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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
74
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.
Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous
Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.
Dose and Formulation: 150 or 200 mg/m\^2; Route of Administration: Intravenous
University of Alabama
Birmingham, Alabama, United States
University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)
Los Angeles, California, United States
University of California
San Francisco, California, United States
Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive
Miami, Florida, United States
Piedmont Healthcare
Atlanta, Georgia, United States
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Hackensack Meridian Health, 92 Second Street
Hackensack, New Jersey, United States
Atlantic Health Systems Hospital Corp.
Morristown, New Jersey, United States
...and 8 more locations
Phase 1a and 1b: Maximum Tolerated Dose of Selinexor
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.
Time frame: At Cycle 1 (up to 42 days)
Phase 1a and 1b: Recommended Phase 2 Dose (RP2D) of Selinexor
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).
Time frame: From Cycle 1 Day 1 up to 14 days after last dose (up to 15.41 months) (Each Cycle length = up to 42 days)
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
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.
Time frame: From first dose of study treatment up to 30 days post last dose (Up to 16.41 months)
Phase 1a and 1b: Percentage of Participants With Progression Free Survival 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.
Time frame: At 3 Months
Phase 1a and 1b: Overall Survival (OS)
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.
Time frame: From date of randomization to the date of death due to any cause or until lost to follow-up (up to 20 months)
Phase 1a and 1b: Time to Progression (TTP)
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.
Time frame: From first dose study treatment until progression or death due to progression (Up to 15.41 months)
Phase 1a and 1b: Progressive Free Survival (PFS)
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.
Time frame: From first dose of study treatment until progression or death due to any cause (Up to 15.41 months)
Phase 1a and 1b: Overall Response Rate (ORR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria in Arm C, D and E
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.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: From first dose of study treatment until death due to any cause (Up to 15.41 months)
Phase 1a and 1b: Disease Control Rate (DCR) Based on Modified Response Assessment in Neuro-Oncology (RANO) Criteria in Arm C, D and E
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.
Time frame: From first dose of study treatment until death due to any cause (Up to 15.41 months)
Phase 1a and 1b: Duration of Response (DOR) in Arm C, D and E
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).
Time frame: From the date of first evidence of objective response until progression (Up to 15.41 months)
Phase 1a and 1b: Maximum Plasma Concentration (Cmax) of Selinexor
Cmax of Selinexor was reported.
Time frame: Cycle 1 Day 1: 2, 4, and 6 hours post-dose (Cycle 1 length = up to 42 days)