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Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00703300
First received: June 20, 2008
Last updated: November 6, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: decitabine
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine [ Time Frame: During course 1 (28 days) ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Overall response rate [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The major criteria for judging response will include physical examination and examination of blood and bone marrow (morphologic CR and cytogenetic CR)


Enrollment: 19
Study Start Date: June 2008
Study Completion Date: October 2014
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00703300

Locations
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: William Blum Ohio State University
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00703300     History of Changes
Other Study ID Numbers: NCI-2009-00263, NCI-2009-00263, OSU-08047, 2008C0034, CDR0000598089, 08047, 8008, U01CA076576, P30CA016058
Study First Received: June 20, 2008
Last Updated: November 6, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Bortezomib
Decitabine
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014