Sorafenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity(s) (DLTs) and maximally tolerated dose (MTD) of BAY 43-9006 given orally.

SECONDARY OBJECTIVES:

I. To obtain preliminary evidence of tumor response to BAY 43-9006 in patients. II. To assess the pharmacokinetic profile of BAY 43-9006. III. To characterize the preliminary profile of adverse events and changes in laboratory parameters in patients treated with BAY 43-9006.

IV. To assess effects of BAY 43-9006 on various cellular properties of leukemic blasts exposed to drug in vivo and in vitro.

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

Patients receive oral sorafenib twice daily on days 1-14 or 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete remission (CR) may be considered for retreatment with sorafenib for up to an additional 6 courses upon disease recurrence provided the duration of CR is longer than 1 month.

Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD.

After completion of study treatment, patients are followed monthly for up to 1 year.

Inclusion criteria

• Patients must have pathological confirmation (histologically or cytologically) of relapsed or refractory acute myeloid leukemia (other than acute promyelocytic leukemia), acute lymphocytic leukemia, or chronic myeloid leukemia in blast crisis
• The morphologic diagnosis of AML (non-APL), ALL, and CML in blast crisis will be made independently by members of the hematologic pathology division; routine staining and standard criteria as outlined by the Report of the NCI-Sponsored Workshop will be followed
• All patients must have been refractory to or relapsed from their most recent therapy AND are considered ineligible for potential curative approaches including allogeneic stem cell transplant; in addition, patients must be at least:

• 3 weeks from last cytotoxic chemotherapy (excluding hydroxyurea)
• Hydroxyurea may be used for blast count control but must be discontinued within 48 hours of the initiation of BAY 43-9006
• 2 weeks from last radiation therapy
• 3 week from last biologic therapy (including myeloid growth factors)
• ECOG performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 2 months
• Multilineage bone marrow failure due to the subject's underlying leukemia
• Total blast count in the peripheral blood < 30,000
• Total bilirubin =< 2 mg/dl
• AST(SGOT)/ALT(SGPT) =< 5 X institutional upper limit of normal
• Serum creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• All women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; the effects of BAY 43-9006 on the developing human fetus at the recommended therapeutic dose are unknown; however, kinase inhibitors are known to be teratogenic; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Patients with APL are not eligible for this clinical trial
• Patients who have not recovered from adverse events due to agents administered more than 3 weeks earlier
• Patients with rapidly increasing peripheral blood blast counts (increase in the absolute peripheral blast count > 50% within one week) or uncontrolled (absolute blast count > 30,000) while on hydroxyurea will be excluded
• Patients with uncontrolled hypertension (i.e., persistent grade 3 while undergoing treatment)
• Patients may not be actively receiving any other investigational agents
• Patients active and / or untreated CNS leukemia will not be eligible
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with BAY 43-9006
• Patients with immune deficiency are at increased risk of lethal infections when treated with marrow suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients must not have any evidence of bleeding diathesis
• Patients must not be on therapeutic anticoagulation; prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for PT, INR or PTT are met
• Patients must not be taking the cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin or St. John's wort