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

NCT04421378 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: XPORT-GBM-0292021-000080-67
• Study Type: interventional
• Target: 74
• Locations: 2 countries
• Sites: 18

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

Conditions

Glioblastoma Multiforme

Keywords

nGBM; rGBM; GBM; Temozolomide; Lomustine; KPT-330; XPOVIO; Selinexor; Newly diagnosed glioblastoma multiforme; Recurrent glioblastoma multiforme; Bevacizumab; TTField

Outcome Measures

Primary Outcomes (5)

• 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.

  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).

  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.

  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.

  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.

  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)

  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)

  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

  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

  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

  From the date of first evidence of objective response until progression (Up to 15.41 months)

Study Arms (8)

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.

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.

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.

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.

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.

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.

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.

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.

Drug: Selinexor; Device: TTField

Interventions

Selinexor DRUG

Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral

Also known as: KPT-330, XPOVIO

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) DRUG

Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral

Also known as: Temodar

Arm A Control: Temozolomide+Radiation Therapy; Arm B Control: Temozolomide+Radiation Therapy; Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy

Lomustine (CCNU) DRUG

Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral

Arm C Control: Lomustine/Carmustine; Arm C: Selinexor+Lomustine/Carmustine

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.

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

Bevacizumab DRUG

Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous

Arm D: Selinexor+Bevacizumab

TTField DEVICE

Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.

Arm E: Selinexor+TTField

Carmustine DRUG

Dose and Formulation: 150 or 200 mg/m\^2; Route of Administration: Intravenous

Arm C Control: Lomustine/Carmustine; Arm C: Selinexor+Lomustine/Carmustine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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) ≥1.5\*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.

You may not qualify if:

• \- 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.

Sponsors & Collaborators

• Karyopharm Therapeutics Inc: lead

Study Sites (18)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)

Los Angeles, California, 90033, United States

Location

University of California

San Francisco, California, 94122, United States

Location

Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive

Miami, Florida, 33176, United States

Location

Piedmont Healthcare

Atlanta, Georgia, 30309, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Hackensack Meridian Health, 92 Second Street

Hackensack, New Jersey, 07601, United States

Location

Atlantic Health Systems Hospital Corp.

Morristown, New Jersey, 07960, United States

Location

Northwell Health

Lake Success, New York, 11042, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Lenox Hill Hospital-Northwell Health

New York, New York, 10075, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Utah - Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

University of Washington - Alvord Brain Tumor Center

Seattle, Washington, 98109, United States

Location

Princess Margaret Hospital (PMH)

Toronto, Ontario, M5G 2MG, Canada

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

selinexor; Temozolomide; Lomustine; Bevacizumab; Carmustine

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The trial was terminated during the Phase 1b portion of the trial as the initial responses to selinexor treatment were not supportive of continued investigation in glioblastoma, therefore there was no reporting of the Phase 2 outcomes.

Results Point of Contact

• Title: Karyopharm Medical Information
• Organization: Karyopharm Therapeutics Inc

clinicaltrials@karyopharm.com

(888) 209-9326

Study Officials

• Andrew B Lassman, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2020
• First Posted: June 9, 2020
• Study Start: June 8, 2020
• Primary Completion: July 3, 2023
• Study Completion: July 3, 2023
• Last Updated: December 16, 2024
• Results First Posted: December 16, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (17); CA (1)