A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)
This phase I/II trial tests the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy in treating children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic change called H3 K27M mutation. It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. Glioma is a type of cancer that occurs in the brain or spine.
Glioma is considered high risk (or high-grade) when it is growing and spreading quickly. The term, risk, refers to the chance of the cancer coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the brainstem that controls functions like breathing, swallowing, speaking, and eye movements).
This trial has two parts. The only difference in treatment between the two parts is that some subjects treated in Part 1 may receive a different dose of selinexor than the subjects treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to determine the dose of selinexor that can be given without causing side effects that are too severe.
This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against HGG or DIPG. Selinexor blocks a protein called CRM1, which may help keep cancer cells from growing and may kill them.
It is a type of small molecule inhibitor called selective inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.
Study details:
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. (STRATUM DIPG AND STRATUM DMG CLOSED TO ACCRUAL 02/14/2025). 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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Patients must be =< 25 years of age at the time of enrollment on APEC14B1 part A central nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening
- Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
- 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.
- 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
- Patients must be >= 12 months and =< 21 years of age at the time of enrollment
- Patients must have newly-diagnosed DIPG or HGG (including DMG).
- 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.
- Patients with pontine tumors that do not meet radiographic criteria for typical DIPG are eligible if the tumors are biopsied and proven to be high-grade gliomas by institutional diagnosis.
- 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
- 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
- Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2.
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)
- Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2 (within 7 days prior to step 1 enrollment) or a serum creatinine based on age/sex as specified.
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L.
- Serum amylase =< 1.5 x ULN
- Serum lipase =< 1.5 x ULN
- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.
- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
- Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis or definitive surgery.
Exclusion criteria
- Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
- Patients who are currently receiving another investigational drug are not eligible.
- Patients who are currently receiving other anti-cancer agents are not eligible.
- Patients >=18 years of age who have H3 K27M-wild type HGG.
- Patients who have an uncontrolled infection.
- Patients who have received a prior solid organ transplantation.
- Patients with grade > 1 extrapyramidal movement disorder.
- Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
- 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.
- Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
- Patients who are not able to receive protocol specified radiation therapy.
- 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.
- 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 for the duration of their study participation and for 90 days after the last dose of selinexor.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE1PHASE2
Study ID
NCT05099003
Intervention or treatment
PROCEDURE: Biopsy Procedure
PROCEDURE: Magnetic Resonance Imaging
RADIATION: Radiation Therapy
DRUG: Selinexor
Conditions
- Malignant Glioma
You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.
Research sites nearby
Closest Location:
Sydney Children's Hospital
Select from list below to view details:
Sydney Children's Hospital
Randwick, New South Wales, Australia
The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Royal Children's Hospital
Parkville, Victoria, Australia
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Who is running the clinical trial?
National Cancer Institute (NCI)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Treatment (selinexor and radiation therapy)
| Procedure: Biopsy Procedure, Procedure: Magnetic Resonance Imaging, Radiation: Radiation Therapy, Drug: Selinexor |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Maximum tolerated dose | Defined as the highest dose of selinexor in combination with standard of care radiation therapy (RT) that does not cause unacceptable side effects. | From day 1 of selinexor treatment until the start of maintenance therapy, assessed up to 10 weeks from treatment start date |
| Event free survival (EFS) | Will be calculated for diffuse midline glioma (DMG)/ high grade glioma (HGG) patients. EFS curve will be estimated by Kaplan Meier estimates. | From the date of enrollment until disease progression date, secondary malignant neoplasm occurrence date, death date of any cause, or last follow-up date, assessed up to 5 years |
| Overall Survival (OS) | Will be calculated for diffuse intrinsic pontine glioma (DIPG) patients. The OS curve will be estimated by Kaplan Meier estimates. | From the date of enrollment until death date of any cause or last follow-up date, assessed up to 5 years |
| Overall response rate (ORR) | Defined as the proportion of patients whose best response is partial response or complete response. | Up to 5 years |
Secondary Outcome
References
Clinical Trials Gov: A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)Other trials to consider
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