Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
Condition: Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Glioblastoma; Gliosarcoma
MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      This phase I trial studies the side effects and the best dose of adavosertib when given
      together with local radiation therapy in treating children with newly diagnosed diffuse
      intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of
      the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays,
      neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib
      with local radiation therapy may work better than local radiation therapy alone in treating
      diffuse intrinsic pontine gliomas.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of
      the adavosertib (Wee1 inhibitor AZD1775 [MK-1775]) administered concurrently with radiation
      therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

      II. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with
      radiation therapy in children with newly diagnosed DIPG.

      III. To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly
      diagnosed DIPG when given concurrently with radiation therapy.

      SECONDARY OBJECTIVES:

      I. To preliminarily define the antitumor activity of AZD1775 (MK-1775) within the confines of
      a phase 1 study, including response rate, progression free survival, and overall survival of
      treated patients.

      II. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of
      phosphorylated-cell division cycle 2 G1 to S and G2 to M (p-CDC2) (cyclin-dependent kinase 1
      [CDK1]) and phosphorylated-histone H3 (p-HH3) in peripheral blood mononuclear cells (PBMCs)
      before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.

      III. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of
      gamma-H2A histone family, member X (H2AX) in PBMCs, a marker of deoxyribonucleic acid (DNA)
      double-strand breaks (dsDNA), before and after administration of AZD1775 (MK-1775) in
      children with newly diagnosed DIPG.

      OUTLINE: This is a dose-escalation study of adavosertib.

      Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients
      also receive adavosertib orally (PO) on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1,
      3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on
      dose level assignment. Treatment continues in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 2 months for
      6 months, and then every 3 months thereafter.
    

Intervention name(s): Adavosertib; Laboratory Biomarker Analysis; Pharmacological Study; Radiation Therapy
Intervention type(s): Drug; Other; Other; Radiation
Intervention description(s): Given PO; Correlative studies; Correlative studies; Undergo radiation therapy
Other intervention name(s): AZD-1775; AZD1775; MK-1775; MK1775; Cancer Radiotherapy; Energy Type; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation
Intervention MeSH terms: Adavosertib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment