A Study of Selinexor in Combination With Standard of Care Therapy for Newly Diagnosed or Recurrent Glioblastoma
- Conditions
- Glioblastoma Multiforme
- Interventions
- Radiation: Standard Fractionated Radiation therapy (RT)Device: TTField
- Registration Number
- NCT04421378
- Lead Sponsor
- 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 74
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm B Control: Temozolomide+Radiation Therapy Temozolomide (TMZ) 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. Phase 1: Arm A: Selinexor+Radiation Therapy Standard Fractionated Radiation therapy (RT) 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. Arm C: Selinexor+Lomustine/Carmustine Lomustine (CCNU) 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. Arm A Control: Temozolomide+Radiation Therapy Temozolomide (TMZ) 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. Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy Standard Fractionated Radiation therapy (RT) 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. Arm A Control: Temozolomide+Radiation Therapy Standard Fractionated Radiation therapy (RT) 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. Arm C Control: Lomustine/Carmustine Lomustine (CCNU) 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. Arm E: Selinexor+TTField 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. Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy Temozolomide (TMZ) 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. Arm B Control: Temozolomide+Radiation Therapy Standard Fractionated Radiation therapy (RT) 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. Phase 1: Arm A: Selinexor+Radiation Therapy Selinexor 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. Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy Selinexor 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. Arm C: Selinexor+Lomustine/Carmustine Selinexor 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. Arm C: Selinexor+Lomustine/Carmustine 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. Arm C Control: Lomustine/Carmustine 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. Arm D: Selinexor+Bevacizumab Selinexor 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. Arm D: Selinexor+Bevacizumab 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. Arm E: Selinexor+TTField Selinexor 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.
- Primary Outcome Measures
Name Time Method Phase 1a and 1b: Maximum Tolerated Dose of Selinexor At Cycle 1 (up to 42 days) MTD was defined as highest dose of selinexor in at which no more than one of six participants experienced a dose-limiting toxicity (DLT). DLT was based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Phase 1a and 1b: Recommended Phase 2 Dose (RP2D) of Selinexor From Cycle 1 Day 1 up to 14 days after last dose (up to 15.41 months) (Each Cycle length = up to 42 days) The RP2D was determined by SRC, based on the MTD and the totality of efficacy and safety data of Phase 1a dose escalation study. RP2D was determined based on the totality of the available safety, efficacy, pharmacokinetic/pharmacodynamic (PK/PD).
Phase 1a and 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) With Grade Greater Than or Equal to (>=) 3, Serious TEAEs and Who Discontinued Treatment Due to TEAEs From first dose of study treatment up to 30 days post last dose (Up to 16.41 months) TEAE: any event that was not present prior to initiation of study treatment or any event already present that worsened in either intensity or frequency following exposure to study treatment. Serious adverse event (SAE): any untoward medical occurrence that, at any dose, resulted in death; was life threatening (i.e., an event in which participant was at risk of death at the time of the event; it did not refer to an event that hypothetically might have caused death if it were more severe); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; or was a congenital anomaly/birth defect. Important medical events that might not result in death, was life-threatening, or require hospitalization might be considered serious when, based upon appropriate medical judgment, they might jeopardize participant and might require medical or surgical intervention to prevent one of the outcomes listed above.
Phase 1a and 1b: Percentage of Participants With Progression Free Survival at 3 Months At 3 Months Progression defined as first occurrence of disease progression (PD) per modified Response Assessment in Neuro-Oncology (RANO) including both radiological PD and clinical deterioration. PD per RANO response criteria:1) At least two sequential scans separated by at \>=4 weeks both exhibiting \>=25 percent (%) increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions. 2) In case where baseline or best response demonstrates no measurable enhancing disease, then any new measurable (\>10mm\*10mm) enhancing lesions considered PD after confirmed by a subsequent scan \>=4 weeks exhibiting \>=25% increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions relative to scan first illustrating new measurable disease. 3) Clear clinical deterioration not attributable to other causes apart from tumor or attributable to changes in steroid dose. 4) Failure to return for evaluation as a result of death.
Phase 1a and 1b: Overall Survival (OS) From date of randomization to the date of death due to any cause or until lost to follow-up (up to 20 months) OS was defined as the time from the date of randomization until death due to any cause or until lost to follow-up for all participants.
- Secondary Outcome Measures
Name Time Method Phase 1a and 1b: Time to Progression (TTP) From first dose study treatment until progression or death due to progression (Up to 15.41 months) TTP was defined for participants as the duration from start of treatment to the date of PD, or death due to PD, whichever occurs first. PD per RANO response criteria: 1) At least two sequential scans separated by at \>=4 weeks both exhibiting \>=25 percent (%) increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions. 2) In case where baseline or best response demonstrates no measurable enhancing disease, then any new measurable (\>10mm\*10mm) enhancing lesions considered PD after confirmed by a subsequent scan \>=4 weeks exhibiting \>=25% increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions relative to scan first illustrating new measurable disease. 3) Clear clinical deterioration not attributable to other causes apart from tumor or attributable to changes in steroid dose. 4) Failure to return for evaluation as a result of death or deteriorating condition.
Phase 1a and 1b: Progressive Free Survival (PFS) From first dose of study treatment until progression or death due to any cause (Up to 15.41 months) Progression defined as first occurrence of PD per modified RANO including both radiological PD and clinical deterioration. PD per RANO response criteria: 1) At least two sequential scans separated by at \>=4 weeks both exhibiting \>=25 percent (%) increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions. 2) In case where baseline or best response demonstrates no measurable enhancing disease, then any new measurable (\>10mm\*10mm) enhancing lesions considered PD after confirmed by a subsequent scan \>=4 weeks exhibiting \>=25% increase in sum of products of perpendicular diameters or \>=40% increase in total volume of enhancing lesions relative to scan first illustrating new measurable disease. 3) Clear clinical deterioration not attributable to other causes apart from tumor or attributable to changes in steroid dose. 4) Failure to return for evaluation as a result of death or deteriorating condition.
Phase 1a and 1b: Overall Response Rate (ORR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria in Arm C, D and E From first dose of study treatment until death due to any cause (Up to 15.41 months) ORR was defined as percentage of participants who achieve a CR or PR per modified RANO criteria. CR defined as that meet all following: 1) Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. 2) No new lesions. 3) Participants must be off corticosteroids (or on physiologic replacement doses only). 4) Stable or improved clinical assessments (i.e., neurological examinations). PR defined as that meet all following: 1) \>=50% decrease in sum of products of perpendicular diameters or \>=65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks. 2) No new lesion. 3. Steroid dose should be the same or lower compared with baseline scan. 4) Stable or improved clinical assessments.
Phase 1a and 1b: Disease Control Rate (DCR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria in Arm C, D and E From first dose of study treatment until death due to any cause (Up to 15.41 months) DCR: percentage of participants who achieve CR, PR, or stable disease (SD) per modified RANO criteria. CR: 1) Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. 2) No new lesions. 3) Participants must be off corticosteroids. 4) Stable or improved clinical assessments. PR: 1) \>=50% decrease in sum of products of perpendicular diameters or \>=65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks. 2) No new lesion. 3) Steroid dose should be same or lower compared with baseline scan. 4) Stable or improved clinical assessments. SD: 1) Does not qualify for CR, PR, or PD. 2) In event that corticosteroid dose was increased without confirmation of PD on neuroimaging, and subsequent follow-up imaging shows steroid increase was required because of PD, last scan considered to show SD was scan obtained when corticosteroid dose was equivalent to baseline dose.
Phase 1a and 1b: Duration of Response (DOR) in Arm C, D and E From the date of first evidence of objective response until progression (Up to 15.41 months) DOR was defined as the time from the date of first evidence of objective response (CR or PR) until PD. CR defined as that meet all following: 1) Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. 2) No new lesions. 3) Participants must be off corticosteroids (or on physiologic replacement doses only). 4) Stable or improved clinical assessments (i.e., neurological examinations). PR defined as that meet all following: 1) \>=50% decrease in sum of products of perpendicular diameters or \>=65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks. 2) No new lesion. 3. Steroid dose should be the same or lower compared with baseline scan. 4) Stable or improved clinical assessments. DOR was analyzed by Kaplan-Meier for participants who have achieved overall response (CR or PR).
Phase 1a and 1b: Maximum Plasma Concentration (Cmax) of Selinexor Cycle 1 Day 1: 2, 4, and 6 hours post-dose (Cycle 1 length = up to 42 days) Cmax of Selinexor was reported.
Trial Locations
- Locations (18)
University of Alabama
🇺🇸Birmingham, Alabama, United States
University of California
🇺🇸San Francisco, California, United States
University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)
🇺🇸Los Angeles, California, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
Lenox Hill Hospital-Northwell Health
🇺🇸New York, New York, United States
Northwell Health
🇺🇸Lake Success, New York, United States
University of Utah - Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
University of Washington - Alvord Brain Tumor Center
🇺🇸Seattle, Washington, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive
🇺🇸Miami, Florida, United States
Piedmont Healthcare
🇺🇸Atlanta, Georgia, United States
Hackensack Meridian Health, 92 Second Street
🇺🇸Hackensack, New Jersey, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Atlantic Health Systems Hospital Corp.
🇺🇸Morristown, New Jersey, United States
Princess Margaret Hospital (PMH)
🇨🇦Toronto, Ontario, Canada