This phase I trial studies the side effects and the best dose of bortezomib and sorafenib tosylate when given together with decitabine in treating patients with acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bortezomib and sorafenib tosylate together with decitabine may work better in treating acute myeloid leukemia.
PRIMARY OBJECTIVES: I. To identify the biologically effective and tolerable dose (BETD) of the bortezomib/sorafenib (sorafenib tosylate) combination in acute myeloid leukemia (AML) with biological activity defined as the dose(s) that induce a 100% increase (i.e. a doubling) in the level of microRNA-29b (miR-29b) in bone marrow (BM) after bortezomib/sorafenib treatment from pretreatment levels in at least 5 out of 6 patients at a given dose levels. II. To recommend a dose level for a Phase II study using this agent combination in patients with AML. III. To define the specific toxicities and the dose limiting toxicity (DLT) of bortezomib in combination with sorafenib and decitabine. SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR) of this combination. II. To determine the rate of complete remission (CR) of this combination. III. To conduct pharmacodynamic studies by measuring the effect of this chemotherapy combination on the micronome, kinome and epigenome. OUTLINE: This is a dose-escalation study of bortezomib and sorafenib tosylate. STEP A: Patients receive bortezomib subcutaneously (SC) on days 1 and 4, sorafenib tosylate orally (PO) twice daily (BID) on days 1-14, and decitabine intravenously (IV) over 1 hour on days 5-14. STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21. STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity. Patients achieving complete response (CR) or incomplete CR (CRi) receive maintenance therapy comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for at least 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
BETD of bortezomib, sorafenib tosylate, and decitabine using National Cancer Institute Common Terminology Criteria for Adverse Events version 4
Analysis will include summarization of the toxicity and tolerability by dose level. Frequency and severity of adverse events and tolerability of the regimen in each of the dose levels will be collected and summarized using descriptive statistics.
Time frame: 28 days
CR rate
Will be correlated with miR29b levels at baseline and day 5 (or days 9 and 12). Assessment of clinical response will be made according to International Working Group criteria.
Time frame: Up to 30 days
Change in miR-29b expression in blood and bone marrow
miR-29b expression as a continuous measure will be summarized quantitatively and graphically by dose level in addition to the assessment of the ability to achieve a two-fold change in this expression from baseline at each of the dose levels.
Time frame: Baseline to up to day 12 of course 1
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