A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric Patients With Refractory Leukemia

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed acute lymphoblastic leukemia, acute nonlymphoblastic
leukemia, juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia
(CML) in blast crisis

- Refractory to standard curative therapy

- Acute promyelocytic leukemia refractory to tretinoin and arsenic trioxide

- Philadelphia chromosome-positive CML refractory to imatinib mesylate

- Greater than 25% blasts in bone marrow (M3 bone marrow) except for patients with JMML

- Active extramedullary disease allowed

- No active leptomeningeal leukemia

PATIENT CHARACTERISTICS:

Age:

- 21 and under

Performance status:

- Karnofsky 50-100% (over 10 years of age)

- Lansky 50-100% (10 years of age and under)

Life expectancy:

- Not specified

Hematopoietic:

- Not required to be normal

Hepatic:

- Bilirubin normal

- SGPT and SGOT normal

- No significant hepatic dysfunction

- No grade 3 or 4 liver function test results within the past month

Renal:

- Creatinine normal OR

- Creatinine clearance at least 60 mL/min

- No significant renal dysfunction

Cardiovascular:

- No significant cardiac dysfunction

Pulmonary:

- No significant pulmonary dysfunction

Neurologic:

- No history of grand mal seizures grade 3 or greater except febrile seizures

- No persistent sensory or motor neuropathy greater than grade 2

Other:

- No clinically significant unrelated systemic illness

- No serious infection

- No organ dysfunction that would preclude study participation

- No requirement for total parenteral nutrition

- No known allergy to azoles (e.g., clotrimazole, fluconazole, ketoconazole,
voriconazole)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- At least 1 week since prior colony-stimulating factor therapy (e.g., filgrastim
[G-CSF] or sargramostim [GM-CSF]) except epoetin alfa

- At least 3 months since prior myeloablative therapy followed by bone marrow or stem
cell transplantation

- No concurrent immunotherapy

- No concurrent GM-CSF or interleukin-11

Chemotherapy:

- At least 2 weeks since prior chemotherapy

- No concurrent intrathecal chemotherapy

- No other concurrent chemotherapy

Endocrine therapy:

- At least 1 week since prior corticosteroids

- No concurrent corticosteroids (except for acute allergic reaction)

Radiotherapy:

- At least 4 weeks since prior radiotherapy

- No concurrent radiotherapy

Surgery:

- Not specified

Other:

- Recovered from nonhematologic toxicity of all prior therapy

- At least 1 week since prior retinoids

- No antacids (magnesium- or aluminum-containing formulations) within 2 hours of study
drug

- No other concurrent investigational agents

- No concurrent retinoids

- No concurrent anticonvulsants