Glioblastoma MultiformePhase 1/2NCT04421378
A Study of Selinexor in Combination With Standard of Care Therapy for Newly Diagnosed or Recurrent Glioblastoma
A Phase 1/2 study testing Selinexor, Temozolomide (TMZ) and Lomustine (CCNU) in people with Glioblastoma Multiforme, run by Karyopharm Therapeutics Inc at 18 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma Multiforme
- What is being tested?
- Selinexor, Temozolomide (TMZ) and Lomustine (CCNU)
- Type of treatment
- Pill or oral medicine, Injection or infusion, Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 74 participants
- Where
- 18 sitesin 2 countries
- Study dates
- 8 Jun 2020to 3 Jul 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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) ≥1.5*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
- 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 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.
Who cannot join
- 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:
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- 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.
Trial locations and contacts
18 sites in 2 countries.
18 sites in 2 countries
United States17 sites
Piedmont Healthcare
Atlanta, Georgia, 30309
University of Alabama
Birmingham, Alabama, 35294
Massachusetts General Hospital
Boston, Massachusetts, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
Cleveland Clinic
Cleveland, Ohio, 44195
Hackensack Meridian Health, 92 Second Street
Hackensack, New Jersey, 07601
MD Anderson Cancer Center
Houston, Texas, 77030
Northwell Health
Lake Success, New York, 11042
University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)
Los Angeles, California, 90033
Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive
Miami, Florida, 33176
Atlantic Health Systems Hospital Corp.
Morristown, New Jersey, 07960
Columbia University Irving Medical Center
New York, New York, 10032
Lenox Hill Hospital-Northwell Health
New York, New York, 10075
University of Utah - Huntsman Cancer Institute
Salt Lake City, Utah, 84112
University of California
San Francisco, California, 94122
University of Washington - Alvord Brain Tumor Center
Seattle, Washington, 98109
About this study
Official title: A Phase 1/2 Study of Selinexor in Combination With Standard of Care (SoC) Therapy for Newly Diagnosed or Recurrent Glioblastoma
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
- Conditions
- Glioblastoma Multiforme
- Being tested
- Selinexor, Temozolomide (TMZ), Lomustine (CCNU), Standard Fractionated Radiation therapy (RT), Bevacizumab
- Keywords
- nGBM, rGBM, GBM, Temozolomide, Lomustine, KPT-330, XPOVIO, Selinexor, Newly diagnosed glioblastoma multiforme, Recurrent glioblastoma multiforme, Bevacizumab, TTField
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SelinexorDrug
Also called KPT-330, XPOVIO
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
Temozolomide (TMZ)Drug
Also called Temodar
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
Lomustine (CCNU)Drug
Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral
Standard Fractionated Radiation therapy (RT)Radiation
Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.
BevacizumabDrug
Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous
TTFieldDevice
Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.
CarmustineDrug
Dose and Formulation: 150 or 200 mg/m^2; Route of Administration: Intravenous
| Study group | Role | What they receive |
|---|---|---|
| Phase 1: Arm A: Selinexor+Radiation Therapy | Experimental | 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. Receives: Drug: Selinexor; Radiation: Standard Fractionated Radiation therapy (RT) |
| Arm A Control: Temozolomide+Radiation Therapy | Active comparator | 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. Receives: Drug: Temozolomide (TMZ); Radiation: Standard Fractionated Radiation therapy (RT) |
| Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy | Experimental | 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. Receives: Drug: Selinexor; Drug: Temozolomide (TMZ); Radiation: Standard Fractionated Radiation therapy (RT) |
| Arm B Control: Temozolomide+Radiation Therapy | Active comparator | 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. Receives: Drug: Temozolomide (TMZ); Radiation: Standard Fractionated Radiation therapy (RT) |
| Arm C: Selinexor+Lomustine/Carmustine | Experimental | 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. Receives: Drug: Selinexor; Drug: Lomustine (CCNU); Drug: Carmustine |
| Arm C Control: Lomustine/Carmustine | Active comparator | 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. Receives: Drug: Lomustine (CCNU); Drug: Carmustine |
| Arm D: Selinexor+Bevacizumab | Experimental | 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. Receives: Drug: Selinexor; Drug: Bevacizumab |
| Arm E: Selinexor+TTField | Experimental | 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. Receives: Drug: Selinexor; Device: TTField |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From date of randomization to the date of death due to any cause or until lost to follow-up (up to 20 months)
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: Cycle 1 Day 1: 2, 4, and 6 hours post-dose (Cycle 1 length = up to 42 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2020
- Study start8 Jun 2020
- Primary completion3 Jul 2023
- Study completion3 Jul 2023
Why it stopped: Upon further consideration of the existing data and the competitive landscape, Karyopharm Therapeutics Inc has decided not to pursue the ongoing development of Selinexor in GBM at this time.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Glioblastoma MultiformeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 74 participants (actual)
Sponsor and investigators
- Lead sponsor
- Karyopharm Therapeutics Inc
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Andrew B Lassman, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04421378
- Sponsor's protocol ID
- XPORT-GBM-029
- Other IDs
- 2021-000080-67
- Status last verified
- Nov 2024
- First submitted
- 1 Jun 2020
- Last updated
- 16 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2 Study of Selinexor in Combination With Standard of Care (SoC) Therapy for Newly Diagnosed or Recurrent Glioblastoma
- ClinicalTrials.gov ID
- NCT04421378
- Acronym / sponsor ID
- XPORT-GBM-029
- Conditions
- Glioblastoma Multiforme
- Keywords
- nGBM, rGBM, GBM, Temozolomide, Lomustine, KPT-330, XPOVIO, Selinexor
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Upon further consideration of the existing data and the competitive landscape, Karyopharm Therapeutics Inc has decided not to pursue the ongoing development of Selinexor in GBM at this time.
- Enrolment
- 74 participants (actual)
- Lead sponsor
- Karyopharm Therapeutics IncIndustry (pharma, biotech, devices)
- Study start
- 8 Jun 2020 (actual)
- Primary completion
- 3 Jul 2023 (actual)
- Study completion
- 3 Jul 2023 (actual)
- First posted
- 9 Jun 2020 (actual)
- Results
- Posted 16 Dec 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| Phase 1: Arm A: Selinexor+Radiation Therapy | Experimental | Drug: Selinexor, Radiation: 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 A Control: Temozolomide+Radiation Therapy | Active comparator | Drug: Temozolomide (TMZ), Radiation: 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. |
| Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy | Experimental | Drug: Selinexor, Drug: Temozolomide (TMZ), Radiation: 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 B Control: Temozolomide+Radiation Therapy | Active comparator | Drug: Temozolomide (TMZ), Radiation: 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. |
| Arm C: Selinexor+Lomustine/Carmustine | Experimental | Drug: Selinexor, Drug: Lomustine (CCNU), Drug: CarmustineParticipants 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 | Active comparator | Drug: Lomustine (CCNU), Drug: CarmustineParticipants 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 | Experimental | Drug: Selinexor, Drug: BevacizumabParticipants 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 | Experimental | Drug: Selinexor, Device: TTFieldParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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:
- 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.
Key exclusion criteria (23 listed)
- Participants who are receiving any other investigational agents and /or have had prior therapy including:
- 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
- Prior nitrosoureas
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SelinexorAlso: KPT-330, XPOVIODose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral | Drug | Arm C: Selinexor+Lomustine/Carmustine, Arm D: Selinexor+Bevacizumab, Arm E: Selinexor+TTField, Phase 1: Arm A: Selinexor+Radiation Therapy, Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy |
| Temozolomide (TMZ)Also: TemodarDose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral | Drug | Arm A Control: Temozolomide+Radiation Therapy, Arm B Control: Temozolomide+Radiation Therapy, Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy |
| Lomustine (CCNU)Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral | Drug | Arm C Control: Lomustine/Carmustine, Arm C: Selinexor+Lomustine/Carmustine |
| 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. | Radiation | Arm A Control: Temozolomide+Radiation Therapy, Arm B Control: Temozolomide+Radiation Therapy, Phase 1: Arm A: Selinexor+Radiation Therapy, Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy |
| BevacizumabDose and Formulation: 10 mg/kg; Route of Administration: Intravenous | Drug | Arm D: Selinexor+Bevacizumab |
| TTFieldDose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays. | Device | Arm E: Selinexor+TTField |
| CarmustineDose and Formulation: 150 or 200 mg/m^2; Route of Administration: Intravenous | Drug | Arm C Control: Lomustine/Carmustine, Arm C: Selinexor+Lomustine/Carmustine |
Primary outcome
Phase 1a and 1b: Maximum Tolerated Dose of Selinexor
Time frame: 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
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)
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
Time frame: 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
Time frame: 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)
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)
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.
6 secondary outcomes
Phase 1a and 1b: Time to Progression (TTP)
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)
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
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
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
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
Time frame: Cycle 1 Day 1: 2, 4, and 6 hours post-dose (Cycle 1 length = up to 42 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Dec 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew B Lassman, MD principal investigator
Columbia University
18 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Selinexor, Temozolomide (TMZ) and Lomustine (CCNU) in people with Glioblastoma Multiforme, run by Karyopharm Therapeutics Inc at 18 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1a and 1b: Maximum Tolerated Dose of Selinexor (time frame: At Cycle 1 (up to 42 days)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Dec 2024.