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

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ClinicalTrials.gov Identifier: NCT04216329
Recruitment Status : Recruiting
First Posted : January 2, 2020
Last Update Posted : July 10, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE December 31, 2019
First Posted Date  ICMJE January 2, 2020
Last Update Posted Date July 10, 2020
Actual Study Start Date  ICMJE July 7, 2020
Estimated Primary Completion Date August 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 31, 2019)
MTD [ Time Frame: 7 weeks ]
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 less than or equal to 6) patients have DLT as a result of selinexor/RT/temozolomide
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2020)
Dose-limiting toxicities [ Time Frame: DLT ]
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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma
Official Title  ICMJE A Phase I Clinical Trial of Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma
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 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

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 once weekly 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Gliosarcoma
  • Newly Diagnosed
  • Glioblastoma
Intervention  ICMJE
  • Drug: Selinexor

    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 100 mg on the same schedule. The third and final dose level will also be 100mg administered once weekly for 6 weeks starting on day 2 of radiation.

  • Drug: Temozolomide
    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.
  • Radiation: Generic
    Radiation therapy (RT) will be administered daily (Monday to Friday)
Study Arms  ICMJE Experimental: Experimental therapy
Selinexor with temozolomide and radiation
Interventions:
  • Drug: Selinexor
  • Drug: Temozolomide
  • Radiation: Generic
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 31, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 30, 2023
Estimated Primary Completion Date August 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. Histological diagnosis

      --Pathologically confirmed glioblastoma or gliosarcoma

    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 KPS greater than or equal to 70
    5. Absolute neutrophil count (ANC) >1.5x109/L; platelet count >100x9/L; and hemoglobin (Hb) >9.0 g/dL within 7 days prior to enrollment. 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:

  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 thrombocytopenia at baseline defined as <100x109/L
  4. 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
  5. Patients with active uncontrolled or suspected infections
  6. Patients with severe liver dysfunction defined as:

    • Total bilirubin greater than or equal to 1.5 x upper limit of normal (ULN)
    • 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 less than or equal to 2 g/dL
  7. Known active hepatitis A, B, or C infection
  8. HIV patients are not eligible because of their immunocompromised status and overlap of side effects between HAART therapy and radiation therapy.
  9. Patients must not have significantly diseased or obstructed gastrointestinal tract malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medication
  10. 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.
  11. Patients with a history of concurrent second malignancy other than non-melanoma skin cancer or cervical cancer <3 years prior to glioblastoma or gliosarcoma diagnosis
  12. Patients with pre-existing known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Theresa Cooley-Zgela, R.N. (301) 451-8905 theresa.cooleyzgela@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04216329
Other Study ID Numbers  ICMJE 200027
20-C-0027
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kevin A Camphausen, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 24, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP