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

Protocol # :
Glioblastoma Multiforme
Disease Sites
Brain and Nervous System
Principal Investigator
Wen, Patrick, Yung

Trial Description

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

Eligibility Requirements

Inclusion Criteria

- Written informed consent in accordance with federal, local, and institutional

- 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

- 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

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

- 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

- 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.