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

Sponsor

Karyopharm Therapeutics Inc (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04421378

Collaborator

(none)

474

Enrollment

Locations

Arms

30.8

Anticipated Duration (Months)

26.3

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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 :

Jun 8, 2020

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

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 Names: 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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

Phase 1a: Maximum Tolerated Dose Per Arm: Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [During Cycle 1 of treatment (42 days/cycle) for each participant]
Phase 1a: Recommended Phase 2 Dose Per Arm [Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle)]
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 [Up to 30 days post last dose]
Phase 1b: Progressive Free Survival at 3 Months for All Arms [3 Months]
Phase 1b: Overall Survival (OS) for All Arms [From date of randomization up to death (Up to 24 months)]
Phase 2: Progression-free Survival (PFS) in Arms A and B [From date of randomization to the date of disease progression or death (Up to 24 months)]
Phase 2: Overall Survival (OS) for Arm C [From date of randomization up to death (Up to 24 months)]

Secondary Outcome Measures

Phase 1a: Overall Survival (OS) for Each Arm [From first dose of study treatment until death due to any cause (Up to 24 months)]
Phase 1a/1b: Time to Progression (TTP) for Each Arm [From first dose of study treatment until progression or death due to progression (Up to 24 months)]
Phase 1a/1b: Progressive Free Survival (PFS) for Each Arm [From first dose of study treatment until progression or death due to any cause (Up to 24 months)]
Phase 1a/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 24 months)]
Phase 1a/1b: Disease Control Rate (DCR) Based on Modified Response Assessment in Neuro-Oncology Criteria in Arm C, D and E [From first dose of study treatment until death due to any cause (Up to 24 months)]
Phase 1a/1b: Duration of Response (DOR) in Arm C, D and E [From the date of first evidence of objective response until progression (Up to 24 months)]
Phase 1a/1b: Maximum Plasma Concentration (Cmax) of Selinexor [2, 4, and 6 hours post-dose]
Phase 1a/1b: Area Under the Concentration-time Curve (AUC) of Selinexor [2, 4, and 6 hours post-dose]
Phase 1a/1b: Apparent Clearance (CL) of Selinexor [2, 4, and 6 hours post-dose]
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 [Up to 30 days post last dose]
Phase 1b: Maximum Tolerated Dose [Up to 24 months]
Phase 1b: Recommended Phase 2 Dose [Up to 24 months]
Phase 2: Progression Free Survival Per (PFS) as Assessed by Investigator per Modified Response Assessment in Neuro-Oncology Criteria in Arms A and B [From date of randomization to the date of disease progression or death (Up to 24 months)]
Phase 2: Overall Survival for Participants With Newly Diagnosed Glioblastoma Multiforme in Arms A and B [From date of randomization to death (Up to 24 months)]
Phase 2: Progression Free Survival (PFS) as Assessed by Independent Review Committee (IRC) per Modified Response Assessment in Neuro-Oncology Criteria in Arm C [From date of randomization to the date of disease progression or death (Up to 24 months)]
Phase 2: Progression Free Survival (PFS) as Assessed by Investigator per Modified Response Assessment in Neuro-Oncology Criteria in Arm C [From date of randomization to the date of disease progression or death (Up to 24 months)]
Phase 2: Overall Response Rate (ORR) as Assessed by IRC in Arm C [From first dose of study treatment until death due to any cause (Up to 24 months)]
Phase 2: Overall Response Rate (ORR) as Assessed by Investigator in Arm C [From first dose of study treatment until death due to any cause (Up to 24 months)]
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 [From first dose of study treatment until death due to any cause (Up to 24 months)]
Phase 2: Disease Control Rate (DCR) as Assessed by Investigator in Arm C [From first dose of study treatment until death due to any cause (Up to 24 months)]
Phase 2: Duration of Response (DOR) as Assessed by IRC in Arm C [From the date of first evidence of objective response until progression (Up to 24 months)]
Phase 2: Duration of Response (DOR) as Assessed by Investigator in Arm C [From the date of first evidence of objective response until progression (Up to 24 months)]
Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by IRC in all Arms [6 Months]
Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by Investigator in all Arms [6 Months]
Phase 2: Overall Survival Rate at 12 and 24 Months in all Arms [12 and 24 Months]
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 [Up to 30 days post last dose]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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
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:

Hematological function ≤7 days prior to Cycle 1 Day 1 (C1 D1): Absolute neutrophil count (ANC) ≥1.510^9 per Liter (/L); platelet count ≥15010^9/L; and hemoglobin (Hb) ≥10.0 gram per deciliter (g/dL). Transfusion is not allowed within 7 days prior to C1 D1
Hepatic function: bilirubin ≤2the upper limit of normal (ULN), alanine transaminase (ALT) ≤2.5ULN, aspartate transaminase (AST) ≤2.5ULN; unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin must be <4ULN
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:

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

For Arm C:

Prior nitrosoureas

For Arms C, D, and E:

<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
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
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)	Los Angeles	California	United States	90033
3	University of California	San Francisco	California	United States	94122
4	Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive	Miami	Florida	United States	33176
5	Piedmont Healthcare	Atlanta	Georgia	United States	30309
6	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	Hackensack Meridian Health, 92 Second Street	Hackensack	New Jersey	United States	07601
10	Atlantic Health Systems Hospital Corp.	Morristown	New Jersey	United States	07960
11	Northwell Health	Lake Success	New York	United States	11042
12	Columbia University Irving Medical Center	New York	New York	United States	10032
13	Lenox Hill Hospital-Northwell Health	New York	New York	United States	10075
14	Cleveland Clinic	Cleveland	Ohio	United States	44195
15	MD Anderson Cancer Center	Houston	Texas	United States	77030
16	University of Utah - Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
17	University of Washington - Alvord Brain Tumor Center	Seattle	Washington	United States	98109
18	Princess Margaret Hospital (PMH)	Toronto	Ontario	Canada	M5G 2MG