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Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

Primary Purpose

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)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
bortezomib
decitabine
pharmacological study
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor therapy and chemotherapy)

Arm 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.

Outcomes

Primary Outcome Measures

Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine
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
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
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
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)
The major criteria for judging response will include physical examination and examination of blood and bone marrow (morphologic CR and cytogenetic CR)

Full Information

First Posted
June 20, 2008
Last Updated
November 6, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00703300
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2014
Overall Recruitment Status
Completed
Study Start Date
June 2008 (undefined)
Primary Completion Date
March 2010 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (enzyme inhibitor therapy and chemotherapy)
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
decitabine
Other Intervention Name(s)
5-aza-dCyd, 5AZA, DAC
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Optional correlative studies
Primary Outcome Measure Information:
Title
Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine
Description
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.
Time Frame
During course 1 (28 days)
Title
Specific toxicities
Description
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.
Time Frame
Up to 30 days post-treatment
Title
DLT of bortezomib in combination with decitabine
Description
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.
Time Frame
During course 1 (28 days)
Secondary Outcome Measure Information:
Title
Overall response rate
Description
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.
Time Frame
Up to 30 days post-treatment
Title
Rate of complete remission (CR)
Description
The major criteria for judging response will include physical examination and examination of blood and bone marrow (morphologic CR and cytogenetic CR)
Time Frame
Up to 30 days post-treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William Blum
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22566605
Citation
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.
Results Reference
derived

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Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

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