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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


Phase 1
18 Months
21 Years
Open (Enrolling)
Both
Diffuse Intrinsic Pontine Glioma, Progressive or Refractory High-Grade Glioma

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Trial Information

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


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.


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;

- Hepatic: Total bilirubin concentration < or equal to 1.5 times the
institutional upper limit of normal for age; SGPT < or equal to 3 times the
institutional upper limit of normal

- Pancreatic: Serum amylase < or equal to 3 times the institutional upper limit
of normal for age; lipase < or equal to 3 times the institutional upper limit
of normal

- Female research participants of childbearing age must not be pregnant as confirmed by
a serum or urine pregnancy test within 1 week of start of treatment. Participants
must not be breast-feeding.

- Males or females of reproductive potential may not participate unless they have
agreed to use two effective contraceptive methods. Abstinence in a non-sexually
active child will be sufficient birth control.

Inclusion Criteria - Stratum A

- Diagnosis of DIPG or high-grade glioma originating from the brainstem.

- Patients have had no previous treatment except corticosteroid use.

Inclusion Criteria - Stratum B

- Patients must have radiologic evidence of recurrent, refractory or progressive
high-grade glioma or DIPG. Patients must have either a diagnosis of HGG within the
brain and/or spinal cord including DIPG or other high-grade glioma originating from
the brainstem. A histologically confirmed diagnosis of anaplastic astrocytoma (WHO
grade III), anaplastic oligodendroglioma (WHO grade III), anaplastic oligoastrocytoma
(WHO grade III), anaplastic ganglioglioma (WHO grade III), pleomorphic
xanthoastrocytoma with anaplastic features (WHO grade III), malignant glioneuronal
tumor, glioblastoma multiforme (WHO grade IV) or gliosarcoma (WHO grade IV) is
required. For patients with radiologic features of DIPG histologic confirmation of
diagnosis is not required.

- Patients must be able to swallow pills or take pills crushed in water based juice or
puree (e.g. applesauce, apple juice) by mouth or gastric tube.

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration.

- Patients who are on dexamethasone must be on a stable or decreasing dose for at least
one week prior to registration.

- Patients must have fully recovered from the acute toxic effects of chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

- Myelosuppressive chemotherapy: Patients must have received their last dose of known
myelosuppressive anticancer chemotherapy at least four weeks prior to study
registration or at least six weeks if nitrosourea. At least two weeks must have
lapsed if patients received lower dose oral etoposide (50 mg/2) without experiencing
evidence of myelosuppression (i.e. neutropenia or requiring transfusion with blood
products)

- Biologic agent: Patient must have recovered from any toxicity potentially related to
the agent and received their last dose of the biologic agent ≥ 7 days prior to study
registration. For biologic agents that have a prolonged half-life, the appropriate
interval since last treatment should be discussed with the study chair prior to
registration.

- Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
registration. Such patients should be discussed with the study chair prior to
registration.

- Radiation: Patient has received radiation therapy prior to study registration
Patients must have had their last fraction of local irradiation to the primary tumor
≥ 3 months prior to registration and their last fraction of craniospinal irradiation
(>24Gy) > or equal to 3 months prior to registration. Patient has not received focal
irradiation for symptomatic metastatic sites within 2 weeks prior to registration.

- Bone Marrow Transplant: Patient must be ≥ 3 months since high dose chemotherapy and
peripheral blood stem cell rescue prior to registration.

- Growth factors: Patients must be off all colony forming growth factors(s) for at
least 1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at
least 2 weeks for long-acting formulations (e.g. neupogen).

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).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Estimate the maximum tolerated dose (MTD) of crenolanib in pediatric research participants with newly diagnosed DIPG

Outcome Description:

This is done using rolling 6 -design

Outcome Time Frame:

2.5 years

Safety Issue:

Yes

Principal Investigator

Cynthia Wetmore, M.D, Ph.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

St. Jude Children's Research Hospital

Authority:

United States: Food and Drug Administration

Study ID:

SJPDGF

NCT ID:

NCT01393912

Start Date:

July 2011

Completion Date:

April 2015

Related Keywords:

  • Diffuse Intrinsic Pontine Glioma
  • Progressive or Refractory High-Grade Glioma
  • crenolanib
  • radiation therapy
  • malignant brain tumors
  • pediatric
  • Glioma
  • Pontine Glioma

Name

Location

St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794