Study of Dasatinib in Combination With Everolimus for Children and Young Adults With Gliomas Harboring Platelet-Derived Growth Factor Receptor (PDGFR) Alterations

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 2 Study of Dasatinib in Combination With Everolimus for Children With Gliomas Harboring PDGFR Alterations

Conditions
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Glioma, High Grade Glioma, Pontine Tumors

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib+Everolimus<br>Dasatinib = 60 mg/m2 orally twice daily Everolimus = starting dose of 3.0 mg/m2, with titration of dosing after first cycle to keep everolimus trough level of 5-15 ug/ml Both agents will be taken daily for 28 day cycles. Cycles will be repeated every 28 days and patients may receive up to 24 cycles. | Drug: Dasatinib<br>* 60 mg/m2 orally twice daily<br>Drug: Everolimus<br>* 3.0 mg/m2, with titration of dosing after first cycle to keep trough level of 5-15 ug/ml<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival in Participants With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) | Percentage of participants without progression, defined as 25% increase in the size of the tumor or appearance of new lesions. | 8 months | 
| Progression-free Survival in Participants With Newly Diagnosed High-grade Glioma (HGG) | Percentage of participants without progression, defined as 25% increase in the size of the tumor or appearance of new lesions. | 12 months | 
| Overall Response Rate (OR) (Partial Response or Better) in Participants With Refractory or Recurrent Glioma | The overall response assessment will take into account response in both target and non-target lesions, as well as the appearance of new lesions. Partial Response (PR) will be defined as ≥50% decrease in size of tumor in comparison to baseline measurements. Complete Response (CR) will be defined as the disappearance of all abnormal signal. This includes return to normal size of the brain stem for brain stem lesions. Reported as percentage of participants with partial or better response at 56 days. | 56 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Percentage of patients alive at one year. | 1 year | 
| Overall Survival | Percentage of participants alive at 2 years. | up to 17 months |