Decitabine, Cytarabine, and Daunorubicin Hydrochloride in Treating Patients With Acute Myeloid Leukemia

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Brief Title

Decitabine, Cytarabine, and Daunorubicin Hydrochloride in Treating Patients With Acute Myeloid Leukemia

Official Title

Randomized Phase II Study of Epigenetic Priming Using Decitabine With Induction Chemotherapy in Patients With Acute Myelogenous Leukemia (AML)

Brief Summary

      This randomized phase II trial studies how well decitabine works when given together with
      daunorubicin hydrochloride and cytarabine in treating patients with acute myeloid leukemia.
      Drugs used in chemotherapy, such as decitabine, daunorubicin hydrochloride, and cytarabine,
      work in different ways to stop the growth of cancer cells, either by killing the cells or by
      stopping them from dividing. Decitabine may help daunorubicin hydrochloride and cytarabine
      kill more cancer cells by making them more sensitive to the drugs. It is not yet known
      whether low-dose decitabine is more effective than high-dose decitabine when giving together
      with daunorubicin hydrochloride and cytarabine in treating acute myeloid leukemia.
    

Detailed Description

      OBJECTIVES: Primary I. To "Pick a Winner" by deciding whether further development of
      epigenetic priming with decitabine prior to standard "7+3" induction chemotherapy should be
      pursued.

      Secondary I. To determine whether epigenetic priming with decitabine prior to standard
      cytarabine and daunorubicin hydrochloride "7+3" induction chemotherapy has sufficient
      efficacy to warrant further development as assessed by an overall CR1 rate ≥ 50%.

      II. To establish the safety and expected toxicities of decitabine when used as priming for
      cytarabine and daunorubicin hydrochloride "7+3" induction chemotherapy in acute myeloid
      leukemia (AML).

      III. To assess the pharmacodynamics of deoxyribonucleic acid (DNA) hypomethylation when
      decitabine is administered as a short infusion.

      IV. To investigate, in selected cases, the molecular and cellular consequences of
      decitabine-induced hypomethylation by assessing the effects of decitabine-mediated
      hypomethylation on transcriptional patterns in AML cells, and by determining the effect of
      hypomethylation on the differentiation and/or apoptosis of leukemic blasts. (exploratory) V.
      To identify biomolecular correlates of treatment response (biomarkers) to induction
      chemotherapy in AML based upon the epigenetic pattern of DNA methylation in AML specimens
      obtained prior to treatment. (exploratory)

      OUTLINE: This is a multicenter study. Patients are stratified according to age (less than 50
      years vs 50-65 years), white blood cell count (≤ 30 K/mL vs greater than 30 K/mL),
      cytogenetic risk group (intermediate vs adverse risk), and antecedent hematological condition
      preceding the diagnosis of acute myeloid leukemia (yes vs no). Patients are randomized to 1
      of 2 treatment arms.

      Arm I: Patients receive induction chemotherapy comprising daunorubicin hydrochloride
      intravenously (IV) daily on days 1-3 and cytarabine IV continuously on days 1-7 in the
      absence of disease progression or unacceptable toxicity. Patients who do not achieve a
      complete remission (CR) after the first induction-chemotherapy course receive a second
      identical induction course.

      Arm II: Patients receive decitabine IV over 1 hour on days -5 to -1. Patients then receive
      induction chemotherapy as in arm I in the absence of disease progression or unacceptable
      toxicity. Patients who do not achieve a CR after the first induction-chemotherapy course
      receive a second identical induction course.

      Patients undergo blood, bone marrow, and oral mucosa cells sample collection at baseline,
      prior to induction therapy, and after treatment for DNA methylation studies and
      pharmacodynamic studies.

      After completion of study treatment, patients are followed up for up to 10 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Complete remission rate (CR1)

Secondary Outcome

 Complete remission rate (CR1 + CR2)

Condition

Acute Myeloid Leukemia

Intervention

Cytarabine

Study Arms / Comparison Groups

 Arm I (daunorubicin hydrochloride, cytarabine)
Description:  Patients receive induction chemotherapy comprising daunorubicin hydrochloride IV daily on days 1-3 and cytarabine IV continuously on days 1-7 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR after the first induction-chemotherapy course receive a second identical induction course.

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

180

Start Date

September 16, 2011


Primary Completion Date

October 1, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of acute myeloid leukemia (AML) as defined by the World Health Organization

          -  Molecular AML-risk group is less-than-favorable as defined by any of the following
             criteria:

               -  The absence of good-risk karyotype t(8;21), inv(16), t(16;16), or
                  t(15;17)identified by metaphase karyotype

               -  The absence of t(8;21), inv(16), t(16;16), or t(15;17) identified by fluorescent
                  in situ hybridization(FISH)

               -  The absence of the corresponding fusion transcripts, AML1-eight-twenty-one
                  corepressor (ETO), core-binding factor, beta subunit (CBFβ)-smooth muscle myosin
                  heavy chain (SMMHC), or progressive multifocal leukoencephalopathy (PML)-retinoic
                  acid receptor alpha (RARa), identified by reverse transcriptase-polymerase chain
                  reaction (RT-PCR)

               -  Patient does not have acute promyelocytic leukemia (APL, French-American-British
                  [FAB] M3)

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

          -  Adequate cardiac function as defined by either of the following:

               -  An echocardiogram demonstrating an ejection fraction within normal limits

               -  A multi gated acquisition (MUGA) scan demonstrating an ejection fraction within
                  normal limits

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤
             2.5 times institutional upper limit of normal (ULN)

          -  Creatinine ≤ 2 mg/dL OR creatinine clearance ≥ 50 mL/min

          -  Total bilirubin ≤ 2 times ULN

               -  Patients with documented diagnosis of Gilbert syndrome resulting in elevated
                  total bilirubin levels will be eligible, provided all other eligibility criteria
                  are met

               -  Patients with a total bilirubin of 2-3 mg/dL and direct (conjugated) bilirubin in
                  the normal range will be eligible, provided all other eligibility criteria are
                  met

          -  Pregnant and nursing subjects may not be enrolled and pregnancy must be avoided; women
             of child-bearing potential—defined as a sexually active woman who has not undergone
             hysterectomy and who has had menses any time within the preceding 24 months—must have
             a negative serum or urine pregnancy test within 7 days prior to registration; women
             and men of childbearing potential must either commit to continued abstinence from
             heterosexual intercourse or commit to two acceptable methods of birth control—one
             highly effective method (e.g., IUD, oral or non-oral hormonal contraceptive, tubal
             ligation or partner's vasectomy) and one additional effective method (e.g., latex
             condom, diaphragm or cervical cap) at the same time from the time of screening through
             final Treatment Response Assessment

               -  NOTE: should a woman become pregnant or suspect she is pregnant while she or her
                  partner is participating in this study, the subject should inform their treating
                  phy-sician immediately

               -  NOTE: the effects of decitabine on the developing human fetus are unknown but it
                  is a know teratogen in mammals (mice)

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Chemotherapy (other than hydroxyurea) or radiation within the 2 weeks prior to planned
             therapy on this study or ongoing adverse events due to agents administered more than 2
             weeks earlier

          -  Concurrent treatment with other investigational agents is not permitted

          -  Cumulative lifetime dose of anthracycline chemotherapeutic > 80 mg/m^2

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition of decitabine, cytarabine or daunorubicin

          -  Uncontrolled intercurrent illness considered by the investigator to constitute an
             unwarranted high risk for investigational drug treatment; examples include, but not
             limited to the following:

               -  Uncontrolled serious infection; or

               -  Unstable angina pectoris; or

               -  Uncontrolled cardiac arrhythmia; or

               -  Active second malignancy requiring treatment; or

               -  Symptomatic congestive heart failure

          -  HIV-positive subjects with a CD4 count < 200 cells/μL are excluded due to the
             increased risk of lethal infections when treated with marrow-suppressive
             chemotherapy(87)

               -  NOTE: subjects with HIV infection and a CD4 count >= 200 cells/μL are eligible
                  but combination antiretroviral therapy should be held during administration of
                  chemotherapy due to the potential for pharmacokinetic interactions with
                  decita-bine, cytarabine or daunorubicin. Antiretroviral therapy may be resumed 24
                  hours after completion of the last dose of induction chemotherapy

          -  Subject has a psychiatric disorder, altered mental status or social situation that
             would preclude understanding of the informed consent process and/or limit compliance
             with study requirements

          -  Subject has an inability or unwillingness, in the opinion of the investigator, to
             comply with the protocol requirements

          -  Subjects with central nervous system (CNS) (or leptomeningeal) infiltration by AML may
             be considered for treatment at the Investigator's discretion and following discussion
             with the Principle Investigator; all neurologic deficits must be noted prior to
             enrollment on study

          -  Subject has circulating blast count > 50,000/μL (subjects may be enrolled if
             circulating blast count is controlled by hydroxyurea and/or, if clinically indicated,
             by leukophoresis)
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Joseph M Scandura, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01627041

Organization ID

NCI-2012-01959

Secondary IDs

NCI-2012-01959

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Joseph M Scandura, Principal Investigator, Weill Medical College of Cornell University


Verification Date

June 2020