PRIMARY OBJECTIVES:
I. To define toxicities and estimate the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of selinexor administered as an oral formulation in combination with standard of care radiation therapy (RT), to pediatric patients with newly diagnosed high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). (Dose-finding phase/phase I) II. To estimate the event-free survival (EFS) distribution for diffuse midline glioma (DMG)/HGG patients and overall survival (OS) distribution for DIPG patients associated with selinexor plus RT, followed by selinexor in patients with newly diagnosed HGG (H3 K27M mutant DMG or H3 K27-wild type HGG) or DIPG, and to compare those outcomes to historical controls. (Efficacy phase/phase II)
EXPLORATORY OBJECTIVE:
I. To bank tumor specimens and body fluids (blood and cerebrospinal fluid) for future studies.
OUTLINE: This is a phase I dose-escalation study of selinexor followed by a phase II study.
CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor orally (PO) on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a magnetic resonance imaging (MRI) and may undergo a biopsy during screening.
MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.
After completion of study treatment, patients are followed every 3 months for year 1 (i.e., 3, 6, 9, 12 months), then every 6 months for years 2-3 (i.e., 18, 24, 30, 36 months), and finally once yearly for years 4-5 of this study.
Inclusion Criteria:
- STEP 0: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
on Step 0.
- Please note:
- This age range includes pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria.
- Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are
>= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
- STEP 0: Patient is suspected of having localized, newly diagnosed HGG, excluding
metastatic disease, OR patient has an institutional diagnosis of DIPG
- STEP 0:
- For patients with non-pontine tumors: Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part
A.
- For patients with DIPG: Patient and/or their parents or legal guardians have
signed informed consent for ACNS1821.
- STEP 0:
- For patients with non-pontine tumors only, the specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably
within 5 calendar days of definitive surgery
- STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
- STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
- STEP 1: Stratum DIPG
- Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine
epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial
T2 weighted image, are eligible. No histologic confirmation is required.
- Patients with pontine tumors that do not meet radiographic criteria for typical
DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine
cross-sectional area with or without extrapontine extension) are eligible if the
tumors are biopsied and proven to be high-grade gliomas (such as anaplastic
astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS],
and/or H3 K27M-mutant) by institutional diagnosis.
- STEP 1: Stratum DMG (with H3 K27M mutation)
- Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
- Note: Patients need not have either measurable or evaluable disease, i.e., DMG
patients may have complete resection of their tumor prior to enrollment. Primary
spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in
non-midline structures (e.g., cerebral hemispheres), these patients will be
considered part of Stratum DMG.
- STEP 1: Stratum HGG (without H3 K27M mutation)
- Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
- Please note:
- Patients who fall in this category and who are >= 18 years of age are not
eligible due to another standard-of-care regimen (radiation/temozolomide)
that is available
- Patients need not have either measurable or evaluable disease, i.e., HGG
patients may have complete resection of their tumor prior to enrollment.
Primary spinal tumors are eligible for enrollment
- STEP 1: Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of
age and Lansky for patients =<16 years of age. 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.
- STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
step 1 enrollment)
- STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
step 1 enrollment)
- STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within
7 days prior to step 1 enrollment)
- STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to step 1
enrollment):
- Age / Maximum Serum Creatinine (mg/dL)
- 1 to < 2 years / male: 0.6; female: 0.6
- 2 to < 6 years / male: 0.8; female: 0.8
- 6 to < 10 years / male: 1; female: 1
- 10 to < 13 years / male: 1.2; female: 1.2
- 13 to < 16 years / male: 1.5; female: 1.4
- >= 16 years / male: 1.7; female: 1.4
- STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine
aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN
for SGPT is 45 U/L.
- STEP 1: Serum amylase =< 1.5 x ULN
- STEP 1: Serum lipase =< 1.5 x ULN
- STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse
oximetry > 94% if there is clinical indication for determination.
- STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants
and well controlled.
- STEP 1: Patients must be enrolled and protocol therapy must begin no later
than 31 days after the date of radiographic diagnosis (in the case of
non-biopsied DIPG patients only) or definitive surgery, whichever is the
later date (Day 0).
For patients who have a biopsy followed by resection, the date of resection will be
considered the date of definitive diagnostic surgery. If a biopsy only was performed, the
biopsy date will be considered the date of definitive diagnostic surgery.
Exclusion Criteria:
- STEP 1: Patients must not have received any prior therapy for their central nervous
system (CNS) malignancy except for surgery and steroid medications.
- STEP 1: Patients who are currently receiving another investigational drug are not
eligible.
- STEP 1: Patients who are currently receiving other anti-cancer agents are not
eligible.
- STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.
- STEP 1: Patients who have an uncontrolled infection.
- STEP 1: Patients who have received a prior solid organ transplantation.
- STEP 1: Patients with grade > 1 extrapyramidal movement disorder.
- STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
- STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and
without contrast must be performed if metastatic disease is suspected by the treating
physician.
- STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the
exception of H3 K27M-mutant bithalamic tumors.
- STEP 1: Patients who are not able to receive protocol specified radiation therapy.
- STEP 1:
- Female patients who are pregnant are ineligible since there is yet no available
information regarding human fetal or teratogenic toxicities.
- Lactating females are not eligible unless they have agreed not to breastfeed
their infants. It is not known whether selinexor is excreted in human milk.
- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained.
- Sexually active patients of reproductive potential are not eligible unless they
have agreed to use two effective methods of birth control (including a medically
accepted barrier method of contraception, e.g., male or female condom) for the
duration of their study participation and for 90 days after the last dose of
selinexor. Abstinence is an acceptable method of birth control.
