Clinical Trials /

A Study of Selinexor in Combination With Standard of Care Therapy for Newly Diagnosed or Recurrent Glioblastoma

NCT04421378

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Selinexor in Combination With Standard of Care Therapy for Newly Diagnosed or Recurrent Glioblastoma
  • Official Title: A Phase 1/2 Study of Selinexor in Combination With Standard of Care (SoC) Therapy for Newly Diagnosed or Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: XPORT-GBM-029
  • NCT ID: NCT04421378

Conditions

  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
SelinexorKPT-330, XPOVIOArm A: Selinexor+Radiation Therapy
Temozolomide (TMZ)TemodarArm A_Control: Temozolomide+Radiation Therapy
Lomustine (CCNU)Arm C: Selinexor+Lomustine

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Selinexor+Radiation TherapyExperimentalParticipants 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.
  • Selinexor
Arm A_Control: Temozolomide+Radiation TherapyActive ComparatorParticipants 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.
  • Temozolomide (TMZ)
Arm B: Selinexor+Temozolomide+Radiation TherapyExperimentalParticipants 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.
  • Selinexor
  • Temozolomide (TMZ)
Arm B_Control: Temozolomide+Radiation TherapyActive ComparatorParticipants 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.
  • Temozolomide (TMZ)
Arm C: Selinexor+LomustineExperimentalParticipants 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.
  • Selinexor
  • Lomustine (CCNU)
Arm C_Control: LomustineActive ComparatorParticipants 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.
  • Lomustine (CCNU)

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Phase 1: Overall Survival Per Arm Independently
Time Frame:From the date of randomization to death (Up to 24 months)
Safety Issue:
Description:
Measure:Phase 1: Progression Free Survival Per Arm Independently
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Phase 2: Rate of Progression Free Survival at 6-month (PFS6)
Time Frame:6 months
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Number of Participants With Abnormalities Related to Vital Signs, Clinical Laboratory Values, and Physical Examinations
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Karyopharm Therapeutics Inc

Trial Keywords

  • nGBM
  • rGBM
  • GBM
  • Temozolomide
  • Lomustine
  • KPT-330
  • XPOVIO
  • Selinexor
  • Newly diagnosed glioblastoma multiforme
  • Recurrent glioblastoma multiforme

Last Updated

June 5, 2020