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PF-04449913 For Patients With Acute Myeloid Leukemia at High Risk of Relapse After Donor Stem Cell Transplant

NCT01841333

Description:

This phase II trial will test whether the Hedgehog signaling pathway inhibitor PF-04449913 can decrease disease relapse in high-risk patients with acute myeloid leukemia after donor stem cell transplant.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PF-04449913 For Patients With Acute Myeloid Leukemia at High Risk of Relapse After Donor Stem Cell Transplant
  • Official Title: A Phase 2 Study of PF-04449913 for the Treatment of Acute Myeloid Leukemia Patients With High Risk of Post-Allogeneic Stem Cell Transplantation Relapse

Clinical Trial IDs

  • ORG STUDY ID: 12-1558.cc
  • SECONDARY ID: NCI-2013-00824
  • NCT ID: NCT01841333

Conditions

  • Adult Acute Lymphoblastic Leukemia in Remission
  • Adult Acute Myeloid Leukemia in Remission
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
PF-04449913Hedgehog inhibitorPF-04449913

Purpose

This phase II trial will test whether the Hedgehog signaling pathway inhibitor PF-04449913 can decrease disease relapse in high-risk patients with acute myeloid leukemia after donor stem cell transplant.

Detailed Description

      Disease relapse is the most common cause of death after allogeneic stem cell transplantation
      for acute myeloid leukemia. Patients at high risk for relapse may benefit from a novel,
      biologically rational therapeutic intervention to prevent this outcome. PF-04449913 is a
      small molecule inhibitor of the hedgehog (Hh) pathway that inhibits the protein Smoothened
      (SMO). Aberrant Hh signaling may contribute to the survival and expansion of the leukemia
      stem cell, and inhibiting the Hh pathway can eliminate these cells. Therefore, targeting Hh
      may be a logical intervention in the post-transplantation setting for those with high risk of
      relapse. The investigators propose a phase 2 study of PF-04449913 in patients with acute
      myeloid leukemia who have received an allogeneic stem cell transplantation and are at high
      risk of relapse.

      This is an open label, phase 2 study employing PF-04449913 in acute myeloid leukemia patients
      who received an allogeneic stem cell transplantation and are at high risk of relapse.
      Patients will receive consecutive 28-day cycles of PF-04449913 at 100 mg/day, beginning on
      post-transplantation day 80 +/- 10 days, after their routine post-transplant bone marrow
      biopsy. Treatment will continue for up to one year or until they experience toxicity or
      disease relapse. 50 patients will be required for a 90% power to detect a 20% difference in
      one-year relapse-free survival.
    

Trial Arms

NameTypeDescriptionInterventions
PF-04449913ExperimentalBeginning 80 days after allogeneic stem cell transplant, patients receive PF-04449913 (100mg) orally once daily on days 1-28. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
  • PF-04449913

Eligibility Criteria

        Inclusion Criteria:

          -  WHO-confirmed AML

          -  Age ≥18 years

          -  Between days 28 and 50 post transplantation at the time of initiation of the study
             drug

          -  ECOG performance status ≤ 2 (See Appendix A: ECOG Performance Status Scale)

          -  Life expectancy > 2 months

          -  Recipient of a myeloablative or non-myeloablative allogeneic HSCT

               -  Conditioning regimen to be prescribed at investigator's discretion, but will be
                  prospectively defined as myeloablative or non-myeloablative

          -  Stable engraftment, as defined by absolute neutrophil count (ANC) ≥ 1000/mm3 and
             platelets ≥ 25,000/mm3

          -  In morphologic remission (< 5% marrow blasts) based on BM biopsy performed +/- 5 days
             of day 28 post- transplantation

          -  Without clinical signs of active central nervous system disease

          -  For non-myeloablative transplants, ≥50% CD3 donor chimerism at screening

          -  High risk of relapse after HSCT, defined as the presence of minimal residual disease
             as measured by flow cytometry in the absence of evidence of morphologic disease on a
             bone marrow biopsy prior to HSCT

          -  Adequate organ function as indicated by the following laboratory values:

               -  Aspartate aminotransferase (AST), alanine aminotransferase, (ALT) ≤ 3.0 x
                  institutional upper limit of normal (ULN)

               -  Total bilirubin ≤ 2.0 x institutional ULN, unless documented Gilbert's syndrome

               -  Either creatinine <1.5 x institutional upper limit of normal (ULN) or creatinine
                  clearance >60 mL/min as calculated by institution's standard formula

          -  Serum/urine pregnancy test (for females of childbearing potential) that is negative
             within 72 hours prior to initiation of first dose of treatment (a patient is of
             childbearing potential if, in the opinion of the investigator, she is biologically
             capable of having children and is sexually active)

          -  Female patients of childbearing potential and sexually active males and female
             partners of childbearing potential must agree to use a highly effective method of
             contraception throughout the study and for at least 90 days after the last dose of
             assigned treatment.

          -  Subject is able to comply with study procedures and follow-up examinations.

        Exclusion Criteria:

          -  Concomitant treatment with other anti-neoplastic agents, with the exception, when
             clinically indicated, of prophylaxis in the post-transplantation setting with
             intrathecal chemotherapy

          -  Use of any other experimental drug or therapy within 28 days of baseline

          -  Inability to swallow or absorb drug

          -  Active uncontrolled acute fungal, bacterial, or other infection that is unresponsive
             to therapy at time of study drug dosing

          -  Unstable angina pectoris

          -  New York Heart Association Class III or IV heart failure

          -  QTc interval (using Fridericia's correction formula, QTcF, if prolonged) >470 msec

          -  Active cardiac arrhythmias with rapid ventricular response (defined as heart rate
             greater than 100 beats/minute)

          -  Known HIV infection

          -  Grade III/IV acute GVHD

          -  Current use or anticipated need for food or drugs that are known moderate/strong
             CYP3A4 inducers (See Table 1 and section 5.9.2: Prohibited Concomitant Therapy), with
             the exception of azole antifungals, which are permitted.

          -  Any medical, psychiatric, addictive or other kind of disorder which compromises the
             ability of the subject to give written informed consent and/or to comply with
             procedures.

          -  Pregnant or lactating females
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free survival
Time Frame:1 year
Safety Issue:
Description:Kaplan-Meier estimates will be used to measure relapse-free survival

Secondary Outcome Measures

Measure:Remission duration
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of patients with adverse events (AE)
Time Frame:30 days
Safety Issue:
Description:Subjects will be evaluated for AEs at each visit with the NCI-CTCAE version 4.03 used as a guide for the grading of severity.
Measure:Overall survival of all patients
Time Frame:1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

  • Lymphoblastic leukemia in remission
  • Myeloid leukemia in remission
  • Recurrent lymphoblastic leukemia
  • Recurrent myeloid leukemia

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