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A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine Glioma and High-Grade Glioma

This phase 1/2 trial is evaluating the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy to treat children and young adults with newly diagnosed high-grade gliomas (HGGs) that have alterations in the gene that encodes histone 3 (H3 K27-altered). It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. 

HGGs are fast-growing brain tumors that can grow back after treatment. Diffuse intrinsic pontine glioma (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. In the first part, the investigators want to determine the highest dose of selinexor that can be given without causing severe side effects. The researchers will then use that dose to determine how effective selinexor is against the tumors in the second part of the study.

Selinexor blocks a protein called CRM1, which may help prevent cancer cells from growing and may destroy them. It is a type of drug known as a selective inhibitor of nuclear export. Radiation therapy uses high energy to destroy tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients newly-diagnosed with these tumors.

Inclusion Criteria
  • STEP 1: Patients must have newly-diagnosed DIPG or HGG (including 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/sex as follows (within 7 days prior to step 1 enrollment):
    • Age: 
      • 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).

Find the most up-to-date criteria for this trial at clinicaltrials.gov.

 

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.
Investigator(s)

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