Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

Recurrent Adult Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00703300
• Other study ID #: NCI-2009-00263
• Secondary ID: NCI-2009-00263OS
• Status: Completed
• Phase: Phase 1
• First received: June 20, 2008
• Last updated: November 6, 2014
• Start date: June 2008
• Est. completion date: October 2014

Study information

• Verified date: September 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: October 2014
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Recurrent Adult Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia
• Untreated Adult Acute Myeloid Leukemia

Intervention

Drug:
• bortezomib
Given IV
• decitabine
Given IV

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Optional correlative studies

Locations

Country	Name	City	State
United States	Ohio State University Medical Center	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	During course 1 (28 days)	Yes
Primary	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.	Up to 30 days post-treatment	Yes
Primary	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.	During course 1 (28 days)	Yes
Secondary	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.	Up to 30 days post-treatment	No
Secondary	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)	Up to 30 days post-treatment	No