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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01567059
First received: March 28, 2012
Last updated: June 9, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
Drug: tosedostat
Drug: cytarabine
Drug: decitabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Tosedostat in Combination With Either Cytarabine or Decitabine in Newly Diagnosed AML or High-Risk MDS

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Proportion of patients alive (survival rate) [ Time Frame: 4 months after beginning treatment ] [ Designated as safety issue: No ]
    Success measured by improvement of survival rate to 80% from the historical 60% while not decreasing the CR rate to < 30% from the historical 50%.

  • Proportion of patients achieving CR [ Time Frame: 4 months after beginning treatment ] [ Designated as safety issue: No ]
    Defined by Cheson et al.


Enrollment: 34
Study Start Date: May 2012
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (tosedostat and cytarabine)
Patients receive tosedostat PO QD on days 1-35 and cytarabine IV on days 1-5.
Drug: tosedostat
Given PO
Other Names:
  • aminopeptidase inhibitor CHR-2797
  • CHR-2797
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Experimental: Arm II (tosedostat and decitabine)
Patients receive tosedostat PO QD on days 1-35 and decitabine IV on days 1-5.
Drug: tosedostat
Given PO
Other Names:
  • aminopeptidase inhibitor CHR-2797
  • CHR-2797
Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01567059

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: John Pagel Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01567059     History of Changes
Other Study ID Numbers: 2566.00, NCI-2012-00274, P30CA015704
Study First Received: March 28, 2012
Last Updated: June 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Neoplasm Metastasis
Leukemia
Syndrome
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplastic Processes
Pathologic Processes
Disease
Cytarabine
Decitabine
Glycine
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
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014