Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00703300

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	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

Detailed Description

PRIMARY OBJECTIVES:

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:

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.
To characterize the biological activity of bortezomib as a potential demethylating agent
To correlate intracellular concentration of decitabine-triphosphate with global DNA methylation and other biological endpoints as well as clinical response.
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 Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia

Study Start Date :

Jun 1, 2008

Actual Primary Completion Date :

Mar 1, 2010

Actual Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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 Names: pharmacological studies Other: laboratory biomarker analysis Optional correlative studies

Arm

Intervention/Treatment

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 Names:

pharmacological studies

Other: laboratory biomarker analysis

Optional correlative studies

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine [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 [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 [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.

Secondary Outcome Measures

Overall response rate [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) [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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