performance scale (KPS) greater than or equal to 70
  5. Absolute neutrophil count (ANC) >1.5x10\^9/L; platelet count >100x10\^9/L; and hemoglobin (Hb) >9.0 g/dL. Note: the use of transfusion or other intervention prior to cycle 1 day 1 to achieve Hb >9.0 g/dL is acceptable.
  6. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
  7. The effects of Selinexor on the developing human fetus are unknown. For this reason and because Selinexor agents as well as other therapeutic agents used in this trial are known to be teratogenic, 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.
  8. Patients must have had surgery and/or biopsy not greater than 8 weeks prior to initial evaluation to be eligible for this study.

     EXCLUSION CRITERIA:

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  1. Patients who are receiving any other investigational agents and have had prior therapy including:

     * Patients who have previously received radiation therapy (RT) to the brain.
     * Patients who received chemotherapy for the treatment of their glioma
     * Patients who are being treated with implanted Gliadel wafers
     * Patients who are being treated with tumor treating fields.
  2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor or temozolomide used in study.

  3 Patients with coagulation problems and medically significant bleeding in the month prior to start of treatment (peptic ulcers, epistaxis, spontaneous bleeding). Prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE) is not exclusionary.

  4\. Patients with active uncontrolled or suspected infections

  5\. Patients with severe liver dysfunction defined as:
  * Total bilirubin > 1.5 x upper limit of normal (ULN) Note: Subjects with Gilberts syndrome should not be excluded as long as total bilirubin is < 3.0 x ULN and documentation to support diagnosis is available.
  * Serum glutamate pyruvate transaminase (SGPT) or called as Alanine aminotransferase (ALT) greater than or equal to 3 x ULN = 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  * Serum glutamic oxaloacetic transaminase (SGOT) or called as Aspartate aminotransferase (AST) greater than or equal to 3 x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L
  * Serum albumin greater than or equal to 2 x ULN

    6\. Known active hepatitis A, B, or C infection

    7\. Human immunodeficiency virus (HIV) patients are not eligible because of their immunocompromised status and overlap of side effects between highly active antiretroviral therapy (HAART) and radiation therapy.

    8 Patients must not have significantly diseased or obstructed gastrointestinal tract malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medication.

    9\. Pregnant women are excluded from this study because Selinexor could have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Selinexor, breastfeeding should be discontinued if the mother is treated with Selinexor. These potential risks may also apply to temozolomide used in this study.

    10\. Patients with pre-existing known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) of Selinexor (Primary), Number, mg/m^2: All Participants 60
• Dose-limiting Toxicities of Selinexor to Concurrent Radiation Therapy and Temozolomide Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG) (Secondary), Number, toxicities: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 8; Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 19; Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 6
• Dose-limiting Toxicities Effects on Quality of Life (QOL) (Secondary), Number, toxicities: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0; Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0; Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 0
• Dose-limiting Toxicities (DLT) Effects on Neurocognition (Secondary), Number, toxicities: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0; Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0; Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 0
• Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Scale (Secondary), Median, Score on a scale: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.63 (1 to 3); Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.71 (1.125 to 2.625); Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 1.71 (1.125 to 2.625) (p 0.02)
• Dose-limiting Toxicities (DLT) Effects on Quality of Life (QOL) Using the MD Anderson Symptom Inventory for Brain Tumors (MDSAI-BT) (Other pre specified), Median, Scores on a scale: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.21 (0 to 5); Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.17 (0.678 to 1.857); Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 1.17 (0.678 to 1.857)
• Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale (Other pre specified), Median, Score on a scale: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.63 (1 to 3); Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 1.71 (1.125 to 2.625); Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 1.71 (1.125 to 2.625) (p 0.09)
• National Cancer Institute (NCI) Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) (Other pre specified), Median, Scores on a scale: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0.29 (0 to 0.85); Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 0.53 (0.25 to 0.95); Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 0.53 (0.25 to 0.95)
• Neuro-quality of Life (QOL) Assessment Cognition Function (Other pre specified), Median, Score on a scale: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 4.42 (3.125 to 5); Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 4.17 (3.625 to 4.5); Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 4.17 (3.625 to 4.5)
• Progression Free Survival (PFS) (Other pre specified)
• Overall Survival (OS) (Other pre specified)
• Number of Participants With Serious and/or Non-Serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) (Other pre specified), Count of participants, Participants: Dose Level 1: Selinexor 80mg on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 3; Dose Level 2: Selinexor 60mg Twice a Week on Weeks 1, 2, 4, 5 With Temozolomide & Radiation 6; Dose Level 3: Selinexor 60mg Twice a Week, Weeks 1-6 With Temozolomide & Radiation 2

Adverse events

Time frame: Adverse events are documented from the first study intervention, Study Day 1, through 30 days after the subject received the last study drug administration, an average of 2.5 months.

Serious adverse events by term

Other adverse events by term

7 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2025-06-30)
• Informed Consent Form (PDF, 2023-02-22)

• Kevin A Camphausen, M.D., Principal investigator, National Cancer Institute (NCI)