Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

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Brief Title

Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Official Title

A Phase II Study of Tosedostat in Combination With Either Cytarabine or Decitabine in Newly Diagnosed AML or High-Risk MDS

Brief Summary

      This study examines a new oral chemotherapy drug called tosedostat, in combination with
      cytarabine or decitabine. Tosedostat is thought to work by decreasing the availability of
      amino acids (building blocks the cell needs to make proteins) in cells. It has been shown in
      early studies to have activity against a variety of cancers, including leukemias. Patients
      with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) with specific
      genetic mutations have a poorer response to chemotherapy and a higher risk of relapse after
      treatment. Researchers are looking to see if combinations of chemotherapy drugs may improve
      outcomes for patients that do not respond as well with the current chemotherapy regimens,
      without increasing the risks of treatment.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the 4 month survival and complete remission (CR) rates of tosedostat in
      combination with either cytarabine or decitabine in untreated acute myeloid leukemia (AML) or
      high-risk myelodysplastic syndrome (MDS).

      SECONDARY OBJECTIVES:

      I. To assess safety and tolerability of tosedostat in combination with either cytarabine or
      decitabine.

      II. To determine the treatment related mortality defined as death within the first 30 days of
      beginning treatment.

      III. To estimate rates of disease-free survival (DFS) and the 1 year overall survival (OS).

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive tosedostat orally (PO) once daily (QD) on days 1-35 and cytarabine
      intravenously (IV) on days 1-5.

      ARM II: Patients receive tosedostat PO QD on days 1-35 and decitabine IV on days 1-5.

      If the patient develops a significant increase in their circulating or bone marrow blast
      count, the subsequent cycle may be started as early as day 21 of the current cycle. In both
      arms, treatment repeats every 35 days for up to 3 courses in the absence of disease
      progression or unacceptable toxicity. Patients achieving CR or partial CR (pCR) may receive 2
      additional courses of treatment.

      After completion of study treatment, patients are followed up every 3 months for 2 years and
      then annually for 3 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of patients achieving CR


Condition

Acute Myeloid Leukemia With Multilineage Dysplasia

Intervention

tosedostat

Study Arms / Comparison Groups

 Arm I (tosedostat and cytarabine)
Description:  Patients receive tosedostat PO QD on days 1-35 and cytarabine IV on days 1-5.

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

34

Start Date

May 2012

Completion Date

June 2013

Primary Completion Date

June 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Capable of understanding the investigational nature, potential risks and benefits of
             the study, and able to provide valid informed consent

          -  All adults >= 60 years of age with untreated AML or high-risk MDS (10-19% marrow
             blasts) including those with prior myelodysplasia (MDS)/AML, therapy-related AML, AML
             with trilineage dysplasia (AML-TLD), and AML with adverse cytogenetics; patients may
             be enrolled if they received prior treatment with hydroxyurea to control blood counts
             or demethylating agents specifically for the purpose of treating MDS

          -  Adults age 18 to 59 with untreated AML or high-risk MDS and a transplant-related
             mortality (TRM) score of >= 9.2; previous data suggests these people would have a 25%
             mortality with standard therapy, making this treatment a reasonable alternative

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2

          -  Serum creatinine =< 2.0 mg/dL; if serum creatinine > 2.0 mg/dL, then the estimated
             glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m^2 as calculated by the
             Modification of Diet in Renal Disease equation

          -  Serum bilirubin =< 1.5 × upper limit of normal (ULN) (in the absence of Gilbert's
             syndrome)

          -  Aspartate transaminase (AST)/alanine transaminase (ALT) =< 3.0 × ULN

          -  Alkaline phosphatase =< 2.5 × ULN

          -  Male subjects, even if surgically sterilized (i.e., status postvasectomy) must agree
             to 1 of the following: practice effective barrier contraception during the entire
             study treatment period and through a minimum of 30 days after the last dose of study
             drug, or completely abstain from heterosexual intercourse

          -  Female subject is either postmenopausal for at least 1 year before the screening
             visit, is surgically sterilized or if they are of childbearing potential, agree to
             practice 2 effective methods of contraception from the time of signing the informed
             consent form through 30 days after the last dose of study drug, or agree to completely
             abstain from heterosexual intercourse

        Exclusion Criteria:

          -  Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
             specified in the protocol

          -  Active uncontrolled infection

          -  Known infection with human immunodeficiency virus (HIV)

          -  Medical condition, serious concurrent illness, or other extenuating circumstance that,
             in the judgment of the Principal Investigator, could jeopardize patient safety or
             interfere with the objectives of the study

          -  Uncontrolled angina or myocardial infarction within 6 months; patients with recent
             myocardial infarction apparently due to medical causes unrelated to underlying cardiac
             abnormalities must have a cardiac consult, and be cleared to participate in the
             research by the cardiologist prior to initiation of treatment and may be enrolled at
             the discretion of the primary investigator (PI) and treating physician

          -  Current or history of congestive heart failure New York Heart Association (NYHA) class
             3 or 4, unless a screening echocardiogram (ECHO) or multiple gate acquisition scan
             (MUGA) performed within 1 month prior to study screening results in a left ventricular
             ejection fraction (LVEF) that is >= 45% (or institutional lower limit of normal value)

          -  Diagnosed or treated for another malignancy within 1 year of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

John Pagel, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01567059

Organization ID

2566.00

Secondary IDs

NCI-2012-00274

Responsible Party

Sponsor

Study Sponsor

Fred Hutchinson Cancer Research Center

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

John Pagel, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


Verification Date

February 2017