A Phase II Study Evaluating the Oral Smoothened Inhibitor PF-04449913 in Patients With Myelodysplastic Syndrome (MDS)
- 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
- 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
- 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
- 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.