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Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS)

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ClinicalTrials.gov Identifier: NCT01842646
Recruitment Status : Completed
First Posted : April 29, 2013
Results First Posted : March 14, 2017
Last Update Posted : June 14, 2021
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief 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).

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome (MDS) Chronic Myelomonocytic Leukemia (CMML) Drug: PF-04449913 Phase 2

Detailed Description:

The main purpose of this study is to see whether the participant's disease responds favorably to the investigational drug, PF-04449913.

Post treatment Phase: After coming off of active treatment study drug (PF-04449913), participants will be followed monthly for survival only. No other data will be captured during this time.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating the Oral Smoothened Inhibitor PF-04449913 in Patients With Myelodysplastic Syndrome (MDS)
Actual Study Start Date : August 29, 2013
Actual Primary Completion Date : January 31, 2016
Actual Study Completion Date : June 10, 2021

Arm Intervention/treatment
Experimental: PF-04449913 Treatment
Treatment will be administered on an outpatient basis. All patients will be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. Patients who demonstrate no evidence of progressive disease (i.e. stable disease or better) may continue on treatment until disease progression or loss of response, limiting toxicity, or death.
Drug: PF-04449913
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.
Other Names:
  • Oral Hedgehog Inhibitor
  • Smoothened (SMO) Inhibitor

Primary Outcome Measures :
  1. Overall International Working Group (IWG) 2006 Response Rate [ Time Frame: Up to 2 years, 4 months ]
    Response 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. Further investigation of PF-04449913 would not be warranted if it produced an overall response rate (CR + PR + marrow CR+HI) of 10% or less (p0), and would be warranted if it produced an overall response rate of 30% or more (p1).

Secondary Outcome Measures :
  1. Median Overall Survival (OS) [ Time Frame: Up to 2 years, 4 months ]
    To estimate the overall survival of patients with refractory/relapsed myelodysplastic Syndrome (MDS) and chronic myelo-monocytic leukemia (CMML) treated with PF-0444913. Overall survival will be defined as the time period between the date of the first dose of drug until the time of death.

  2. Median Event Free Survival [ Time Frame: Up to 2 years, 4 months ]
    To estimate the event-free survival of patients of this population. Event-free survival will be defined as the date of the first dose of study drug until failure (disease progression) or death from any cause.

  3. Median Time to Transformation to Acute Myeloid Leukemia (AML) [ Time Frame: Up to 2 years, 4 months ]
    To estimate the time to transformation to AML in patients with <20% blasts. In patients with less than 20% blasts, the time to transformation to AML will be defined as the date of the first dose of drug until either the percentage of bone marrow blasts or the percentage of peripheral blasts exceeds 20%, whichever is first.

  4. Number of Participants With Treatment Emergent Adverse Events [ Time Frame: 2 years, 4 months ]
    Treatment emergent adverse events occurring in equal to or more than 10% of participants.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01842646

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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
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Principal Investigator: Jeffrey Lancet, M.D. H. Lee Moffitt Cancer Center and Research Institute
Additional Information:
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Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01842646    
Other Study ID Numbers: MCC-17302
First Posted: April 29, 2013    Key Record Dates
Results First Posted: March 14, 2017
Last Update Posted: June 14, 2021
Last Verified: June 2021
Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Myeloid Malignancies
Additional relevant MeSH terms:
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Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases