A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia
Condition: Thrombocytopaenia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Thrombocytopenia
Intervention: eltrombopag; placebo
Intervention description: 100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage); 100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)
Phase: Phase 2
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 162.0
Sex: All
Minimum age: 18 Years
Maximum age: 110 Years
Healthy volunteers: No
Keywords: acute myeloid leukemia (AML); acute myelogenous leukemia (AML); acute non lymphocytic leukemia (ANLL); myeloproliferative disease (MDS); myelodysplastic syndrome ( secondary acute myeloid leukemia); refractory acute myeloid leukemia

Summary:

      This was a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part
      3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with
      myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due
      to bone marrow insufficiency from their underlying disease or prior chemotherapy. This
      objective was assessed by a composite primary endpoint that consists of the following: the
      proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or platelet
      transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow
      insufficiency from their underlying disease or prior chemotherapy were enrolled in the study.
      No low or intermediate-1 risk MDS subjects were enrolled in the study. Subjects must have had
      at least one of the following during the 4 weeks prior to enrolment: platelet count <10 Gi/L,
      platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC),
      including hydroxyurea, was allowed as indicated by local practice throughout the study. The
      study had 3 sequential parts. Subjects who were enrolled in Part 1 (open-label) cannot be
      enrolled in Part 2 of the study (randomized, double-blind); however, subjects who completed
      the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) continued in Part 3
      (extension) if the investigator determined that the subject was receiving clinical benefit on
      treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%)
             with thrombocytopenia due to bone marrow insufficiency from the disease or prior
             treatment. Subjects with transient thrombocytopenia due to active treatment with
             disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.

          -  Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone
             marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or
             equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at
             least one of the following during the 4 week screening period: platelet transfusion,
             or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia
             below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever,
             infection, autoimmune disease) are not eligible.

          -  Subjects must have platelet count, bleeding and platelet transfusion data available
             over a period of at least 4 weeks prior to randomization.

          -  Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have
             been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the
             following: chemotherapy, demethylating agents (azacitidine or decitabine),
             lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before
             Day 1 for antithymocyte/antilymphocyte globulin.

          -  Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.

          -  Subjects must be stable and, in the opinion of the investigator, be expected to
             complete a 12 week treatment period.

          -  ECOG Status 0-2.

          -  Subject must be able to understand and comply with protocol requirements and
             instructions.

          -  Subject has signed and dated an informed consent form.

          -  Adequate baseline organ function defined by the criteria below: total bilirubin ≤
             1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate
             liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT
             abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN

          -  Women must be either of non-child bearing potential or women with child-bearing
             potential and men with reproductive potential must be willing to practice acceptable
             methods of birth control during the study Women of childbearing potential must have a
             negative serum or urine pregnancy test within 7 days prior to the first dose of study
             treatment.

          -  In France, a subject eligible for inclusion in this study only if either affiliated
             to, or a beneficiary of, a social security category.

        Exclusion Criteria:

          -  Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.

          -  Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML
             secondary to a myeloproliferative neoplasm.

          -  History of treatment with romiplostim or other TPO-R agonists.

          -  Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block).

          -  Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.

          -  Subjects with known thrombophilic risk factors. Exception: Subjects for whom the
             potential benefits of participating in the study outweigh the potential risks of
             thromboembolic events, as determined by the investigator.

          -  Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic
             gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.

          -  Current alcohol or drug abuse.

          -  Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
             longer) preceding the first dose of study medication.

          -  Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).

          -  Subjects infected with Human Immunodeficiency Virus (HIV).

          -  Subjects with liver cirrhosis (as determined by the investigator).

          -  Subjects receiving or planned to receive any prohibited medication.

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol,
             polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose,
             titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the
             subjects' participation.

          -  In France, subjects who have participated in any study using an investigational drug
             during the previous 30 days.