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AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT01798901
Recruitment Status : Active, not recruiting
First Posted : February 26, 2013
Last Update Posted : January 20, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
This phase I trial studies the side effects and best dose of AR-42 when given together with decitabine in treating patients with acute myeloid leukemia. AR-42 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 AR-42 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 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 Recurrent Childhood Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia Drug: HDAC inhibitor AR-42 Drug: decitabine Other: laboratory biomarker analysis Other: pharmacological study Phase 1

Detailed Description:


I. To determine the biologic effective and tolerable dose (BETD) of AR-42 (histone deacetylase [HDAC] inhibitor AR-42) in combination with a 10 day schedule of decitabine in acute myeloid leukemia (AML) in adults (Stratum 1) and children (Stratum 2).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of AR-42 in combination with a 10 day schedule of decitabine in adults and children.


I. To describe biologic activity of the combination of AR-42 and decitabine (changes in micro ribonucleic acid [RNA] [miR]-29b expression; specificity protein 1 [Sp1], deoxyribonucleic acid [DNA] (cytosine-5-)-methyltransferase [DNMT]1, 3A and 3B, KIT and FMS-like tyrosine kinase 3 [FLT3] RNA and protein levels).

II. To provide preliminary data for clinical response with the combination of AR-42 and decitabine in adults and in children.

III. To provide preliminary data on correlation of biologic endpoints and clinical response (particularly miR-29b expression).

OUTLINE: This is a dose-escalation study of HDAC inhibitor AR-42.

INDUCTION THERAPY: Patients receive HDAC inhibitor AR-42 orally (PO) daily on days 1, 3, and 5 or 1, 3, 4, 5 and decitabine intravenously (IV) over 1 hour on days 6-15. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi) receive HDAC inhibitor AR-42 as in Induction Therapy and decitabine IV over 1 hour on days 6-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of AR-42 and Decitabine in Acute Myeloid Leukemia
Actual Study Start Date : September 17, 2013
Primary Completion Date : August 24, 2016
Estimated Study Completion Date : December 31, 2017

Arms and Interventions

Arm Intervention/treatment
Experimental: Treatment (HDAC inhibitor AR-42, decitabine)

INDUCTION THERAPY: Patients receive HDAC inhibitor AR-42 PO daily on days 1, 3, and 5 or 1, 3, 4, 5 and decitabine IV over 1 hour on days 6-15. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving CR or CRi receive HDAC inhibitor AR-42 as in Induction Therapy and decitabine IV over 1 hour on days 6-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: HDAC inhibitor AR-42
Given PO
Other Name: AR-42
Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Outcome Measures

Primary Outcome Measures :
  1. BETD (biologic effective and tolerable dose) of HDAC inhibitor AR-42, defined as a doubling in miR-29b levels from baseline [ Time Frame: Up to 28 days ]
  2. Maximum tolerated dose (MTD) based on incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 28 days ]
  3. Incidence of adverse events, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 3 years ]
    Toxicities will be tabulated by dose level and summarized in addition to assessing the incidence of DLTs. Severe (grade 3+) toxicities will be summarized by type as well as in summary format of hematologic vs. non-hematologic severe toxicity incidence. DLT-level toxicities will also be summarized and tracked beyond the first cycle of therapy.

Eligibility Criteria

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Ages Eligible for Study:   3 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Adult patients (stratum 1) must be age >= 18 with relapsed or refractory acute myeloid leukemia (AML) or age >= 60 with previously untreated AML who are not candidates for or refuse standard/conventional induction chemotherapy (e.g. the 7+3 combination of cytarabine and an anthracycline); pediatric patients, age 3 to < 18 years (stratum 2) will be eligible with AML in second relapse or with refractory disease
  • Patients with secondary AML or therapy related disease (t-AML) are eligible
  • Patients who received decitabine or 5-azacitidine as prior treatment for myelodysplastic syndrome (MDS) (or AML) remain eligible for the dose escalation phase of the study; however, neither of these agents is permitted within 3 months of study entry; patients who have received prior decitabine or 5- azacitidine will be excluded from the expansion phase of the trial
  • If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
  • Performance status: Adults (>= 18 years) must be Eastern Cooperative Oncology Group (ECOG) performance status =< 2; pediatric patients (< 18 years) must be at least Lansky > 50%
  • Total bilirubin < 2.0 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
  • Creatinine < 2.0 mg/dL (adults > 18 years); < 1.3 x upper limit normal for age (pediatric patients < 18 years)
  • New York Heart Association (NYHA) congestive heart failure (CHF) class II or better
  • The effects of decitabine and AR-42 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, both men and women must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; if the patient does not agree, the patient is not eligible; should a woman become pregnant or suspect she is pregnant while participating in the study, she should inform her treating physician immediately
  • Ability to understand and willingness to sign the written informed consent document
  • Patients must have recovered from the toxicity of prior therapy to less than grade 2

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; hydroxyurea may be administered for control of leukocytosis both pre-treatment and during cycle 1 only
  • Patients receiving any other investigational agents or patients that have received other investigational agents within 28 days of enrollment
  • Patients with active central nervous system disease or with a single granulocytic sarcoma as sole site of disease
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine or AR-42 that cannot be managed with oral antihistamines, antipyretics (ie. acetaminophen) or low dose corticosteroids (< 10 mg oral prednisone or equivalent corticosteroid)
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; as infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control; myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV) infection (due to concern for increased toxicity with the regimen in combination with highly active antiretroviral therapy [HAART])
  • Patients with a known diagnosis of chronic hepatitis B infection (ie. persistence of hepatitis B surface antigen in the blood for 6 months or longer) or a diagnosis of hepatitis C (ie. the presence of anti-hepatitis C (hepatitis C virus [HCV]) antibodies in the peripheral blood) are excluded; patients with a recent diagnosis (< 6 months) of active viral hepatitis B or C are excluded
  • Patients who have advanced malignant solid tumors at the time of consideration for enrollment on this trial are excluded; patients who have a history of an advanced malignant solid tumor, but have no evidence of disease at the time of consideration for enrollment, are eligible
  • Patients with a known impairment of gastrointestinal (GI) function due to a GI disease such as inflammatory bowel disease (Crohn's disease, ulcerative colitis) or celiac disease, that may significantly alter the absorption of AR-42 are excluded
  • Pregnant women or women who are breastfeeding are excluded from this study; confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
  • Diagnosis of prolonged QT syndrome
  • Patients with a mean corrected QT interval (QTc) > 450 msec in males and > 470 msec in females
  • Inability to swallow capsules
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01798901

United States, Ohio
Cincinnati Children's Hospital
Cincinnati, Ohio, United States, 45229
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Alison Walker
Principal Investigator: Alison Walker, MD Ohio State University Comprehensive Cancer Center
More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Alison Walker, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01798901     History of Changes
Other Study ID Numbers: OSU-11130
NCI-2013-00122 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: February 26, 2013    Key Record Dates
Last Update Posted: January 20, 2017
Last Verified: January 2017

Keywords provided by Alison Walker, Ohio State University Comprehensive Cancer Center:
Acute Myeloid Leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors