Inclusion Criteria:

- Age must be ≥ 18 months and < or equal to 21 years

- Body surface Area (BSA) ≥ 0.55 m^2

- Lansky (for research participants ≤ 16 years) or Karnofsky (for research participants
> 16 years) performance score ≥ 40 at the time of study enrollment

- Adequate organ function at the time of study enrollment as follows:

- Bone marrow: Absolute neutrophil count (ANC) ≥ 1,000/μL, platelet count ≥
75,000/μL (transfusion independent), hemoglobin concentration ≥ 8g/dL (may be
transfused)

- Renal: Normal serum creatinine concentration based on age as shown below or
glomerular filtration rate (GFR) > 70 ml/min/1.73m^2

- Age (years): < or equal to 5 and the maximum serum creatinine (mg/dL) is
0.8;

- 5 < age < or equal to 10 and the maximum serum creatinine (mg/dL) is 1.0;

- 10< age < or equal to 15 and the maximum serum creatinine (mg/dL) is 1.2;

- >15 and the maximum serum creatinine (mg/dL) is 1.5;

- Hepatic: Total bilirubin concentration < or equal to 1.5 times the
institutional upper limit of normal for age; SGPT < or equal to 3 times the
institutional upper limit of normal

- Pancreatic: Serum amylase < or equal to 3 times the institutional upper limit
of normal for age; lipase < or equal to 3 times the institutional upper limit
of normal

- Female research participants of childbearing age must not be pregnant as confirmed by
a serum or urine pregnancy test within 1 week of start of treatment. Participants
must not be breast-feeding.

- Males or females of reproductive potential may not participate unless they have
agreed to use two effective contraceptive methods. Abstinence in a non-sexually
active child will be sufficient birth control.

Inclusion Criteria - Stratum A

- Diagnosis of DIPG or high-grade glioma originating from the brainstem.

- Patients have had no previous treatment except corticosteroid use.

Inclusion Criteria - Stratum B

- Patients must have radiologic evidence of recurrent, refractory or progressive
high-grade glioma or DIPG. Patients must have either a diagnosis of HGG within the
brain and/or spinal cord including DIPG or other high-grade glioma originating from
the brainstem. A histologically confirmed diagnosis of anaplastic astrocytoma (WHO
grade III), anaplastic oligodendroglioma (WHO grade III), anaplastic oligoastrocytoma
(WHO grade III), anaplastic ganglioglioma (WHO grade III), pleomorphic
xanthoastrocytoma with anaplastic features (WHO grade III), malignant glioneuronal
tumor, glioblastoma multiforme (WHO grade IV) or gliosarcoma (WHO grade IV) is
required. For patients with radiologic features of DIPG histologic confirmation of
diagnosis is not required.

- Patients must be able to swallow pills or take pills crushed in water based juice or
puree (e.g. applesauce, apple juice) by mouth or gastric tube.

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration.

- Patients who are on dexamethasone must be on a stable or decreasing dose for at least
one week prior to registration.

- Patients must have fully recovered from the acute toxic effects of chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

- Myelosuppressive chemotherapy: Patients must have received their last dose of known
myelosuppressive anticancer chemotherapy at least four weeks prior to study
registration or at least six weeks if nitrosourea. At least two weeks must have
lapsed if patients received lower dose oral etoposide (50 mg/2) without experiencing
evidence of myelosuppression (i.e. neutropenia or requiring transfusion with blood
products)

- Biologic agent: Patient must have recovered from any toxicity potentially related to
the agent and received their last dose of the biologic agent ≥ 7 days prior to study
registration. For biologic agents that have a prolonged half-life, the appropriate
interval since last treatment should be discussed with the study chair prior to
registration.

- Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
registration. Such patients should be discussed with the study chair prior to
registration.

- Radiation: Patient has received radiation therapy prior to study registration
Patients must have had their last fraction of local irradiation to the primary tumor
≥ 3 months prior to registration and their last fraction of craniospinal irradiation
(>24Gy) > or equal to 3 months prior to registration. Patient has not received focal
irradiation for symptomatic metastatic sites within 2 weeks prior to registration.

- Bone Marrow Transplant: Patient must be ≥ 3 months since high dose chemotherapy and
peripheral blood stem cell rescue prior to registration.

- Growth factors: Patients must be off all colony forming growth factors(s) for at
least 1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at
least 2 weeks for long-acting formulations (e.g. neupogen).

Exclusion Criteria:

- Metastatic disease outside the CNS.

- Use of enzyme-inducing anticonvulsants (EIACs) within 7 days prior to registration.

- Research participants with uncontrolled infection

- Research participants with any concomitant significant medical illness that in the
investigator's opinion cannot be adequately controlled with appropriate therapy, or
that would impair the evaluation of side effects related to this treatment, alter
drug metabolism or the tolerance to this treatment

- Research participants receiving any other anticancer or investigational drug therapy

- Prior therapy with crenolanib

Of note, the use of any concomitant medication that may affect CYP3A function except for
dexamethasone, should be discussed with the principal investigator of this study (or her
designee).