Tipifarnib in Treating Young Patients With Refractory Leukemia

RATIONALE: Tipifarnib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth.

PURPOSE: Phase I trial to study the effectiveness of tipifarnib in treating young patients who have refractory leukemia.

OBJECTIVES:

Primary

* Determine the maximum tolerated dose and toxicity profile of tipifarnib in pediatric patients with refractory leukemia.
* Determine the pharmacokinetics of this drug in these patients.
* Determine the toxicity profile of this drug in these patients.

Secondary

* Analyze the gene expression profile of leukemic blasts from these patients before and after treatment with this drug.
* Determine circulating levels of nerve growth factor and correlate these levels with clinical neurotoxicity from this drug in these patients.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. At least 9 additional patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 12-34 patients will be accrued for this study within 1-2 years.

Eligibility 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