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

Glioblastoma Multiforme Clinical Trial

Official title:

A Phase 1/2 Study of Selinexor in Combination With Standard of Care (SoC) Therapy for Newly Diagnosed or Recurrent Glioblastoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04421378
• Other study ID #: XPORT-GBM-029
• Secondary ID: 2021-000080-67
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: June 8, 2020
• Est. completion date: July 3, 2023

Study information

• Verified date: August 2023
• Source: Karyopharm Therapeutics Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 74
• Est. completion date: July 3, 2023
• Est. primary completion date: July 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

1. 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

2. 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:

1. 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

2. 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

3. 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:

1. Participants who have previously received RT to the brain

2. Participants who received chemotherapy for the treatment of their glioma

3. Participants who are being treated with implanted Gliadel wafers

For Arm C:

4. Prior nitrosoureas

For Arms C, D, and E:

5. <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

6. 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

7. 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.

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme

Intervention

Drug:
• Selinexor
Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral
• Temozolomide (TMZ)
Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral
• Lomustine (CCNU)
Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral

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.

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

Device:
• TTField
Dose and Formulation: 200 kHz =18h/day; Route of administration: Scalp application of transducer arrays.

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

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital (PMH)	Toronto	Ontario
United States	Piedmont Healthcare	Atlanta	Georgia
United States	University of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Hackensack Meridian Health, 92 Second Street	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	Northwell Health	Lake Success	New York
United States	University of Southern California (USC Norris Comprehensive Cancer Center and LAC+USC Medical Center)	Los Angeles	California
United States	Baptist Hospital of Miami Cancer Institute, 8900 North Kendall Drive	Miami	Florida
United States	Atlantic Health Systems Hospital Corp.	Morristown	New Jersey
United States	Columbia University Irving Medical Center	New York	New York
United States	Lenox Hill Hospital-Northwell Health	New York	New York
United States	University of Utah - Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of California	San Francisco	California
United States	University of Washington - Alvord Brain Tumor Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Phase 1a: Recommended Phase 2 Dose Per Arm		Cycle 1 Day 1 up to 14 days after last dose (42 days/cycle)
Primary	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
Primary	Phase 1b: Progressive Free Survival at 3 Months for All Arms		3 Months
Primary	Phase 1b: Overall Survival (OS) for All Arms		From date of randomization up to death (Up to 24 months)
Primary	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)
Primary	Phase 2: Overall Survival (OS) for Arm C		From date of randomization up to death (Up to 24 months)
Secondary	Phase 1a: Overall Survival (OS) for Each Arm		From first dose of study treatment until death due to any cause (Up to 24 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Phase 1a/1b: Maximum Plasma Concentration (Cmax) of Selinexor		2, 4, and 6 hours post-dose
Secondary	Phase 1a/1b: Area Under the Concentration-time Curve (AUC) of Selinexor		2, 4, and 6 hours post-dose
Secondary	Phase 1a/1b: Apparent Clearance (CL) of Selinexor		2, 4, and 6 hours post-dose
Secondary	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
Secondary	Phase 1b: Maximum Tolerated Dose		Up to 24 months
Secondary	Phase 1b: Recommended Phase 2 Dose		Up to 24 months
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by IRC in all Arms		6 Months
Secondary	Phase 2: Progression Free Survival at 6 Months (PFS6) as Assessed by Investigator in all Arms		6 Months
Secondary	Phase 2: Overall Survival Rate at 12 and 24 Months in all Arms		12 and 24 Months
Secondary	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