Phase I Study of Decitabine, Vorinostat, and Cytarabine in Acute Myeloid Leukemia
18 Years
59 Years
Both
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), 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
Trial Information
Phase I Study of Decitabine, Vorinostat, and Cytarabine in Acute Myeloid Leukemia
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of the combination of decitabine,
vorinostat, and cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML)
and select subsets of high risk leukemia/myelodysplastic syndromes (MDS).
II. To define the specific toxicities and the dose limiting toxicity (DLT) of the
combination.
SECONDARY OBJECTIVES:
I. To develop a platform for specifically targeting MLL PTD, for future efficacy studies.
II. To determine the overall response rate (ORR) of this regimen in relapsed/ refractory
AML.
III. To examine the role of decitabine and vorinostat in re-expression of MLL- WT in
patients with MLL PTD via correlative studies specific to patients with MLL PTD and the
preliminary relationship of this to clinical response in patients with MLL PTD+ AML.
IV. 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 V. To explore the biologic role of microRNAs in determining clinical
response to the combination and achievement of the other pharmacodynamic endpoints.
OUTLINE: This is a dose-escalation study of cytarabine.
INDUCTION THERAPY: Patients receive decitabine IV over 1 hour on days 1-10; oral vorinostat
on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14, and 16 in the absence
of disease progression or unacceptable toxicity. Patients who achieve complete response (CR)
proceed to maintenance therapy. Patients who achieve CR with incomplete blood count recovery
undergo bone marrow aspiration and biopsy at count recovery or day 42 before proceeding to
maintenance therapy.
MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and oral
vorinostat on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence
of disease progression or unacceptable toxicity.
Blood samples and additional bone marrow aspirate and biopsy are collected at baseline and
during study for re-expression of mixed lineage leukemia-wild-type, changes in target gene
methylation and gene expression, DNMT1 protein expression, global methylation, and other
pharmacodynamic studies.
After completion of study therapy, patients are followed up for 30 days.
Inclusion Criteria:
- Diagnosis of acute myeloid leukemia (AML)
- Relapsed or refractory disease
- Secondary AML or therapy related disease (t-AML) allowed
- AML with mixed-lineage leukemia partial-tandem duplication (MLL PTD)
- No advanced malignant solid tumors or additional active hematologic malignancies
- No active CNS disease or granulocytic sarcoma as sole site of disease
- ECOG performance status 0-2
- Life expectancy > 6 months (for patients with co-morbid medical illness)
- Total bilirubin < 2.0 mg/dL
- AST and/or ALT 2.5 times upper limit of normal
- Creatinine < 2.0 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must agree to use effective contraception before and during study
therapy
- Known HIV infection allowed provided the following criteria are met:
- No history of AIDS
- High CD4 cell count (> 400/mm^3)
- Low HIV viral load (< 30,000 copies/mL plasma)
- No requirement for anti-HIV therapy
- No history of medically serious allergic reactions attributed to decitabine,
vorinostat, or cytarabine, or compounds of similar chemical or biologic composition
that are not easily managed
- No uncontrolled intercurrent illness including, but not limited to, any of the
following:
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Serious cardiac arrhythmia
- Psychiatric illness or social situations that would limit compliance with study
requirements
- Myocardial infarction within the past 6 months
- NYHA class III-IV heart failure
- Severe uncontrolled ventricular arrhythmias
- Electrocardiographic evidence of acute ischemia or active conduction system
abnormalities
- Medical comorbidities that would preclude safety evaluation of the combination
therapy
- No serious medical or psychiatric illness likely to interfere with participation in
this clinical study
- No history of neurologic toxicity attributed to cytarabine or vorinostat
- Active infection that is under control allowed
- Patients with uncontrolled infection shall not be enrolled until it is treated
and brought under control
- Able to swallow pills
- Prior decitabine or azacitidine for myelodysplastic syndrome or AML allowed
- Prior high-dose cytarabine (> 1 g/m²/dose) allowed
- More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
or radiotherapy and recovered to toxicities < grade 2
- More than 2 weeks since valproic acid or any other histone deacetylase inhibitor
- More than 14 days since prior and no other concurrent investigational agents
- No concurrent anti-HIV therapy
- No concurrent warfarin or Coumadin® derivative
- No other concurrent anticancer agents or therapies
- No concurrent palliative radiotherapy
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
MTD of decitabine and vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0
Outcome Time Frame:
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-2011-01488
NCT ID:
NCT01130506
Start Date:
May 2010
Completion Date:
Related Keywords:
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
- Adult Acute Myeloid Leukemia With Del(5q)
- 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
- Congenital Abnormalities
- Leukemia
- Leukemia, Myeloid, Acute
- Leukemia, Myeloid
Name | Location |
|---|---|
| Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center | Columbus, Ohio 43210-1240 |
| M D Anderson Cancer Center | Houston, Texas 77030 |
