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Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT00703300
Recruitment Status : Completed
First Posted : June 23, 2008
Last Update Posted : November 7, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

June 20, 2008
June 23, 2008
November 7, 2014
June 2008
March 2010   (Final data collection date for primary outcome measure)
  • Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine [ Time Frame: During course 1 (28 days) ]
    If a patient meets the definition of dose-limiting toxicity (DLT), the patient may continue on with study therapy provided that the toxicity can be managed according to the dose modification guidelines. For DLT = 2, dose level will stop. This dose level will be declared the MTD administered dose (highest dose administered). As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
  • Specific toxicities [ Time Frame: Up to 30 days post-treatment ]
    Toxicity will be characterized using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
  • DLT of bortezomib in combination with decitabine [ Time Frame: During course 1 (28 days) ]
    Toxicity will be characterized using the National Cancer Institute CTCAE version 3.0. As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
  • Maximum tolerated dose of bortezomib
  • Specific toxicities and dose-limiting toxicity
Complete list of historical versions of study NCT00703300 on ClinicalTrials.gov Archive Site
  • Overall response rate [ Time Frame: Up to 30 days post-treatment ]
    Assessment of clinical response will be made according to International Working Group criteria. The major criteria for judging response will include physical examination and examination of blood and bone marrow.
  • Rate of complete remission (CR) [ Time Frame: Up to 30 days post-treatment ]
    The major criteria for judging response will include physical examination and examination of blood and bone marrow (morphologic CR and cytogenetic CR)
  • Overall response rate
  • Rate of complete remission
Not Provided
Not Provided
 
Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia
Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia
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.

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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • 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)
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Drug: decitabine
    Given IV
    Other Names:
    • 5-aza-dCyd
    • 5AZA
    • DAC
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Optional correlative studies
Experimental: Treatment (enzyme inhibitor therapy and chemotherapy)
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.
Interventions:
  • Drug: bortezomib
  • Drug: decitabine
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Blum W, Schwind S, Tarighat SS, Geyer S, Eisfeld AK, Whitman S, Walker A, Klisovic R, Byrd JC, Santhanam R, Wang H, Curfman JP, Devine SM, Jacob S, Garr C, Kefauver C, Perrotti D, Chan KK, Bloomfield CD, Caligiuri MA, Grever MR, Garzon R, Marcucci G. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood. 2012 Jun 21;119(25):6025-31. doi: 10.1182/blood-2012-03-413898. Epub 2012 May 7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
19
36
October 2014
March 2010   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00703300
NCI-2009-00263
NCI-2009-00263 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
OSU-08047
2008C0034
CDR0000598089
08047 ( Other Identifier: Ohio State University Medical Center )
8008 ( Other Identifier: CTEP )
U01CA076576 ( U.S. NIH Grant/Contract )
P30CA016058 ( U.S. NIH Grant/Contract )
Not Provided
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: William Blum Ohio State University
National Cancer Institute (NCI)
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP