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

Phase 2
18 Years
Not Enrolling
Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML)

Thank you

Trial Information

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Response Rate (ORR)

Outcome Description:

Assessment of response by bone marrow biopsy and aspirate will be performed at weeks 9 and 17 according to International Working Group 2006 criteria as outlined below. The primary endpoint is best response on study, recorded from the start of the treatment until disease progression/recurrence. All responses must last for at least 8 weeks. Complete Remission (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, Persistent dysplasia will be noted, Peripheral blood: Hemoglobin ≥ 11 g/dL, Platelets ≥ 100 x 10^9/L, Neutrophils ≥ 1.0 x 10^9/L, Blasts 0% ; Partial Remission (PR): All CR criteria if abnormal before treatment, except: Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5%, Cellularity and morphology not relevant; Marrow CR or Hematological Improvement (HI): Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment Peripheral blood: if HI responses, they will be noted in addition to marrow CR.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Jeffrey Lancet, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

August 2013

Completion Date:

November 2014

Related Keywords:

  • Myelodysplastic Syndrome (MDS)
  • Chronic Myelomonocytic Leukemia (CMML)
  • Leukemia
  • Myeloid Malignancies
  • Leukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612