Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This randomized phase I trial is studying the side effects and best dose of two different schedules of sorafenib in treating patients with refractory or relapsed acute leukemia, myelodysplastic syndromes, or blastic phase chronic myelogenous leukemia. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of sorafenib when administered in two different schedules in patients with refractory or relapsed acute leukemia, myelodysplastic syndromes, or blastic phase chronic myelogenous leukemia. II. Determine the dose-limiting toxicity of this drug in these patients. SECONDARY OBJECTIVES: I. Determine the clinical activity of this drug in these patients. II. Determine the biologic effect of this drug in these patients. OUTLINE: This is a randomized, dose-escalation phase I study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral sorafenib once or twice daily on days 1-5, 8-12, and 15-19. Arm II: Patients receive oral sorafenib once or twice daily on days 1-14. In both arms, treatment repeats every 21 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission or partial remission after 6 months may continue therapy at the discretion of the principal investigator. In both arms, 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 at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 10 patients are treated at the MTD.

Official Title
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Phase I Study of BAY 43-9006 (NSC 724772) in Patients With Acute Leukemias, Myelodysplastic Syndromes and Chronic Myeloid Leukemia in Blast Phase

Conditions
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Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Alkylating Agent-Related Acute Myeloid Leukemia, Blastic Phase, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Sorafenib Tosylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 1 of the following: Acute myeloid leukemia (Acute promyelocytic leukemia (M3) allowed provided patient has failed prior therapy with both tretinoin and arsenic alone or in combination); Acute lymphoblastic leukemia; Myelodysplastic syndromes; Blastic phase chronic myelogenous leukemia (Failed OR intolerant to imatinib mesylate) Must have failed prior therapy with >= 1 cytotoxic- or biologic-targeted agent (e.g., hypomethylating agents, farnesyl transferase inhibitors, thalidomide, or tyrosine kinase inhibitors); Any number of prior regimens allowed Performance status: ECOG 0-1 ALT =< 2.5 times upper limit of normal Bilirubin =< 1.5 mg/dL Creatinine =< 2.0 mg/dL OR Creatinine clearance >= 60 mL/min Fertile patients must use effective contraception No psychiatric illness or social situation that would preclude study compliance Prior bone marrow transplantation allowed At least 2 weeks since prior cytotoxic agents OR at least 5 half-lives for non-cytotoxic agents in the absence of rapidly progressing disease At least 24 hours since prior hydrea for control of peripheral blood leukemia cell counts Hydroxyurea allowed up to 72 hours after start of therapy with sorafenib No persistent, chronic, clinically significant toxicities > grade 1 from prior chemotherapy Exclusion Criteria: Cytopenias secondary to multilineage bone marrow failure allowed Ineligible for or not willing to undergo allogeneic stem cell transplantation OR no donor available Absolute blast count=< 20,000/mm^3 unless patient has documented fms-like tyrosine kinase 3 internal tandem duplication No evidence of bleeding diathesis (except due to low platelets associated with the primary disease) No New York Heart Association class III or IV congestive heart failure No uncontrolled hypertension (i.e., sustained systolic blood pressure [BP] >= 150 mm Hg or diastolic BP >= 90 mm Hg) No unstable angina pectoris No symptomatic cardiac arrhythmia requiring and not responding to medical intervention Not pregnant or nursing No history of allergic reaction attributed to compounds of similar chemical or biological composition to the study drug No swallowing dysfunction that would impede oral ingestion of tablets No active uncontrolled infection No other uncontrolled illness No prior sorafenib No other concurrent investigational or commercial agents, except for standard intrathecal chemotherapy for the treatment of isolated CNS leukemic involvement No other concurrent anticancer agents No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent therapeutic anticoagulation (Concurrent prophylactic anticoagulation [i.e., low-dose warfarin, catheter flushing with heparin] of venous or arterial access devices allowed) No concurrent cytochrome P450 enzyme-inducing antiepileptic agents, including, but not limited to, any of the following: Phenytoin; Carbamazepine; Phenobarbital; Rifampin No concurrent Hypericum perforatum (St. John's wort)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral sorafenib once or twice daily on days 1-5, 8-12, and 15-19. | Drug: Sorafenib Tosylate<br>* Given orally<br>* Other names: sorafenib;|
| Experimental: Arm II<br>Patients receive oral sorafenib once or twice daily on days 1-14. | Drug: Sorafenib Tosylate<br>* Given orally<br>* Other names: sorafenib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 |  | 21 days |