Platelet Derived Growth Factor Receptor (PDGFR) Inhibitor Crenolanib in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma Including Diffuse Intrinsic Pontine Glioma
Overview
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 55
- Locations
- 1
- Primary Endpoint
- Estimate the maximum tolerated dose (MTD) of crenolanib in pediatric research participants with newly diagnosed DIPG
Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Months to 21 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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;
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).
Arms & Interventions
Stratum A Patients
The patients are newly diagnosed Diffuse Intrinsic Pontine Glioma patients. Patients may take crenolanib as an intact tablet or crushed in apple sauce/juice. Currently accruing to dose level 3 (170 mg/m^2).
Intervention: Crenolanib (Drug)
Stratum B Patients
The patients are recurrent, refractory or progressive high-grade glioma including Diffuse Intrinsic Pontine Glioma patients. Patients may take crenolanib as an intact tablet or crushed in apple sauce/juice. Currently accruing to dose level 4 (220 mg/m^2).
Intervention: Crenolanib (Drug)
Outcomes
Primary Outcomes
Estimate the maximum tolerated dose (MTD) of crenolanib in pediatric research participants with newly diagnosed DIPG
Time Frame: 2.5 years
This is done using rolling 6 -design
Estimate the MTD of crenolanib in children and young adults with recurrent/refractory HGG including DIPG
Time Frame: 2.5years
This is done using rolling 6 design
Characterize the pharmacokinetics of crenolanib in pediatric patients and relate drug disposition to toxicity
Time Frame: 2.5 years
Individual pharmacokinetic parameters will be estimated using nonlinear mixed effects modeling methods (NONMEM) to estimate both the inter- and intra-subject variability.
Secondary Outcomes
No secondary outcomes reported