Study of Dasatinib in Combination With Everolimus for Children and Young Adults With Gliomas Harboring Platelet-Derived Growth Factor Receptor (PDGFR) Alterations
Condition: Glioma; High Grade Glioma; Pontine Tumors
MeSH terms: Glioma; Brain Stem Neoplasms
Intervention: Dasatinib; Everolimus
Intervention description: 60 mg/m2 orally twice daily; 3.0 mg/m2, with titration of dosing after first cycle to keep trough level of 5-15 ug/ml
Intervention MeSH terms: Everolimus; Dasatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 1 Year
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      This trial will evaluate the activity of dasatinib in combination with everolimus for
      children with gliomas harboring PDGFR alterations, including newly diagnosed high-grade
      glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) after radiation (stratum A); and
      recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histological confirmation of a newly diagnosed high-grade glioma or diffuse intrinsic
             pontine glioma (DIPG) (Stratum A)

          -  Histological confirmation (at diagnosis or relapse) of a recurrent or progressive
             grade II-IV glioma (including DIPG) (Stratum B)

          -  Participants must have a genomic (DNA and/or RNA) alteration (mutation, fusion, and/or
             amplification) involving PDGF-A, PDGF-B, PDGFR-A or PDGFR-B, as identified by tumor
             sequencing.

          -  Age at enrollment: Greater than 1 year and less than 50 years

          -  BSA (body surface area): BSA greater than 0.3 m2

          -  Karnofsky (Measure of performance for cancer patients where 100% represents perfect
             health) > 50% for patients > 16 years of age and Lansky (Measure of performance for
             pediatric cancer patients where 100% represents perfect health) > 50% for patients <
             16 years of age. Neurologic deficits in patients with CNS tumors must have been
             relatively stable for a minimum of 7 days. Patients who are unable to walk because of
             paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for
             the purpose of assessing the performance score.

          -  Adequate bone marrow function per protocol

          -  Adequate liver function per protocol

          -  Adequate renal and metabolic function per protocol

          -  Patients with known seizure disorder must have seizures adequately controlled with
             non- enzyme inducing antiepileptic medications

          -  No increase in steroid dose within the past 7 days

          -  Primary brain or spine tumor are eligible, including tumors with metastases, multiple
             lesions.

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy.

          -  Myelosuppressive chemotherapy: Must not have received within 3 weeks.

          -  Hematopoietic growth factors: At least 7 days since the completion of therapy with a
             growth factor, 14 days for long- acting.

          -  Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives (whichever is
             longer) since the completion of therapy.

          -  Radiation therapy:

               -  Stratum A: ≥ 2 weeks and </= to 12 weeks must have elapsed from radiation.

               -  Stratum B: ≥ 2 weeks must have elapsed from focal radiation.

          -  > 3 weeks from major surgery. If recent craniotomy, adequate wound healing must be
             determined by neurosurgical team.

          -  Autologous Stem Cell Transplant or Rescue: No evidence of active graft vs. host
             disease and ≥ 4 weeks must have elapsed.

          -  All patients and/or a legal guardian must sign institutionally approved written
             informed consent and assent documents.

        Exclusion Criteria:

          -  Patients who are breastfeeding, pregnant or refuse to use an effective form of birth
             control are excluded.

          -  Patients with uncontrolled infection are excluded.

          -  Patients receiving other anti-neoplastic agents are excluded.

          -  Patients requiring strong CYP3A4 or PGP inhibitors are excluded (per protocol)

          -  Patients requiring anticoagulation or with uncontrolled bleeding are excluded.

          -  Patients on steroids for symptom management must be on a stable dose for 7 days prior
             to start of treatment.

          -  Patients within 1 year of allogeneic stem cell transplant, patients with active GVHD
             or requiring immunosuppression are excluded.

          -  Previous hypersensitivity to rapamycin or rapamycin derivatives