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Phase I and Pharmacokinetic Study of Enzastaurin (LY317615) in Children and Adolescents With Refractory Primary CNS Tumors

Phase 1
21 Years
Not Enrolling
Brain and Central Nervous System Tumors, Neuroblastoma

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Trial Information

Phase I and Pharmacokinetic Study of Enzastaurin (LY317615) in Children and Adolescents With Refractory Primary CNS Tumors



- To estimate the maximum tolerated dose (MTD) and/or recommend a phase II dose of
enzastaurin hydrochloride in children with recurrent or refractory CNS tumors who are
not receiving enzyme-inducing anticonvulsants.

- To further characterize the pharmacokinetics and toxicity of the recommended phase II
dose of enzastaurin hydrochloride given twice daily in these patients.


- To characterize the pharmacokinetics of enzastaurin hydrochloride at the recommended
phase II dose given once a day or twice a day in children.

- To document and describe toxicities associated with enzastaurin hydrochloride.

- To document antitumor activity in children with recurrent or refractory CNS tumors.

- To explore changes in MR perfusion scans obtained within 15 ± 2 days after initiation
of enzastaurin hydrochloride therapy as compared to baseline and to correlate these
changes with clinical outcome.

- To evaluate a panel of biological surrogate markers in this patient population at
baseline and following enzastaurin hydrochloride administration.

OUTLINE: This is a multicenter study.

Patients receive oral enzastaurin hydrochloride once daily until the maximum tolerated dose
(MTD) is determined. Patients then receive enzastaurin hydrochloride at the MTD twice daily
on days 1-28. Treatment repeats every 28 days for 13 courses in the absence of disease
progression or unacceptable toxicity. Patients may receive 13 additional courses (for a
total of 26 courses) of oral enzastaurin hydrochloride if the patient is benefitting from
the treatment and the investigator and subject agree to continue treatment.

Patients undergo blood sample collection periodically for pharmacokinetic studies.

After completion of study treatment, patients are followed periodically.


- Histologically confirmed primary CNS malignancy including low-grade glioma

- All tumors, except intrinsic brain stem and diffuse optic pathway tumors, must
have histological verification at either the time of diagnosis or recurrence

- Patients with intrinsic brain stem or diffuse optic pathway tumors must
have clinical and/or radiographic evidence of progression

- Recurrent or progressive disease or disease refractory to standard therapy and for
which there is no known curative therapy


Inclusion Criteria:

- Karnofsky performance scale (for > 16 years of age) or Lansky performance score (for
≤ 16 years of age) ≥ 60% assessed within two weeks prior to registration

- Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL

- Platelet count ≥ 100,000/μL (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR maximum serum creatinine
based on age as follows:

- 0.8 mg/dL (≤ 5 years of age)

- 1.0 mg/dL (6 to 10 years of age)

- 1.2 mg/dL (11 to 15 years of age)

- 1.5 mg/dL (≥ 16 years of age)

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

- ALT ≤ 5 x ULN for age

- Serum albumin ≥ 2.5 g/dL

- Patients of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while being
treated on this study

- Negative pregnancy test

- Patients must have a normal QTc for age and no evidence of a clinically significant
arrhythmia on ECG

- No evidence of active graft-versus-host disease

Exclusion Criteria:

- Pregnant or lactating

- Body surface area < 0.5 m^2

- Clinically significant unrelated systemic illness that would compromise the patient's
ability to tolerate protocol therapy or would likely interfere with the study
procedures or results

- Known hypersensitivity to enzastaurin hydrochloride or its components

- Inability to return for follow-up visits or obtain follow-up studies required to
assess toxicity to therapy


Inclusion Criteria:

- Must have recovered from the acute toxic effects (grade ≤ 2) of all prior therapy
before entering this study

- Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto
this study (6 weeks for prior nitrosourea)

- At least 7 days since the completion of therapy with a hematopoietic growth agent
(i.e., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)

- At least 14 days since long-acting formulations

- Therapeutic use of myeloid growth factors in patients with serious neutropenic
conditions, such as sepsis, may be considered at the investigator's discretion

- At least 7 days since the completion of therapy with a biologic agent

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 6 months must have elapsed after prior total body irradiation (TBI) or
craniospinal radiotherapy

- At least 6 weeks must have elapsed after other substantial bone marrow irradiation

- At least 6 months since prior allogeneic bone marrow transplantation

- At least 3 months since prior autologous bone marrow or stem cell transplantation

- Patients who are receiving dexamethasone must be on a stable or decreasing dose for
at least 1 week prior to registration

- Corticosteroids should be used at the lowest dose to control symptoms of edema
and mass effect

Exclusion Criteria:

- Routine concurrent use of growth factors (i.e., G-CSF, GM-CSF, or erythropoietin)

- Any other concurrent anticancer or investigational drug therapy

- Concurrent enzyme-inducing anticonvulsants (EIACDs)

- Concurrent gents that prolong the QTc

- Concurrent drugs that are substrates or inhibitors of CYP3A4 or CYP2C9

- Other concurrent drugs that are sensitive substrates of CYP2C8, CYP2C9, or CYP2C19
and/or have a narrow therapeutic window

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Description:

The maximum tolerated dose or recommended phase II dose will be based on the dose-limiting toxicities observed during the first 28 days of therapy in those participants receiving enzastaurin on a once per day dosing schedule.

Outcome Time Frame:

First 28 days of therapy

Safety Issue:


Principal Investigator

Susan M. Blaney, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Texas Children's Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2007

Completion Date:

May 2010

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Neuroblastoma
  • recurrent childhood brain stem glioma
  • childhood central nervous system germ cell tumor
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • childhood choroid plexus tumor
  • childhood craniopharyngioma
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • recurrent childhood ependymoma
  • recurrent childhood medulloblastoma
  • childhood oligodendroglioma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • recurrent childhood visual pathway and hypothalamic glioma
  • recurrent childhood visual pathway glioma
  • childhood grade I meningioma
  • childhood grade II meningioma
  • childhood grade III meningioma
  • recurrent childhood subependymal giant cell astrocytoma
  • recurrent childhood pineoblastoma
  • recurrent childhood brain tumor
  • disseminated neuroblastoma
  • recurrent neuroblastoma
  • Nervous System Neoplasms
  • Neuroblastoma
  • Central Nervous System Neoplasms



Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Texas Children's Cancer Center and Hematology Service at Texas Children's HospitalHouston, Texas  77030-2399
UCSF Medical Center at ParnassusSan Francisco, California  94143-0296