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

DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT 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