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

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Brief Title

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

Official Title

Phase I Study of AR-42 and Decitabine in Acute Myeloid Leukemia

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.
    

Detailed Description

      PRIMARY OBJECTIVES:

      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.

      SECONDARY OBJECTIVES:

      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 Phase

Phase 1

Study Type

Interventional


Primary Outcome

BETD (biologic effective and tolerable dose) of HDAC inhibitor AR-42, defined as a doubling in miR-29b levels from baseline


Condition

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Intervention

HDAC inhibitor AR-42

Study Arms / Comparison Groups

 Treatment (HDAC inhibitor AR-42, decitabine)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

13

Start Date

September 17, 2013

Completion Date

February 19, 2015

Primary Completion Date

February 19, 2015

Eligibility Criteria

        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
      

Gender

All

Ages

3 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alison Walker, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01798901

Organization ID

OSU-11130

Secondary IDs

NCI-2013-00122

Responsible Party

Sponsor-Investigator

Study Sponsor

Alison Walker


Study Sponsor

Alison Walker, MD, Principal Investigator, Ohio State University Comprehensive Cancer Center


Verification Date

March 2018