Phase I and Pharmacokinetic Trial of PTC299 in Pediatric Patients With Refractory or Recurrent CNS Tumors

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of primary central nervous system (CNS) malignancy
at time of diagnosis or recurrence

- Histology verification not required for intrinsic brain stem tumors and optic
pathway gliomas

- Must have radiographic evidence of progression

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

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS
50-100% (patients ≤ 16 years of age)

- Body weight ≥ 15 kg and ≤ 100 kg

- Patients with neurological deficits allowed provided they are stable for ≥ 1 week

- Able to swallow capsules

- ANC ≥ 1,000/μL (unsupported)

- Platelet count ≥ 100,000/μL (unsupported)

- Hemoglobin ≥ 8 g/dL (may be supported)

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70
mL/min/1.73 m^2 OR serum creatinine normal based on age as follows:

- 0.8 mg/dL (≤ 5 years of age)

- 1.0 mg/dL (> 5 to ≤ 10 years of age)

- 1.2 mg/dL (> 10 to ≤ 15 years of age)

- 1.5 mg/dL (> 15 years of age)

- Urine protein/creatinine ratio < 1.0

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN

- Albumin ≥ 2.5 g/dL

- PT and activated PTT ≤ 1.2 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No 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, including any of the following:

- Serious infections including ongoing systemic bacterial, fungal, or viral
infection

- Significant cardiac, pulmonary, hepatic, or other organ dysfunction

- Willing and able to comply with schedule visits, drug administration plan, laboratory
tests, including pharmacokinetic and pharmacodynamic assessments, or other study
procedures

- No known coagulopathy or bleeding diathesis

- No known history of drug-induced liver injury

- No CNS, pulmonary, gastrointestinal, or urinary bleeding within the past month

- No uncontrolled systemic hypertension (systolic BP or diastolic BP > 95% percentile
for age)

- No alcohol or drug addiction

- Able to tolerate periodic MRI scans and gadolinium contrast

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from the acute toxic of all prior therapy (excluding alopecia and
neurotoxicity)

- At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for
nitrosourea)

- At least 14 days since prior investigational or biological agent

- At least 3 half-lives since prior biological agents that have a prolonged
half-life

- At least 3 half-lives since prior monoclonal antibody

- At least 2 weeks since prior local palliative radiotherapy

- At least 6 weeks since prior total-body irradiation, craniospinal radiotherapy, or
radiotherapy to ≥ 50% of the pelvis

- At least 90 days since prior allogeneic bone marrow transplantation

- No active graft-versus-host disease

- Concurrent dexamethasone or other corticosteroids allowed provided dose is stable for
≥ 7 days

- At least 1 week since prior colony-forming growth factors (e.g., filgrastim,
sargramostim, erythropoietin)

- At least 14 days since long-acting colony-forming growth factor formulations
(e.g., pegfilgrastim)

- More than 4 weeks since prior major surgical procedures

- More than 2 weeks since prior intermediate surgical procedures

- More than 7 days since minor surgical procedures

- No other concurrent anticancer or investigational drug therapy