Selinexor in Treating Younger Patients With Recurrent or Refractory Solid Tumors or High-Grade Gliomas

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) of
the tablet formulation of selinexor in children with recurrent/refractory solid and central
nervous system (CNS) tumors.

II. To describe the toxicities of selinexor in children with recurrent/refractory solid and
CNS tumors.

III. To characterize the pharmacokinetics of the tablet formulation of selinexor in children
with recurrent/refractory solid and CNS tumors.

SECONDARY OBJECTIVES:

I. To determine the antitumor effect of selinexor in a preliminary manner in children with
recurrent/refractory solid and CNS tumors.

II. To determine the pharmacodynamic properties of selinexor in children and adolescents with
refractory solid tumors in plasma proteins and whole blood ribonucleic acid (RNA).

III. To explore the penetration, pharmacodynamic effects, and biologic effects of selinexor
in tumor tissue of patients with recurrent/refractory high-grade gliomas (HGG) requiring
resection.

IV. To further assess the toxicity and antitumor effects of selinexor in children with
recurrent/refractory HGG in expanded cohorts following dose-escalation by measuring rate of
objective radiographic response (medical patients) and rate of progression-free survival
(PFS) six months from the start of treatment (surgical patients).

OUTLINE: This is a dose escalation study.

Patients receive selinexor orally (PO) twice weekly (days 1, 3, 8, 10, 15, and 17). Treatment
repeats every 28 days for up to 24 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have a body surface area (BSA) >= 0.84 m^2

- Diagnosis:

- Part A: Patients with recurrent or refractory solid tumors, including lymphoma
and CNS tumors, are eligible; patients must have had histologic verification of
malignancy at original diagnosis or relapse except in patients with intrinsic
brain stem tumors, optic pathway gliomas, or patients with pineal tumors and
elevations of cerebrospinal fluid (CSF) or serum tumor markers including
alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

- Part B: Patients with recurrent or refractory high grade glioma (World Health
Organization [WHO] grade III/IV) including disseminated tumors (excluding diffuse
intrinsic pontine glioma [DIPG]), not requiring surgical resection; patients must
have had histologic verification of malignancy at original diagnosis or relapse

- Part C: Patients with recurrent or refractory high grade glioma (WHO grade
III/IV) and requiring surgical resection (excluding DIPG and disseminated
tumors), who in the opinion of treating physicians, are medically stable to
receive 3-4 doses of selinexor (8-10 days of treatment) before undergoing surgery
without compromising the success of the procedure; note that if, in the opinion
of treating physicians, current symptoms necessitate surgery before 3-4 doses
will be able to be received, surgery should not be delayed to administer
selinexor, and the patient would be ineligible for protocol therapy

- Disease status:

- Part A: Patients must have either measurable or evaluable disease

- Parts B and C: Patients must have measurable disease on imaging

- Patient?s current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age; Note: Neurologic deficits in patients with CNS tumors must have been
relatively stable for at least 7 days prior to study enrollment; patients who are
unable to walk because of paralysis, but who are up in a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment; if after the required timeframe, the
numerical eligibility criteria are met, e.g. blood count criteria, the patient is
considered to have recovered adequately

- Myelosuppressive chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration of this interval must be discussed with
the study chair

- Biologic (anti-neoplastic agent): At least 7 days after the last dose of a
biologic agent; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during which
adverse events are known to occur; the duration of this interval must be
discussed with the study chair

- Immunotherapy: At least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1

- Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid

- External beam radiation therapy (XRT): At least 14 days after local palliative
XRT (small port); at least 150 days must have elapsed if prior total body
irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42
days must have elapsed if other substantial bone marrow (BM) radiation

- Stem cell infusion without TBI: No evidence of active graft vs. host disease and
at least 56 days must have elapsed after transplant or stem cell infusion

- Patients must not have received prior exposure to selinexor

- For patients with solid tumors without known bone marrow involvement:

- * Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- * Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- * Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)

- Patients with known bone marrow metastatic disease will be eligible for study if they
meet the blood counts (may receive transfusions provided they are not known to be
refractory to red cell or platelet transfusions); these patients will not be evaluable
for hematologic toxicity; at least 5 of every cohort of 6 patients must be evaluable
for hematologic toxicity for the dose-escalation part of the study; if dose-limiting
hematologic toxicity is observed, all subsequent patients enrolled on Part A must be
evaluable for hematologic toxicity

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or

- A serum creatinine based on age/gender as follows:

- =< 0.6 mg/dL (patients age 1 to < 2 years)

- =< 0.8 mg/dL (patients age 2 to < 6 years)

- =< 1 mg/dL (patients age 6 to < 10 years)

- =< 1.2 mg/dL (patients age 10 to < 13 years)

- =< 1.4 mg/dL (female patients age >= 13 years)

- =< 1.5 mg/dL (male patients age 13 to < 16 years)

- =< 1.7 mg/dL (male patients age >= 16 years)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
ULN = 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L

- Serum albumin >= 2 g/dL

- Serum amylase =< 1.5 x ULN

- Serum lipase =< 1.5 x ULN

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled

- Patients must be able to swallow tablets whole

- Part C: Archived paraffin-embedded tissue (20 unstained slides or a tumor block) from
a prior resection must be available as a control for correlative studies; if tissue
blocks or slides are unavailable, the study chair must be notified prior to enrollment

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive use two effective methods of birth control- including a medically
accepted barrier method of contraceptive method (e.g., male or female condom) for the
entire period in which they are receiving protocol therapy; abstinence is an
acceptable method of birth control

- Concomitant medications

- Corticosteroids: Patients receiving corticosteroids who have not been on a stable
or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
not eligible; if used to modify immune adverse events related to prior therapy,
>= 14 days must have elapsed since last dose of corticosteroid

- Investigational drugs: Patients who are currently receiving another
investigational drug are not eligible

- Anti-cancer agents: Patients who are currently receiving other anti-cancer agents
are not eligible

- Patients who have an uncontrolled infection are not eligible

- Patients who have received a prior solid organ transplantation are not eligible

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible

- Patients with body mass index (BMI) < 3rd percentile for age, as defined by WHO
criteria for patients 1-2 years of age and Centers for Disease Control and Prevention
(CDC) criteria for patients > 2 years of age, are not eligible

- Patients with grade 3 ataxia or grade >1 extrapyramidal movement disorder are not
eligible

- Patients with known macular degeneration, uncontrolled glaucoma, or cataracts are not
eligible