Phase II Study of Idarubicin, Cytarabine, and Vorinostat With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT00656617
First received: April 7, 2008
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Drug: Idarubicin
Drug: Cytarabine
Drug: Vorinostat
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Idarubicin, Cytarabine, and Vorinostat in Patients With High-Risk MDS and AML

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: Baseline to disease progression, up to 18 treatment cycles (4-6 week cycle) ] [ Designated as safety issue: No ]
    Progression-free survival defined as time from date of randomization to first occurrence of having documented disease progression or death due to any cause, whichever comes first. Progression based on tumor assessments according to Response Evaluation Criteria in Solid Tumors (RECIST).


Secondary Outcome Measures:
  • Participant Response [ Time Frame: Monitoring with each 4 week cycle, up to 18 cycles of treatment ] [ Designated as safety issue: No ]
    Response assessed according RECIST: Complete Response (CR) defined as normalization of marrow (< 5% blasts) and of peripheral blood counts (neutrophil count > 1.109/L, platelet count > 100 x 109/L). Partial response (PR) defined as for CR in terms of peripheral counts but with reduction of marrow blasts by >50% compared to pretreatment values but above <5%. CRp = CR, but platelets <100 x 109/L. Progressive disease defined as increase of blasts to > 10% after an initial response.


Enrollment: 106
Study Start Date: April 2008
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Idarubicin + Ara-C + Vorinostat
Idarubicin 12 mg/m^2 by vein (IV) over 1 hour daily for 3 days (days 4 to 6). Ara-C (Cytarabine) 1.5 g/m^2 IV as a continuous infusion over 24 hours daily (days 4 to 7). Vorinostat initial dose level 500 mg orally three times a day for 3 days (days 1 to 3).
Drug: Idarubicin
12 mg/m^2 IV over 1 hour daily for 3 days (days 4 to 6)
Other Name: Idamycin PFS®
Drug: Cytarabine
1.5 g/m^2 IV as a continuous infusion over 24 hours daily (days 4 to 7)
Other Names:
  • Ara-C
  • Cytosine arabinoside
  • Cytosar-U®
  • DepoCyt
Drug: Vorinostat
Initial dose level 500 mg orally three times a day for 3 days (days 1 to 3).
Other Names:
  • Zolinza®
  • SAHA
  • Suberoylanilide Hydroxamic Acid
  • MSK-390

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   15 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00656617

Locations
United States, Texas
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Merck Sharp & Dohme Corp.
Investigators
Study Chair: Guillermo Garcia-Manero, M.D. M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00656617     History of Changes
Other Study ID Numbers: 2007-0835, NCI-2010-01500
Study First Received: April 7, 2008
Last Updated: June 19, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Acute Myeloid Leukemia
(AML)
Myelodysplastic syndrome
(MDS)
Leukemia
Idarubicin
Cytarabine
Vorinostat
Ara-C

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia
Syndrome
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Disease
Pathologic Processes
Cytarabine
Vorinostat
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on September 22, 2014