Tipifarnib in Treating Young Patients With Refractory Leukemia

A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric 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.

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