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
Intervention: Adavosertib; Laboratory Biomarker Analysis; Pharmacological Study; Radiation Therapy
Intervention description: Given PO; Correlative studies; Correlative studies; Undergo radiation therapy
Intervention MeSH terms: Adavosertib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: All
Minimum age: 37 Months
Maximum age: 21 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and
             diffuse involvement of the pons, are eligible without histologic confirmation

               -  Patients with brainstem tumors that do not meet these criteria or are not
                  considered to be typical intrinsic pontine gliomas will only be eligible if the
                  tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma,
                  gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic
                  mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma,
                  gangliogliomas, or other mixed gliomas without anaplasia are not eligible

               -  Patients with disseminated disease are not eligible, and magnetic resonance
                  imaging (MRI) of spine must be performed if disseminated disease is suspected by
                  the treating physician

               -  Enrollment must be no later than 28 days after the date of radiographic diagnosis
                  or surgery, whichever is the later date

          -  Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment

          -  Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 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

          -  Patients must not have received any prior anti-cancer therapy such as chemotherapy,
             radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG;
             prior dexamethasone and/or surgery are allowed

          -  Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
             platelet transfusions for at least 7 days prior to enrollment)

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 or

          -  A serum creatinine based on age/gender as follows:

               -  0.8 mg/dL (3 to < 6 years of age)

               -  1.0 mg/dL (6 to < 10 years of age)

               -  1.2 mg/dL (10 to < 13 years of age)

               -  1.5 mg/dL (male) or 1.4 mg/dl (female) (13 to < 16 years of age)

               -  1.7 mg/dL (male) or 1.4 mg/dl (female) (>= 16 years of age)

          -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
             age

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
             ULN = 135 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45
             U/L

          -  Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] =< 3 x
             ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L

          -  Serum albumin >= 2 g/dL

          -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
             anticonvulsants and well controlled

          -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
             version [v]5) resulting from prior therapy must be =< grade 2 with the exception of
             tendon reflex (deep tendon reflex [DTR]); any grade of DTR is eligible

          -  Corrected QT interval (QTc) =< 480 msec

          -  All patients and/or their parents or legally authorized representatives must sign a
             written informed consent; assent, when appropriate, will be obtained according to
             institutional guidelines

        Exclusion Criteria:

          -  Pregnant or breast-feeding women may not be entered on this study; pregnancy tests
             must be obtained in girls who are post-menarchal; negative serum or urine pregnancy
             test within 3 days prior to enrollment

          -  Males or females of reproductive potential may not participate unless they have agreed
             to use an effective contraceptive methods as follows: fertile females of childbearing
             potential who agree to use adequate contraceptive measures from 2 weeks prior to the
             study and until 1 month after study treatment discontinuation; male patients willing
             to abstain or use barrier contraception (i.e. condoms) for the duration of the study
             and for 3 months after treatment stops

          -  Patients receiving corticosteroids are eligible for this trial

          -  Patients who are currently receiving another investigational drug are not eligible

          -  Patients who are currently receiving other anti-cancer agents are not eligible

          -  Patients must not currently be receiving enzyme inducing anticonvulsants

          -  Patients should avoid concomitant medication known or suspected to prolong QTc
             interval or cause Torsades De Pointes; if possible, alternative agents should be
             considered; patients who are receiving drugs that prolong the QTc are eligible if the
             drug is necessary and no alternatives are available

          -  Patients who are currently receiving drugs that are strong or moderate inhibitors
             and/or inducers of CYP3A4, sensitive CYP3A4 substrates and CYP3A4 substrates with a
             narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as
             an antiemetic is prohibited due to early drug interaction data demonstrating increased
             exposure to AZD1775; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A)
             inhibitors such as atorvastatin is prohibited

          -  Herbal preparations are not allowed throughout the study; these herbal medications
             include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko
             biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients
             should stop using these herbal medications 7 days prior to study enrollment

          -  Any known hypersensitivity or contraindication to the components of the study drug
             AZD1775

          -  Patients must not receive metformin for at least 5 days prior to enrollment and for
             the duration of study treatment

          -  Patients must be able to swallow capsules; nasogastric or gastrostomy feeding (G) tube
             administration is not allowed

          -  Patients who have an uncontrolled infection are not eligible

          -  Patients who have received a prior solid organ transplantation are not eligible

          -  Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart
             failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not
             eligible for this trial

          -  Major surgical procedures =< 28 days of beginning study treatment, or minor surgical
             procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy
             of the tumor) =< 7 days; no waiting period required following port-a-cath or other
             central venous access placement

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible