A Phase 1/2 Trial of Selinexor (KPT-330) and Radiation Therapy in Newly-Diagnosed Pediatric Diffuse Intrinsic Pontine Glioma (DIPG) and High-Grade Glioma (HGG).
Primary Objectives:
1. (Dose-finding phase) 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).
2. (Efficacy phase) To estimate the event-free survival (EFS) distribution for 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.
Chemotherapy single agent systemic
- Rutgers Cancer Institute of New Jersey
Inclusion Criteria
- PRE ENROLLMENT: Patients must be =< 25 years of age at the time of enrollment on
APEC14B1 part A cnetral nervous system (CNS)/high grade glioma (HGG) pre-enrollment
eligibility screening
- Please note:
- This required age range applies to pre-enrollment eligibility 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).
- PRE ENROLLMENT: Patient is suspected of having localized, newly diagnosed HGG,
excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
- Please note: there are specific radiographic criteria for DIPG patient
enrollment on ACNS1821 (Step 1)
- PRE ENROLLMENT:
- For patients with non-pontine tumors: Patients and/or their parents or legal
guardians must have signed informed consent for eligibility screening on
APEC14B1 Part A.
- For patients with DIPG: Patients and/or their parents or legal guardians must
have signed informed consent for ACNS1821.
- PRE ENROLLMENT:
- 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.
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.