tipifarnib in treating young patients with refractory leukemia

Conditions: Leukemia

Summary: 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

Keywords: recurrent childhood acute lymphoblastic leukemia recurrent childhood acute myeloid leukemia relapsing chronic myelogenous leukemia blastic phase chronic myelogenous leukemia chronic myelogenous leukemia, bcr-abl1 positive childhood acute promyelocytic leukemia (m3) acute undifferentiated leukemia juvenile myelomonocytic leukemia childhood chronic myelogenous leukemia