Brief Title
Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia
Official Title
Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia
Brief Summary
This phase I trial is studying the side effects and best dose of bortezomib when given
together with decitabine in treating patients with acute myeloid leukemia. Bortezomib 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 or by stopping them from dividing. Giving bortezomib
together with decitabine may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of bortezomib (Velcade, PS-341) in
combination with decitabine in patients with acute myeloid leukemia (AML) II. To define the
specific toxicities and the dose limiting toxicity (DLT) of decitabine plus bortezomib
combination
SECONDARY OBJECTIVES:
I. To determine the overall response rate (ORR). II. To determine the rate of complete
remission (CR) of decitabine plus bortezomib in AML III. To correlate the biological activity
of decitabine as demethylating agent (changes in target gene methylation and gene expression,
DNMT1 protein expression, global methylation) with clinical endpoints and plasma
pharmacokinetics of decitabine.
IV. To characterize the biological activity of bortezomib as a potential demethylating agent
V. To correlate intracellular concentration of decitabine-triphosphate with global DNA
methylation and other biological endpoints as well as clinical response.
VI. To explore the biologic role of microRNAs in determining clinical response to the
decitabine plus bortezomib combination and achievement of the other pharmacodynamic
endpoints.
OUTLINE: This is a dose-escalation study of bortezomib.
Patients receive decitabine intravenously (IV) over 1 hour on days 1-5 or 1-10 and bortezomib
IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined,
an additional 6 patients are treated at the recommended phase II dose.
After completion of study treatment, patients are followed for at least 30 days.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine
Secondary Outcome
Overall response rate
Condition
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Intervention
bortezomib
Study Arms / Comparison Groups
Treatment (enzyme inhibitor therapy and chemotherapy)
Description: Patients receive decitabine IV over 1 hour on days 1-5 or 1-10 and bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined, an additional 6 patients are treated at the recommended phase II dose.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
19
Start Date
June 2008
Completion Date
October 2014
Primary Completion Date
March 2010
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of acute myeloid leukemia (AML), meeting one of the following criteria:
- Relapsed or refractory disease (≥ 18 years of age)
- Previously untreated disease (≥ 60 years of age)
- Secondary AML or therapy-related AML allowed
- No granulocytic sarcoma as the sole site of disease
- No active or relapsed CNS disease
- No advanced malignant solid tumors
- ECOG performance status 0-2
- Life expectancy > 6 months (if patient has co-morbid illness)
- Total bilirubin < 2.0 mg/dL
- AST and ALT < 2.5 times upper limit of normal
- Creatinine < 2.0 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Patients with HIV infection are eligible provided the following criteria are met:
- No history of AIDS
- Has a sufficiently high CD4 count (> 400/mm³)
- Has low HIV viral loads (< 30,000 copies/mL plasma)
- Does not require anti-HIV therapy
- No uncontrolled active infection
- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to decitabine or bortezomib that are not easily managed
- No hypersensitivity to boron or mannitol
- No concurrent uncontrolled illness including, but not limited to, any of the
following:
- Symptomatic congestive heart failure
- Unstable or uncontrolled angina pectoris
- Serious cardiac arrhythmia
- Myocardial infarction within the past 6 months
- New York Heart Association class III-IV heart failure
- Severe uncontrolled ventricular arrhythmias
- Acute ischemia or active conduction system abnormalities by ECG
- No serious medical or psychiatric illness or social situation that would preclude
participation in this study
- No pre-existing neuropathy ≥ grade 2
- No other serious neurologic toxicity that would significantly increase the risk of
complications from bortezomib therapy
- Recovered from prior therapy (toxicity < grade 2)
- More than 14 days since prior investigational agents
- More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
or radiotherapy
- Prior decitabine or azacitidine for myelodysplastic syndromes (MDS) or AML allowed
- More than 6 months since prior decitabine, azacitidine, or bortezomib
- No concurrent palliative radiotherapy
- No other concurrent investigational agents
- No other concurrent direct anti-leukemia therapy
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
William Blum, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00703300
Organization ID
NCI-2009-00263
Secondary IDs
NCI-2009-00263
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
William Blum, Principal Investigator, Ohio State University
Verification Date
September 2014