Dasatinib and Everolimus in Treating Children with Newly Diagnosed, Recurrent, or Progressive High-Grade Glioma with PDGFR Alterations

Status: Active

Description

This phase II trial studies how well dasatinib and everolimus work in treating children with high-grade glioma with PDGFR alterations that is newly diagnosed, has come back, or is growing, spreading or getting worse. Dasatinib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Body surface area (BSA) greater than 0.3 m^2
  • Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients < 16 years of age; neurologic deficits in patients with central nervous system (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
  • Absolute neutrophil count (ANC) > 750
  • Platelet count > 100,000/uL without platelet transfusion within the past 7 days
  • Bilirubin < 1.5 x upper limit of normal
  • Alanine aminotransferase (ALT) < 2.5 x upper limit of normal
  • 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: * Age 1 to < 2 years maximum serum creatinine (mg/dL) 0.6 (male); 0.6 (female) * Age 2 to < 6 years maximum serum creatinine (mg/dL) 0.8 (male); 0.8 (female) * Age 6 to < 10 years maximum serum creatinine (mg/dL) 1 (male); 1 (female) * Age 10 to < 13 years maximum serum creatinine (mg/dL) 1.2 (male); 1.2 (female) * Age 13 to < 16 years maximum serum creatinine (mg/dL) 1.5 (male); 1.4 (female) * Age >=16 years maximum serum creatinine (mg/dL) 1.7 (male) 1.4 (female)
  • Urine protein: creatinine (UPC) ratio of < 1; or a urinalysis that is negative for protein; or 24-hour urine protein level < 1000 mg/dL
  • 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
  • STRATUM A: Histological confirmation of a newly diagnosed high-grade glioma or DIPG
  • STRATUM B: Histological confirmation (at diagnosis or relapse) of a recurrent or progressive grade II-IV glioma (including DIPG)
  • Primary brain or spine tumor are eligible, including tumors with metastases, multiple lesions
  • Prior therapies * 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 (6 weeks if prior nitrosourea) * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor, 14 days for long- acting (e.g. PEG-filgrastim) * Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives (whichever is longer) since the completion of therapy with a biologic agent * Radiation therapy: ** Strata A: >= 2 weeks and =< to 12 weeks must have elapsed from radiation ** Strata B: >= 2 weeks must have elapsed from focal radiation * Surgery: > 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 versus (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
  • Participants must have a genomic (DNA and/or ribonucleic acid [RNA] alteration (mutation, fusion, and/or amplification) involving PDGF-A, PDGF-B, PDGFR-A, PDGFR-B, as identified by tumor (formalin-fixed, paraffin-embedded [FFPE] or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing; sequencing will be performed through the University of Michigan MI-ONCOSEQ study (Clinical Laboratory Improvement Act [CLIA]-certified), or other (non-university [U] of Michigan) CLIA-certified tumor DNA or RNA sequencing; for Michigan Oncology Sequencing Center (MI-ONCOSEQ), at least 1 mm cubed of tumor tissue or > 1 core biopsy of tumor tissue is required, fresh or formalin-fixed paraffin-embedded (FFPE)

Exclusion Criteria

  • Patients who are breastfeeding, pregnant or refuse to use an effective form of birth control are excluded; abstinence is considered an effective form of birth control
  • Patients with uncontrolled infection are excluded
  • Other medications: * Patients receiving other anti-neoplastic agents are excluded * Patients requiring strong CYP3A4 or PGP inhibitors are excluded * 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 graft versus host disease (GVHD) or requiring immunosuppression are excluded
  • Previous hypersensitivity to rapamycin or rapamycin derivatives

Locations & Contacts

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: Carl Johannes Koschmann
Phone: 734-615-2736
Email: ckoschma@med.umich.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the 1 year and 2 year progression-free and overall survival rates in patients receiving dasatinib in combination with everolimus as an adjuvant therapy following surgery and radiation therapy for children with newly diagnosed high-grade glioma or diffuse intrinsic pontine glioma (DIPG) harboring PDGFR alterations. (Stratum A)

II. To determine the overall response rate after 2 cycles of dasatinib in combination with everolimus in children with refractory or recurrent glioma (grade II-IV, including DIPG) with PDGFR alterations. (Stratum B)

EXPLORATORY OBJECTIVES:

I. To define and describe the toxicities of dasatinib and everolimus administered as dual therapy.

II. To prospectively evaluate high b-value diffusion weighted imaging (DWI) as an imaging biomarker for dasatinib and everolimus activity.

III. To prospectively evaluate cerebrospinal fluid (CSF) and plasma cell-free tumor deoxyribonucleic acid (DNA) (ct-DNA) as a marker of disease activity in refractory glioma with PDGFR alterations.

IV. To prospectively evaluate CSF dasatinib level as (1) a marker of blood-CSF permeability of dasatinib and (2) a predictor of treatment response.

OUTLINE:

Patients receive dasatinib orally (PO) once daily (QD) or twice daily (BID), and everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 months, 1 year, and 2 years

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Carl Johannes Koschmann

Trial IDs

Primary ID UMCC 2017.042
Secondary IDs NCI-2017-02017, HUM00123094
Clinicaltrials.gov ID NCT03352427