Phase II Study of Idarubicin, Cytarabine, and Vorinostat With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Condition: Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Idarubicin; Cytarabine; Vorinostat
Intervention description: 12 mg/m^2 IV over 1 hour daily for 3 days (days 4 to 6); 1.5 g/m^2 IV as a continuous infusion over 24 hours daily (days 4 to 7); Initial dose level 500 mg orally three times a day for 3 days (days 1 to 3).
Intervention MeSH terms: Cytarabine; Vorinostat; Idarubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 106.0
Sex: All
Minimum age: 15 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia; (AML); Myelodysplastic syndrome; (MDS); Leukemia; Idarubicin; Cytarabine; Vorinostat; Ara-C

Summary:

      The goal of this clinical research study is to find the highest safe dose of vorinostat that
      can be given in combination with idarubicin and ara-C for the treatment of AML and high-risk
      MDS.

      Once the highest safe dose is found, researchers will then try to learn if this combination
      treatment can help to control AML and high-risk MDS in newly diagnosed patients. The safety
      of this treatment combination will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of 1) AML (World Health Organization (WHO) classification definition of >/=
             20% blasts), or 2) intermediate-2 or high-risk MDS (defined by the IPSS
             classification2).

          2. Patients aged 15 to 65 years;

          3. For the initial run-in phase of the study, patients with relapsed or refractory
             disease or patients with secondary untreated disease are eligible, however, these
             patients must not have had prior exposure to a histone deacetylase inhibitor, prior
             antecedent hematological disorder or secondary disease with complex cytogenetics.

          4. For the actual phase II portion of the study: patients must be chemonaïve, i.e., not
             have received any chemotherapy (except hydrea) for AML or MDS. They may have received
             hypomethylating agents for prior MDS and transfusions, hematopoietic growth factors or
             vitamins. Temporary prior measures such as apheresis or hydrea are allowed;

          5. In those patients that have received prior therapy, at least 2 weeks need to have
             elapsed before participating in this study. Treatment may start earlier if deemed in
             the best interest of the patient after discussion with the PI of the study ;

          6. Eastern Cooperative Oncology Group (ECOG) performance status </= 2

          7. Serum biochemical values with the following limits unless considered due to leukemia:
             creatinine </=2 mg/dl; total bilirubin </=2 mg/dL, unless increase is due to hemolysis
             or congenital disorder; transaminases (SGPT or SGOT) </=2.5* upper limit of normal
             (ULN);

          8. Ability to swallow oral medication;

          9. Ability to understand and provide signed informed consent;

         10. Cardiac ejection fraction must be >/=50% (by either multiple gated acquisition scan
             (MUGA) scan or echocardiography).

         11. Diagnosis of 1) AML (WHO classification definition of > 20% blasts), or 2)
             intermediate-2 or high-risk MDS (defined by the International Prognostic Scoring
             System (IPSS) classification) with Flt-3 mutation. Flt-3 extension phase.

         12. Patients aged 15 to 65 years are eligible. Flt-3 extension phase.

         13. Patients with relapsed or refractory disease or patients with secondary untreated
             disease are eligible, however, these patients must not have had prior exposure to a
             histone deacetylase inhibitor. All patients should be Flt-3 positive. Flt-3 extension
             phase.

         14. Patients with newly diagnosed Flt3 positive AML are allowed. Flt-3 extension phase.

         15. In those patients that have received prior therapy, at least 2 weeks need to have
             elapsed before participating in this study. Treatment may start earlier if deemed in
             the best interest of the patient after discussion with the PI of the study. Flt-3
             extension phase.

         16. ECOG performance status </= 2. Flt-3 extension phase.

         17. Serum biochemical values with the following limits unless considered due to leukemia.
             creatinine </=2 mg/dl; total bilirubin </=2 mg/dL, unless increase is due to hemolysis
             or congenital disorder - transaminases (SGPT or SGOT) </=2.5* ULN. Flt-3 extension
             phase.

         18. Ability to swallow oral medication. Flt-3 extension phase.

         19. Ability to understand and provide signed informed consent. Flt-3 extension phase.

         20. Cardiac ejection fraction must be >/=50% (by either MUGA scan or echocardiography).
             Flt-3 extension phase.

        Exclusion Criteria:

          1. Diagnosis of acute promyelocytic leukemia;

          2. Active, uncontrolled, systemic infection considered opportunistic, life threatening or
             clinical significant at the time of treatment, or any severe concurrent disease, which
             in the opinion of the investigator and after discussion with the principal
             investigator, would make the patient inappropriate for study entry;

          3. Male and female patients who are fertile agree to use an effective barrier method of
             birth control (i.e., latex condom, diaphragm, cervical cap, etc.) to avoid pregnancy.
             Female patients need a negative serum or urine pregnancy test within 7 days of study
             enrollment (applies only if patient of childbearing potential. Non childbearing is
             defined as 1 year or more postmenopausal or surgically sterilized);

          4. Symptomatic central nervous system (CNS) involvement;

          5. Patient is unable to take and/or tolerate oral medications on a continuous basis;

          6. Patient has known human immunodeficiency virus (HIV) infection or known HIV-related
             malignancy;

          7. Patient has active hepatitis B or C infection. Active disease is defined as elevated
             liver enzymes and/or clinical symptoms of hepatitis in addition to positive blood test
             for hepatitis surface antigen. In the absence of elevated liver enzymes and/or
             clinical symptoms, the blood test for hepatitis core antigens is not required.

          8. Patient is pregnant or breast-feeding;

          9. Patient has a known allergy or hypersensitivity to any component of vorinostat;

         10. Patient has a history of thrombotic disorders;

         11. History of any psychiatric condition that might impair the patient's ability to
             understand or to comply with the requirements of the study or to provide informed
             consent.

         12. Diagnosis of acute promyelocytic leukemia. Flt-3 extension phase.

         13. Active, uncontrolled, systemic infection considered opportunistic, life threatening or
             clinical significant at the time of treatment, or any severe concurrent disease, which
             in the opinion of the investigator and after discussion with the principal
             investigator, would make the patient inappropriate for study entry. Flt-3 extension
             phase.

         14. Male and female patients who are fertile agree to use an effective barrier method of
             birth control (i.e., latex condom, diaphragm, cervical cap, etc.) to avoid pregnancy.
             Female patients need a negative serum or urine pregnancy test within 7 days of study
             enrollment (applies only if patient of childbearing potential. Non childbearing is
             defined as 1 year or more postmenopausal or surgically sterilized). Flt-3 extension
             phase.

         15. Symptomatic CNS involvement. Flt-3 extension phase.

         16. Patient is unable to take and/or tolerate oral medications on a continuous basis.
             Flt-3 extension phase.

         17. Patient has known human immunodeficiency virus (HIV) infection or known HIV-related
             malignancy. Flt-3 extension phase.

         18. Patient has active hepatitis B or C infection. Active disease is defined as elevated
             liver enzymes and/or clinical symptoms of hepatitis in addition to positive blood test
             for hepatitis surface antigen. In the absence of elevated liver enzymes and/or
             clinical symptoms, the blood test for hepatitis core antigens is not required. Flt-3
             extension phase.

         19. Patient is pregnant or breast-feeding. Flt-3 extension phase.

         20. Patient has a known allergy or hypersensitivity to any component of vorinostat. Flt-3
             extension phase.

         21. Patient has a history of thrombotic disorders. Flt-3 extension phase.

         22. History of any psychiatric condition that might impair the patient's ability to
             understand or to comply with the requirements of the study or to provide informed
             consent. Flt-3 extension phase.