Sorafenib and Low Dose Cytarabine in Older Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the cancer. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with cytarabine may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving sorafenib together with cytarabine and to see how well it works in treating older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.

Detailed Description
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OBJECTIVES: To determine the recommended dose of sorafenib tosylate and cytarabine when given in combination to elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndromes who are not suitable for intensive chemotherapy. (Phase I) To determine the safety, tolerability, toxicity profile, and dose-limiting toxicities in patients treated with this regimen. (Phase I) To estimate the efficacy (as measured by complete response rate) in patients treated with this regimen. (Phase II) To describe the toxic effects and overall response rate (complete and partial) in patients treated with this regimen. (Phase II) To evaluate potential correlates of response in translational research studies including FLT-3 internal tandem duplications and point mutations in blasts. (Phase II) OUTLINE: This is a multicenter study. Phase I: Patients receive oral sorafenib tosylate twice daily on days 2-28 and cytarabine subcutaneously twice daily on days 1-10 at the dose level assigned at registration. Doses of both drugs will be escalated and the recommended doses for the combination will be determined. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who respond to treatment will receive 2 cycles after response criteria are met. Phase II: Patients receive sorafenib tosylate and cytarabine as in phase I at the recommended doses for the combination determined in phase I. Bone marrow (or blood) samples are collected at baseline and at the end of each course of study treatment. Baseline samples are analyzed for mutational status of FLT-3 (i.e., internal tandem duplication [ITD] and point mutations). After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter until progression and toxicities resolve.

Official Title
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A Phase I/II Study of Sorafenib (BAY 43-9006) in Combination With Low Dose ARA-C (CYTARABINE) in Elderly Patients With AML or High-Risk MDS

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: cytarabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Acute myeloid leukemia (AML) by FAB criteria (By morphology and routine histochemistry and confirmed, when possible, by flow cytometric analysis of surface immunophenotype; co-expression of lymphoid markers permitted) High-risk myelodysplastic syndromes defined as IPSS category of intermediate-2 or greater Must be considered unsuitable for intensive chemotherapy regimens No documented CNS involvement PATIENT CHARACTERISTICS: ECOG performance status 0-2 AST and ALT ≤ 2 times upper limit of normal (ULN) Bilirubin normal Creatinine ≤ 1.2 times ULN OR creatinine clearance ≥ 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in situ carcinoma of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years No upper gastrointestinal or other conditions that would preclude compliance with or administration of oral medication No serious illness or medical condition that would not permit the patient to be managed according to the protocol, including any of the following: History of significant neurologic or psychiatric disorder that would impair the ability to obtain consent Active, uncontrolled, serious infections Active peptic ulcer disease Evidence of bleeding diathesis No myocardial infarction within the past 6 months No congestive heart failure No unstable angina No active cardiomyopathy or unstable ventricular arrhythmia No poorly controlled hypertension (e.g., systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg) No known hypersensitivity to the study drugs or their components No preexisting hypothyroidism prior to enrollment unless patient is euthyroid on medication No neuropathy ≥ grade 2 PRIOR CONCURRENT THERAPY: At least 2 days since prior hydroxyurea No other prior chemotherapy No concurrent therapeutic doses (≥ 2 mg/day) of anticoagulants (e.g., warfarin) Doses of up to 2 mg/day given for prophylaxis of thrombosis are accepted provided INR is ≤ 1.5 No other concurrent experimental drugs or anticancer therapy

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib and Cytarabine<br>Cytarabine: subcutaneously twice daily from day 1 - 10. Sorafenib: Days 2-28; at the dose level assigned at registration. Sorafenib will be given orally twice daily. | Drug: cytarabine<br>* subcutaneously twice daily from Day 1 to 10<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose of sorafenib tosylate when given in combination with cytarabine (Phase I) |  | 29 months | 
| Dose-limiting toxicity (Phase I) |  | 29 months | 
| Complete remission (Phase II) |  | 29 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (complete and partial response) (Phase II) |  | 29 months | 
| Time to progression (Phase II) |  | 29 months | 
| Overall survival (Phase II) |  | 29 months | 
| FLT-3 ITD endpoint mutation response correlation. |  | 29 months | 
| Toxicity (Phase II) |  | 29 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), untreated adult acute myeloid leukemia, secondary acute myeloid leukemia, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes