Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

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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