Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS)
Condition: Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)
MeSH terms: Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome
Intervention: PF-04449913
Intervention description: Patients will be enrolled according to a two-step study design. Twenty patients will be enrolled in the first stage. All patients will be given a daily oral dose of PF-0444913 100 mg for up to 4 cycles, with an optional continuation phase. Dose escalation to 200 mg will be provided for patients who do not have at least hematologic improvement following 2 cycles, and dose reduction to 50 mg will be permitted for patients with significant toxicity. If at least 2 patients respond in the initial stage, and additional 15 patients will be enrolled in the second stage.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Leukemia; Myeloid Malignancies

Summary:

      This study is being done to see how safe an investigational drug is and test how well it will
      work to help people with refractory/relapsed myelodysplastic syndrome (MDS) or chronic
      myelomonocytic leukemia (CMML).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have a pathologically confirmed diagnosis by World Health Organization (WHO)
             Criteria of MDS, CMML, or acute myeloid leukemia (AML) (except acute promyelocytic
             leukemia) with < 30% bone marrow blasts (RAEB-t by French American British criteria)

          -  Hypomethylating agent (azacitidine and/or decitabine) failure, defined as lack of
             response, disease progression, loss of response, or intolerance as deemed by the study
             investigator

          -  Adequate renal function, as evidenced by a serum creatinine ≤ 2 times the
             institutional upper limit of normal

          -  Adequate hepatic function, as evidenced by a serum bilirubin < 2 times the
             institutional upper limit of normal and an aspartic transaminase (AST) and alanine
             transaminase (ALT) < 2 times the institutional upper limit of normal. Indirect
             hyperbilirubinemia due to Gilbert's disease or hemolysis is permitted.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with a history of prior therapy with another investigational agent within 4
             weeks of the first planned dose of PF-0444913

          -  Patients may not be receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to PF-04449913

          -  Prior therapy with another hedgehog inhibitor

          -  Concurrent use of any other agent for MDS, CMML, or AML. Growth factor use with
             epoetin, darbepoetin, or granulocyte colony-stimulating factor must be terminated at
             least 2 weeks before initiation of study treatment.

          -  Any uncontrolled concurrent illness that would, in the opinion of the investigator,
             limit compliance with study requirements

          -  Second malignancy requiring active therapy

          -  A prolonged corrected QT interval (QTc) of ≥480 ms interval on electrocardiogram

          -  History of metastatic cancer diagnosed less than 2 years prior to the first planned
             dose of PF-0444913

          -  Uncontrolled concurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because PF-04449913 is smoothened
             inhibitor with the potential for teratogenic or abortifacient effects. Because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with PF-04449913. Breastfeeding should be discontinued if the
             mother is treated with PF-04449913.

          -  Patients with immune deficiency are at increased risk of lethal infections when
             treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving
             combination antiretroviral therapy are excluded from the study because of possible
             pharmacokinetic interactions with PF-04449913.