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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
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

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

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

Outcome 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.

Outcome Time Frame:

During course 1 (28 days)

Safety Issue:

Yes

Principal Investigator

William Blum

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00263

NCT ID:

NCT00703300

Start Date:

June 2008

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Ohio State University Medical CenterColumbus, Ohio  43210