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

Phase 1

Active, not recruiting

Conditions: Glioblastoma
Gliosarcoma
Newly Diagnosed

Interventions: Drug: Selinexor
Drug: Temozolomide
Radiation: Generic Radiation therapy (RT)
Other: Selective serotonin receptor (5-HT3) antagonists
Other: Olanzapine
Dietary Supplement: Salt tablets
Other: Anti-diarrheal

Registration Number: NCT04216329

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 11

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Temozolomide	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Generic Radiation therapy (RT)	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Selective serotonin receptor (5-HT3) antagonists	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Olanzapine	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Salt tablets	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Anti-diarrheal	Selinexor with temozolomide and radiation
1/Experimental Therapy - Selinexor with Temozolomide and Radiation	Selinexor	Selinexor with temozolomide and radiation

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 AE's 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.