PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma
Condition: Diffuse Intrinsic Pontine Glioma; Progressive or Refractory High-Grade Glioma
MeSH terms: Glioma; Diffuse Intrinsic Pontine Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase I clinical trial evaluating crenolanib (CP-868,596), an inhibitor of Platelet
      Derived Growth Factor Receptor (PDGFR)-kinase in children and young adults with newly
      diagnosed diffuse intrinsic pontine glioma (DIPG) (Stratum A) or in recurrent, progressive or
      refractory High Grade Glioma (HGG) including DIPG (Stratum B). This study drug targets the
      most commonly amplified region of genome found in DIPG and pediatric high grade glioma (HGG)
      which encodes for the PDGF receptor kinase. An oral investigational agent crenolanib will be
      administered daily during and after local radiation therapy (RT) in Diffuse Intrinsic Pontine
      Glioma DIPG (Stratum A), or daily for children with recurrent/refractory HGG (Stratum B).
    

Detailed description: 
      Primary Objectives:

        -  To estimate the maximum tolerated dose (MTD) of crenolanib administered concurrently
           with RT in pediatric research participants with DIPG

        -  To estimate the MTD of crenolanib in children and young adults with recurrent/refractory
           HGG including DIPG

        -  To characterize the pharmacokinetics of crenolanib in pediatric patients and relate drug
           disposition to toxicity

      Exploratory Secondary Objectives:

        -  To characterize toxicities and/or adverse events associated with the chronic use of
           crenolanib

        -  To evaluate the association between specific polymorphisms of drug metabolizing enzymes
           and the pharmacokinetics of crenolanib

        -  To evaluate changes in phosphorylation of targets of PDGF pathway activation in
           peripheral blood mononuclear cells and investigate the possible relationship between
           these changes, plasma drug levels of crenolanib and outcome measures

        -  To evaluate PDGFR, genotype, protein expression and DNA amplification in tumor tissue
           where available

        -  To investigate whether magnetic resonance imaging (MRI) techniques that reflect tumor
           pathophysiology (metabolism, oxygenation, perfusion and vessel wall integrity) are
           correlated with clinical response

        -  To characterize the neural tract involvement and tumor progression routes of pediatric
           brainstem glioma based upon anatomical magnetic resonance imaging and diffusion tensor
           imaging

        -  To assess the pattern of failure in radiation therapy in Stratum A participants.

        -  To describe the research participants' and parents' perspective of symptoms and the
           quality of life of children enrolled on this phase I trial

        -  To describe the quality of life and the impact of self-care activities of parents of
           pediatric research participants enrolled on this phase I trial

        -  To assess the impact of therapeutic alliance and social support on peace of mind, hope,
           anxiety/depression and quality of life among parents of pediatric research participants
           enrolled on this phase I trial

      Stratum A- Appropriate dose RT will be administered in 30-33 fractions over approximately 6
      weeks for Stratum A patients. Treatment with crenolanib will start on the same day as RT and
      continue daily during and after Radiation Therapy for a maximum treatment duration of 2
      years. We plan to treat a maximum of 5 cohorts of research participants (dosage levels 0, 1,
      2, 3, and 4) with escalating doses of crenolanib. A cycle is defined as 28 days and the first
      8 weeks of therapy will constitute the dose-limiting toxicity (DLT)-evaluation period.

      Stratum B - Crenolanib will be administered orally on a daily basis continuously for 28 days,
      which defines one cycle. The maximum treatment duration will be 2 years. We plan to treat a
      maximum of 5 cohorts of research participants (dosage levels 0, 1, 2, 3, and 4) with
      escalating doses of crenolanib. Dose escalation will be independent of Stratum A escalation.
      The DLT evaluation period will be four weeks.
    

Intervention name(s): Crenolanib
Intervention type(s): Drug
Intervention description(s): Crenolanib orally administered as whole or crushed tablets once per day with concurrent Radiation Therapy. Crenolanib will continue at the same dose level post Radiation Therapy
Other intervention name(s): CP-868,596
Intervention MeSH terms: Crenolanib
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: crenolanib; radiation therapy; malignant brain tumors; pediatric