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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 : October 15, 2021
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Brief Summary:

This is a Phase 1/2 study of selinexor in combination with standard of care (SoC) therapy for newly diagnosed glioblastoma (nGBM) or recurrent glioblastoma (rGBM). This study will be conducted in 2 phases: a Phase 1a dose finding study followed by Phase 1b (dose expansion) and a Phase 2 randomized efficacy exploration study and will independently evaluate 3 different combination regimens in 3 treatment arms in patients with nGBM (Arms A and B) or with rGBM (Arm C).

  • Arm A: evaluating the combination of selinexor with radiation therapy (S-RT) in nGBM participants with uMGMT
  • Arm B: evaluating the combination of selinexor with radiation therapy and temozolomide (TMZ) (S-TRT) in nGBM participants with methylated-O6-methylguanine-DNA-methyltransferase (mMGMT)
  • Arm C: evaluating the combination of selinexor with lomustine (or carmustine, if lomustine is not available) (S-L/C) in rGBM participants regardless of MGMT status
  • Arm D: evaluating the combination of selinexor with bevacizumab in rGBM participants regardless of MGMT status
  • Arm E: evaluating the combination of selinexor with tumor treating fields (TTField) in rGBM participants regardless of MGMT status

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 474 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
Actual Study Start Date : June 8, 2020
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Selinexor

Arm Intervention/treatment
Experimental: Phase 1: 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 on Day 1 and 15 in a 28-day Cycle 2 and subsequently will continue at 80 mg QW until progressive disease (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 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 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: Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy
Participants with nGBM mMGMT will receive 40-80 mg of selinexor oral tablet QW across dose level -1, 1, 2, 2a, 2b and 3a 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 60 mg (dose level 2a) or 80 mg (dose level 2b and 3a) of selinexor oral tablet on Day 1 and 15 in a 28-day Cycle 2, followed by 150 mg/m^2 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycle 4 to 8 during adjuvant therapy period. Participants will continue selinexor weekly per dose level assigned until PD.
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 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 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/Carmustine
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 or 150-200 mg/m^2 of carmustine (substituted if lomustine is not available) 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

Drug: Carmustine
Dose and Formulation: 150 or 200 mg/m^2; Route of Administration: Intravenous

Active Comparator: Arm C Control: Lomustine/Carmustine
Participants with rGBM uMGMT or mMGMT will receive 110 mg/m^2 of lomustine or 200 mg/m^2 of Carmustine (substituted if lomustine is not available) 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

Drug: Carmustine
Dose and Formulation: 150 or 200 mg/m^2; Route of Administration: Intravenous

Experimental: Arm D: Selinexor+Bevacizumab
Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and 10 mg/kg of Bevacizumab intravenous (IV) infusion every 2 weeks (Q2W) in 28-day cycle for all cycles.
Drug: Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Other Names:
  • KPT-330
  • XPOVIO

Drug: Bevacizumab
Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous

Active Comparator: Arm D Control: Bevacizumab
Participants with rGBM will receive 10 mg/kg of Bevacizumab IV infusion Q2W in each cycle in a 28 Day cycle for all cycles.
Drug: Bevacizumab
Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous

Experimental: Arm E: Selinexor+TTField
Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and will receive scalp application of 200 kilohertz (kHz) of transducer array ≥18 hours/day daily for each cycle in 28 day cycle for all cycles.
Drug: Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Other Names:
  • KPT-330
  • XPOVIO

Device: TTField
Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.

Active Comparator: Arm E Control: TTField
Participants with rGBM will receive scalp application of 200 kHz of transducer array ≥18 hours/day daily for each cycle in 28 day cycle for all cycles.
Device: TTField
Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.




Primary Outcome Measures :
  1. Phase 1a: 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 1a: Recommended Phase 2 Dose Per Arm [ Time Frame: Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle) ]
  3. Phase 1a: Number of Participants with Adverse Events (AEs) with Grade Greater Than or Equal to (>=) 3, Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [ Time Frame: Up to 30 days post last dose ]
  4. Phase 1b: Progressive Free Survival at 3 Months for All Arms [ Time Frame: 3 Months ]
  5. Phase 1b: Overall Survival (OS) for All Arms [ Time Frame: From date of randomization up to death (Up to 24 months) ]
  6. Phase 2: Progression-free Survival (PFS) in Arms A and B [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  7. Phase 2: Overall Survival (OS) for Arm C [ Time Frame: From date of randomization up to death (Up to 24 months) ]

Secondary Outcome Measures :
  1. Phase 1a: Overall Survival (OS) for Each Arm [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  2. Phase 1a/1b: Time to Progression (TTP) for Each Arm [ Time Frame: From first dose of study treatment until progression or death due to progression (Up to 24 months) ]
  3. Phase 1a/1b: Progressive Free Survival (PFS) for Each Arm [ Time Frame: From first dose of study treatment until progression or death due to any cause (Up to 24 months) ]
  4. Phase 1a/1b: Overall Response Rate (ORR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria in Arm C, D and E [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  5. Phase 1a/1b: Disease Control Rate (DCR) Based on Modified Response Assessment in Neuro-Oncology Criteria in Arm C, D and E [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  6. Phase 1a/1b: Duration of Response (DOR) in Arm C, D and E [ Time Frame: From the date of first evidence of objective response until progression (Up to 24 months) ]
  7. Phase 1a/1b: Maximum Plasma Concentration (Cmax) of Selinexor [ Time Frame: 2, 4, and 6 hours post-dose ]
  8. Phase 1a/1b: Area Under the Concentration-time Curve (AUC) of Selinexor [ Time Frame: 2, 4, and 6 hours post-dose ]
  9. Phase 1a/1b: Apparent Clearance (CL) of Selinexor [ Time Frame: 2, 4, and 6 hours post-dose ]
  10. Phase 1b: Number of Participants with Adverse Events (AEs) with Grade Greater Than or Equal to (>=) 3, Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [ Time Frame: Up to 30 days post last dose ]
  11. Phase 1b: Maximum Tolerated Dose [ Time Frame: Up to 24 months ]
  12. Phase 1b: Recommended Phase 2 Dose [ Time Frame: Up to 24 months ]
  13. Phase 2: Progression Free Survival Per (PFS) as Assessed by Investigator per Modified Response Assessment in Neuro-Oncology Criteria in Arms A and B [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  14. Phase 2: Overall Survival for Participants With Newly Diagnosed Glioblastoma Multiforme in Arms A and B [ Time Frame: From date of randomization to death (Up to 24 months) ]
  15. Phase 2: Progression Free Survival (PFS) as Assessed by Independent Review Committee (IRC) per Modified Response Assessment in Neuro-Oncology Criteria in Arm C [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  16. Phase 2: Progression Free Survival (PFS) as Assessed by Investigator per Modified Response Assessment in Neuro-Oncology Criteria in Arm C [ Time Frame: From date of randomization to the date of disease progression or death (Up to 24 months) ]
  17. Phase 2: Overall Response Rate (ORR) as Assessed by IRC in Arm C [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  18. Phase 2: Overall Response Rate (ORR) as Assessed by Investigator in Arm C [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  19. Phase 2: Disease Control Rate (DCR) as Assessed by IRC in Arm C(TEAEs) by Severity Grade ≥3, Serious Adverse event (SAEs), and AEs Leading to Treatment Discontinuation [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  20. Phase 2: Disease Control Rate (DCR) as Assessed by Investigator in Arm C [ Time Frame: From first dose of study treatment until death due to any cause (Up to 24 months) ]
  21. Phase 2: Duration of Response (DOR) as Assessed by IRC in Arm C [ Time Frame: From the date of first evidence of objective response until progression (Up to 24 months) ]
  22. Phase 2: Duration of Response (DOR) as Assessed by Investigator in Arm C [ Time Frame: From the date of first evidence of objective response until progression (Up to 24 months) ]
  23. Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by IRC in all Arms [ Time Frame: 6 Months ]
  24. Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by Investigator in all Arms [ Time Frame: 6 Months ]
  25. Phase 2: Overall Survival Rate at 12 and 24 Months in all Arms [ Time Frame: 12 and 24 Months ]
  26. Phase 2: Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) by 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

  • Written informed consent in accordance with federal, local, and institutional guidelines.
  • Age ≥18 years at the time of informed consent and ≥22 year for Arm E.
  • 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, D and E) after 1 to 2 line of systemic therapy (RT ± TMZ or RT ± TMZ in combination with other drug) (surgical resection of recurrent disease allowed). For Arms A and B, MGMT status should be available.
  • Prior therapy:

    1. Arms A and B: participants who have not received RT or any systemic therapy for brain tumor and must be eligible for definitive external beam RT and TMZ
    2. Arm C, D and E: participants must have received prior treatment with RT with or without TMZ and only 1 prior line of therapy (RT ± TMZ in combination with other drug is allowed).
  • Measurable disease according to RANO/modified RANO guidelines is required only for Arm C, D and E; it is not required for Arms A or B.
  • Participants enrolling into Arms C, D, and E 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 Arms C, D, and E).
  • Participants must have adequate organ function ≤2 weeks of study treatment as defined by the following laboratory criteria:

    1. Hematological function ≤7 days prior to Cycle 1 Day 1 (C1 D1): 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 C1 D1
    2. 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
    3. 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 6 months 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 6 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 molecular testing for correlative studies.
  • Limited to supratentorial disease for Arm E only.

Exclusion Criteria

- Participants who are receiving any other investigational agents and /or have had prior therapy including:

For Arms A and B only:

  1. Participants who have previously received RT to the brain
  2. Participants who received chemotherapy for the treatment of their glioma
  3. Participants who are being treated with implanted Gliadel wafers

    For Arm C:

  4. Prior nitrosoureas

    For Arms C, D, and E:

  5. <4 weeks from prior TMZ or other chemotherapy, or <4 weeks or 5 half-lives (whichever is shorter) for investigational agents prior to start of study treatment
  6. Prior treatment bevacizumab or other direct Vascular endothelial growth factor/Vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors. For any questions of the definition of a direct VEGF/VEGFR inhibitor, consult the study Medical Monitor
  7. Any AE which has not recovered to Grade <=1, or returned to baseline, related to the previous GBM therapy, except alopecia, and some other Grade 2 AEs that have been stabilized (upon Medical Monitor approval)

    • Participants who are being treated or plan to be treated during this study with TTField for participants in Arms A to D.
    • Major surgery <2 weeks prior to the start of study treatment for Arms A to C and E, <4 weeks for Arm D.
    • 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, intracranial hemorrhage, 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.
    • Participants with mutated isocitrate dehydrogenase (IDH) should be excluded for Phase 2.
    • For participants in Arm C, Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) below 70% of predicted.
    • For Arm E: implanted active electronic medical devices such as programmable intraventricular shunts, spinal cord, vagus nerve or deep brain stimulators, pacemakers or implantable automatic defibrillators, skull defect (i.e. missing bone with no replacement), sensitivity to conductive hydrogels as used in electrocardiograms (ECGs), an underlying serious scalp condition that may interfere with placement of arrays, or bullet fragments, or documented clinically significant arrhythmias.

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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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
2021-000080-67 ( EudraCT Number )
First Posted: June 9, 2020    Key Record Dates
Last Update Posted: October 15, 2021
Last Verified: October 2021
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
Bevacizumab
TTField
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
Bevacizumab
Temozolomide
Carmustine
Lomustine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action