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

Study Overview
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Brief Summary
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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 CT scan or 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
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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 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

Official Title
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A Phase I Clinical Trial of Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Conditions
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Gliosarcoma, Newly Diagnosed, Glioblastoma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Temozolomide
* Radiation: Generic Radiation therapy (RT)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histological diagnosis --Pathologically confirmed glioblastoma or gliosarcoma (including astrocytoma, grade IV) Patients must be eligible for definitive external beam radiotherapy and temozolomide. 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. Patients should have a KPS greater than or equal to 70 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. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. 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. 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: 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 DVT or 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. HIV patients are not eligible because of their immunocompromised status and overlap of side effects between HAART therapy 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Experimental therapy<br>Selinexor with temozolomide and radiation | Drug: Selinexor<br>* 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.<br>Drug: Temozolomide<br>* Temozolomide will begin on the first day or evening prior of radiation and be administered orally daily at a dose of 75 mg/m2 during the radiation treatment. Temozolomide will continue until the completion of radiation and then will be stopped. Beginning 1-month post-RT, the adjuvant temozolomide will be given per standard of care.<br>Radiation: Generic Radiation therapy (RT)<br>* Radiation therapy (RT) will be administered daily (Monday to Friday)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | The MTD is the dose level at which no more than 1 of up to 6 patients experience DLT within 1 month of completion of treatment, and the dose below that at which at least 2 (of< =6) patients have DLT as a result of selinexor/RT/temozolomide. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities | Define the dose-limiting toxicities including effects on QOL and neurocognition in the setting of the addition of Selinexor to concurrent radiation therapy and temozolomide. | DLT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, GBM, Gliosarcoma