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Trial record 1 of 1 for:    NCT04421378
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A Study of Selinexor in Combination With Standard of Care Therapy for Newly Diagnosed or Recurrent Glioblastoma

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ClinicalTrials.gov Identifier: NCT04421378
Recruitment Status : Recruiting
First Posted : June 9, 2020
Last Update Posted : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Brief Summary:
This is a global, Phase 1/2, multicenter, open-label study. The clinical study will include of Phase 1: Dose Escalation (non-randomized, dose finding study) and Phase 2: Dose Expansion (randomized efficacy exploration). For Phase 1, the purpose of this study is to assess the maximum tolerated dose (MTD), recommend phase 2 dose (RP2D), preliminary efficacy, and safety of selinexor in combination with SoC therapy for newly diagnosed glioblastoma multiforme (GBM) (nGBM) or recurrent GBM (rGBM). The study will independently evaluate 3 different combination regimens in 3 treatment arms in participants with nGBM O6-methylguanine-DNA-methyltransferase [MGMT] promotor unmethylated [uMGMT] disease in Arm A, MGMT methylated [mMGMT]) in Arm B, and participants with rGBM regardless of MGMT status in Arm C. The second phase of the study will compare selinexor+SoC treatments versus SoC treatment alone in the three treatment Arms.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Drug: Selinexor Drug: Temozolomide (TMZ) Drug: Lomustine (CCNU) Radiation: Standard Fractionated Radiation therapy (RT) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 402 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Selinexor in Combination With Standard of Care (SoC) Therapy for Newly Diagnosed or Recurrent Glioblastoma
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: Selinexor+Radiation Therapy
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 QW in a 28-day cycle for 6 cycles and beyond until PD during adjuvant therapy period.
Drug: Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Other Names:
  • KPT-330
  • XPOVIO

Radiation: Standard Fractionated Radiation therapy (RT)
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.

Active Comparator: Arm A_Control: Temozolomide+Radiation Therapy
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 of Temozolomide oral capsule daily for 5 days in a 28-day cycle during Cycles 2 to 7 for 6 cycles during adjuvant therapy period.
Drug: Temozolomide (TMZ)
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
Other Name: Temodar

Radiation: Standard Fractionated Radiation therapy (RT)
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.

Experimental: Arm B: Selinexor+Temozolomide+Radiation Therapy
Participants with nGBM mMGMT will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1, 2 and 3 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 150 mg/m^2 of Temozolomide oral capsule daily for 5 days in a 28-day cycle during Cycle 2 to 7 during adjuvant therapy period.
Drug: Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Other Names:
  • KPT-330
  • XPOVIO

Drug: Temozolomide (TMZ)
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
Other Name: Temodar

Radiation: Standard Fractionated Radiation therapy (RT)
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.

Active Comparator: Arm B_Control: Temozolomide+Radiation Therapy
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 of Temozolomide oral capsule daily for 5 days in a 28-day cycle during Cycles 2 to 7 for 6 cycles during adjuvant therapy period.
Drug: Temozolomide (TMZ)
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
Other Name: Temodar

Radiation: Standard Fractionated Radiation therapy (RT)
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.

Experimental: Arm C: Selinexor+Lomustine
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 capsule on Day 1 of each cycle across dose level -1, 1, 2, 2a, and 3 in a 42-day cycle for all cycles.
Drug: Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Other Names:
  • KPT-330
  • XPOVIO

Drug: Lomustine (CCNU)
Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral

Active Comparator: Arm C_Control: Lomustine
Participants with rGBM uMGMT or mMGMT will receive 110 mg/m^2 of Lomustine capsule on Day 1 of each cycle in a 42-day cycle for all cycles.
Drug: Lomustine (CCNU)
Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral




Primary Outcome Measures :
  1. Phase 1: Maximum Tolerated Dose Per Arm: Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [ Time Frame: During Cycle 1 of treatment (42 days/cycle) for each participant ]
  2. Phase 1: Recommended Phase 2 Dose Per Arm [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  3. Phase 2: Progression-free Survival (PFS) in Newly Diagnosed Glioblastoma Multiforme Participants [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  4. Phase 2: Overall Survival (OS) in Recurrent Glioblastoma Multiforme Participants [ Time Frame: From date of randomization up to death (Up to 24 months) ]

Secondary Outcome Measures :
  1. Phase 1: Overall Response Rate (ORR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria Per Arm [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  2. Phase 1: Disease Control Rate (DCR) Based on Modified Response Assessment in Neuro-Oncology Criteria Per Arm [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  3. Phase 1: Duration of Response (DOR) Per Arm Independently [ Time Frame: From the date of first response to the date of first documentation of progression (Up to 24 months) ]
  4. Phase 1: Time-to-progression (TTP) Per Arm Independently [ Time Frame: From the date of first dose to disease progression or death (Up to 24 months) ]
  5. Phase 1: Overall Survival Per Arm Independently [ Time Frame: From the date of randomization to death (Up to 24 months) ]
  6. Phase 1: Progression Free Survival Per Arm Independently [ Time Frame: Up to 24 months ]
  7. Phase 1: Maximum Plasma Concentration (Cmax) of Selinexor in Plasma When Administered With Radiation Therapy, Temozolomide, and/or Lomustine [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at 2, 4, and 6 hours post-dose (42 days/cycle) ]
  8. Phase 1: Area Under the Concentration-time Curve (AUC) of Selinexor in Plasma When Administered With Radiation Therapy, Temozolomide, and/or Lomustine [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at 2, 4, and 6 hours post-dose (42 days/cycle) ]
  9. Phase 1: Apparent Clearance (CL) of Selinexor in Plasma When Administered With Radiation Therapy, Temozolomide, and/or Lomustine [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at 2, 4, and 6 hours post-dose (42 days/cycle) ]
  10. Phase 2: Progression Free Survival Per Modified Response Assessment in Neuro-Oncology Criteria in Arms A, B, and C: Per Investigator Assessment [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  11. Phase 2: Progression Free Survival Per Modified Response Assessment in Neuro-Oncology Criteria in Participants With Recurrent Glioblastoma Multiforme Per Independent Review Committee Assessment [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  12. Phase 2: Overall Survival for Newly Diagnosed Glioblastoma Multiforme Participants in Arms A and B [ Time Frame: From date of randomization to death (Up to 24 months) ]
  13. Phase 2: Rate of Progression Free Survival at 6-month (PFS6) [ Time Frame: 6 months ]
  14. Phase 2: Overall Response Rate Per Independent Review Committee and Investigator Assessment [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  15. Phase 2: Disease Control Rate Per Independent Review Committee and Investigator Assessment [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  16. Phase 2: Duration of Response Per Independent Review Committee and Investigator Assessment [ Time Frame: Cycle1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  17. Phase 2: 1 and 2-year Overall Survival Rate of Participants in Arms A, B, and C [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  18. Number of Participants With Abnormalities Related to Vital Signs, Clinical Laboratory Values, and Physical Examinations [ Time Frame: Up to 30 days post last dose ]
  19. Number of Participants With Any Treatment-emergent Adverse Events (AEs) (TEAEs) by Severity Grade ≥3, Serious Adverse event (SAEs), and AEs Leading to Treatment Discontinuation [ Time Frame: Up to 30 days post last dose ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Participants meeting all of the following inclusion criteria are eligible to enroll in this study:

  • Written informed consent in accordance with federal, local, and institutional Guidelines.
  • Age ≥18 years at the time of informed consent.
  • Pathologically confirmed glioblastoma (including all histological variants; documentation to be provided) that are newly diagnosed (for Arms A and B) or relapsed disease (for Arm C) after 1 line of systemic therapy (RT+TMZ or RT+TMZ in combination with other drug) that have not received the second line systemic treatment for relapsed disease (surgical resection of recurrent disease allowed).
  • Prior therapy:
  • Arms A and B: participants who have not received radiation or any systemic therapy for brain tumor and must be eligible for definitive external beam radiotherapy and temozolomide.
  • Arm C: participants must have received prior treatment with radiation therapy and temozolomide (RT+TMZ in combination with other drug is allowed).
  • Measurable disease according to modified RANO guidelines.
  • Participants enrolling must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to the baseline magnetic resonance imaging (MRI).
  • Karnofsky Performance Score (KPS) ≥70 (for Arms A and B) and 60 (for Arm C).
  • Participants must have adequate organ function ≤2 weeks of study treatment as defined by the following laboratory criteria:
  • Hematological function ≤7 days prior to Cycle 1 Day 1: absolute neutrophil count (ANC) ≥1.5*10^9 per Liter (/L); platelet count ≥150*10^9/L; and hemoglobin (Hb) ≥10.0 gram per deciliter (g/dL). Transfusion is not allowed within 7 days prior to Cycle 1 Day 1.
  • Hepatic function: bilirubin ≤2*the upper limit of normal (ULN), alanine transaminase (ALT) ≤2.5*ULN, aspartate transaminase (AST) ≤2.5*ULN; unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin must be <4*ULN.
  • Renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥30 milliliter per minute (mL/min).
  • Female participants of childbearing potential must have a negative serum pregnancy test at Screening and agree to use highly effective methods of contraception throughout the study and for 2 weeks following the last dose of study treatment.
  • Fertile male participants who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 4 months following the last dose of study treatment.
  • For Arms A and B: participants must have had surgery and/or biopsy not greater than [>] 8 weeks prior to initial screening.
  • Participants must consent to provide tumor tissue and blood samples to be used for future genetic testing for correlative studies.

Exclusion Criteria

Participants meeting any of the following exclusion criteria are not eligible to enroll in this study:

  • 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.
  • Participants who are being treated or plan to be treated during this study with tumor treating fields.
  • For Arm C:
  • <6 weeks from nitrosourea, <4 weeks from prior temozolomide or other chemotherapy or investigational agents prior to start of study treatment.
  • Prior treatment bevacizumab or other direct vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors. For any questions of the definition of a direct VEGF/VEGFR inhibitor, consult the study Medical Monitor.
  • Any AE which has not recovered to Grade ≤1, or returned to baseline, related to the previous GBM therapy, except alopecia.
  • Major surgery <2 weeks prior to the start of study treatment.
  • History of allergic reactions attributed to compounds of similar chemical or biological composition to selinexor or other study treatment.
  • Participants must not have significantly diseased or obstructed gastrointestinal tract malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medication.
  • Participants 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 or pulmonary embolism is not exclusionary.
  • Currently pregnant or breastfeeding.
  • For Arms A and B: participants with pre-existing known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.
  • Any life-threatening illness, active medical condition, organ system dysfunction, or serious active psychiatric issue which, in the Investigator's opinion, could compromise the participant's safety or the participant's ability to remain compliant with study procedures
  • Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable even if parenteral.
  • Inability to swallow tablets, malabsorption syndrome, or any other gastrointestinal disease or dysfunction that could interfere with absorption of study treatment.
  • In the opinion of the Investigator, participants who are significantly below their ideal body weight.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04421378


Contacts
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Contact: Jatin Shah Executive Vice President, Chief Medical Officer, MD (617) 658-0600 jshah@karyopharm.com
Contact: Sharon Shacham President and Chief Scientific Officer, PhD, MBA (617) 658-0600 sshacham@karyopharm.com

Locations
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United States, Florida
Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive Recruiting
Miami, Florida, United States, 33176
Contact: Dr. Yazmin Odia         
United States, New Jersey
Hackensack Meridian Health, 92 Second Street Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Dr. Samuel Goldlust         
Sponsors and Collaborators
Karyopharm Therapeutics Inc
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Responsible Party: Karyopharm Therapeutics Inc
ClinicalTrials.gov Identifier: NCT04421378    
Other Study ID Numbers: XPORT-GBM-029
First Posted: June 9, 2020    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Karyopharm Therapeutics Inc:
nGBM
rGBM
GBM
Temozolomide
Lomustine
KPT-330
XPOVIO
Selinexor
Newly diagnosed glioblastoma multiforme
Recurrent glioblastoma multiforme
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Lomustine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents