A Dose Confirmation Study of Oral Clofarabine for Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)
Condition: Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Clofarabine
Intervention description: Pharmaceutical form: Tablet,
Route of administration: Oral
Intervention MeSH terms: Clofarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Previously treated MDS; oral clofarabine; Intermediate-1, Intermediate-2 and High Risk MDS; secondary AML (with history of MDS)

Summary:

      There was no well accepted standard of care for participants who failed or were intolerant to
      any of the currently approved therapies for myelodysplastic syndromes (MDS). In this study,
      participants were initially assigned to receive 55 or 35 milligrams (mg) of oral clofarabine
      daily for 5 days. After safety review of the first participants enrolled, the dose was
      reduced to 25 milligrams per day (mg/day) for up to 8 cycles as long as the participants
      continued to benefit and in the absence of progressive disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Had a pathologically confirmed secondary Acute Myeloid Leukemia ([sAML]; following a
             history of MDS) or MDS with an intermediate-1 (with marrow blasts greater than or
             equal to [>=] 5%) or intermediate-2 or high risk score as assessed by the
             International Prognostic Scoring System at study entry. Participants with refractory
             anemia with excess blasts in transformation recognized by the French-American-British
             system, and chronic myelomonocytic leukemia were allowed into the study. Pathologic
             confirmation was the responsibility of the site investigator.

          -  Had previously treated MDS defined as follows: a) Participants must had at least one,
             but no more than two, prior treatment regimens [a.) treatment regimen was defined as
             any drug or drug combination administered for treatment of MDS with the intent of
             inducing at least hematologic improvement (consistent with International Working Group
             criteria); Inadequate treatment, due to drug intolerance or other factors, was
             considered a prior treatment regimen. Hematopoietic growth factors, hydroxyurea,
             anti-thymocyte globulin, or supportive care measures (e.g., blood transfusions,
             immunosuppressive agents, antibiotics) were not considered treatment regimens for the
             purpose of study entry.] b.) One of the treatment regimens had to be either
             5-azacytidine or decitabine. If 5-azacytidine or decitabine was given as a treatment
             regimen more than once, it was considered as 2 different treatment regimens. c.)
             Participants could not be refractory (i.e., progression of disease, or no evidence of
             response, while on the treatment) to more than one prior treatment regimen (to be
             considered refractory to decitabine or 5-azacitidine, participants must have received
             >= 4 cycles).

          -  Had documentation of prior transfusion requirements for the preceding 8 weeks (8 weeks
             prior to first dose of study drug).

          -  Had Eastern Cooperative Oncology Group performance status 0-2.

          -  Was able to comply with study procedures and follow-up examinations.

          -  Had adequate renal and hepatic functions as indicated by predefined laboratory values:
             a.) Total bilirubin less than or equal to (<=) 1.5 * institutional Upper Limit of
             Normal (ULN) except for unconjugated hyperbilirubinemia secondary to treatment for MDS
             or Gilbert's syndrome; and b.) Aspartate aminotransferase and Alanine aminotransferase
             <= 2.5*ULN; and c.) Serum creatinine <= 1.0 milligrams per deciliter, then the
             estimated glomerular filtration rate (GFR) had to be greater than (>) 30 mL/min/1.73
             m^2 as calculated by the Modification of Diet in Renal Disease equation.

          -  Was non-fertile or agreed to use birth control during the study through the end of
             last treatment visit and at least 90 days after.

        Exclusion Criteria:

          -  Had an adjustment of dose and/or schedule of erythropoietin, granulocyte colony
             stimulating factor or other growth factors within 8 weeks prior to the first dose of
             oral clofarabine.

          -  Had any prior therapy for treatment of sAML. Hydroxyurea must not have been received
             within 24 hours prior to first dose of study drug.

          -  Had any other chemotherapy or any investigational therapy within four weeks of first
             dose of study drug.

          -  Had any prior pelvic radiotherapy.

          -  Had a prior hematopoietic stem cell transplant for MDS.

          -  Had not recovered to <= Grade 2 from any drug-related non-hematologic toxicity prior
             to first dose of the study drug.

          -  Had an uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
             exhibiting ongoing signs/symptoms related to the infection and without improvement,
             despite appropriate antibiotics or other treatment).

          -  Had a psychiatric disorder that would interfere with consent, study participation, or
             follow-up.

          -  Had any other severe concurrent disease, or had a history of serious organ dysfunction
             or disease involving the heart, kidney, or liver, in particular: a.) New York Heart
             Association classification stage II, III, or IV congestive heart failure; b.) Coronary
             artery disease or arteriosclerotic cardiovascular disease (angina, myocardial
             infraction) within 3 months of first dose of study drug; c.) Any other primary cardiac
             disease that, in the opinion of the investigator, increases the risk of ventricular
             arrhythmia.

          -  Had any other severe concurrent disease, or had a history of serious organ dysfunction
             or disease involving the heart had any prior treatment with Clofarabine.

          -  Had a diagnosis of another malignancy, unless the participants had been disease-free
             for at least 3 years following the completion of curative intent therapy with the
             following exceptions: a.) Participants with treated non-melanoma skin cancer, in situ
             carcinoma, or cervical intraepithelial neoplasia, regardless of the disease -free
             duration, were eligible for this study if definitive treatment for the condition had
             been completed. b.) Participants with organ-confined prostate cancer with no evidence
             of recurrent or progressive disease based on prostate-specific antigen values were
             also eligible for this study if hormonal therapy had been initiated or a radical
             prostatectomy had been performed.

          -  Had prior positive test for the Human Immunodeficiency Virus.

          -  Had currently active gastrointestinal disease, or prior surgery that might affect the
             ability of the participants to absorb oral Clofarabine.

          -  Participating in other concurrent investigational protocols that were not restricted
             to data and/or sample collection for participants demographic and/or sample collection
             for participants demographic and/or disease purposes.

          -  Had prior treatment with a known nephrotoxic drug within 2 weeks of the first dose of
             study drug, unless the participants had a calculated GFR >30 at 2 time points no <7
             days apart during the 2-week period prior to the first dose of study drug.