Overview

This trial is active, not recruiting.

Conditions adult acute myeloid leukemia with inv(16)(p13.1q22); cbfb-myh11, adult acute myeloid leukemia with t(16;16)(p13.1;q22); cbfb-myh11, adult acute myeloid leukemia with t(8;21)(q22;q22); runx1-runx1t1, adult acute myeloid leukemia with t(9;11)(p22;q23); mllt3-mll, adult acute promyelocytic leukemia with t(15;17)(q22;q12); pml-rara, alkylating agent-related acute myeloid leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia
Treatments decitabine, vorinostat, cytarabine, pharmacological study, diagnostic laboratory biomarker analysis
Phase phase 1
Target HDAC
Sponsor National Cancer Institute (NCI)
Start date May 2010
End date November 2012
Trial size 17 participants
Trial identifier NCT01130506, 09150, 2010C0009, 8485, CDR0000673876, NCI-2011-01488, P30CA016058, U01CA076576

Summary

This phase I trial is studying the side effects and the best dose of cytarabine when given together with decitabine and vorinostat in treating patients with relapsed or refractory acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cytarabine together with decitabine and vorinostat may kill more cancer cells.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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 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.
decitabine 5AZA
Given IV
vorinostat L-001079038
Given orally
cytarabine CHX-3311
Given IV
pharmacological study pharmacological studies
Correlative studies
diagnostic laboratory biomarker analysis
Correlative studies

Primary Outcomes

Measure
MTD of decitabine and vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0
time frame: 28 days
Toxicity, graded according to NCI CTCAE version 4.0
time frame: Up to 30 days after completion of study treatment

Secondary Outcomes

Measure
Overall response rate, assessed using International Working Group criteria
time frame: Up to 30 days after completion of study treatment

Eligibility Criteria

Male or female participants from 18 years up to 59 years old.

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

Additional Information

Official title Phase I Study of Decitabine, Vorinostat, and Cytarabine in Acute Myeloid Leukemia
Principal investigator William Blum
Description 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2014.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).