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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Colorado, Denver
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01841333
First received: April 23, 2013
Last updated: July 21, 2014
Last verified: July 2014
  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 leukemia after donor stem cell transplant.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Drug: Hedgehog inhibitor PF-04449913
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of PF-04449913 for the Treatment of Acute Leukemia Patients With High Risk of Post-Allogeneic Stem Cell Transplantation Relapse

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Relapse-free survival [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates will be used to measure relapse-free survival


Secondary Outcome Measures:
  • Remission duration [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 28
Study Start Date: April 2013
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hedgehog inhibitor PF-04449913
Beginning 80 days after allogeneic stem cell transplant, patients receive Hedgehog inhibitor PF-04449913 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.
Drug: Hedgehog inhibitor PF-04449913
Given orally
Other Name: PF-04449913

Detailed Description:

Disease relapse is the most common cause of death after allogeneic stem cell transplantation for acute 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 post-allogeneic stem cell transplantation patients at high risk of relapse.

This is an open label, phase 2 study employing PF-04449913 in acute leukemia patients who received 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. Seventeen patients will be required for an 80% power to detect a 30% difference in one-year relapse free survival.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • World Health Organization (WHO)-confirmed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) refractory anemia with excess blasts (RAEB)-1 or 2
  • Between days 28 and 50 post transplantation at the time of initiation of the study drug
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Life expectancy > 2 months
  • Recipient of a myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant (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/mm^3 and platelets 25,000/mm^3
  • In morphologic remission (< 5% marrow blasts) based on bone marrow (BM) biopsy performed +/- 5 days of day 28 post-transplantation to day 50 post-transplantation
  • Without clinical signs of active central nervous system disease
  • For non-myeloablative transplants, >= 50% cluster of differentiation (CD)3 donor chimerism at screening
  • High risk of relapse after fully myeloablative HSCT, defined for acute leukemia as:

    • Any level of minimal residual disease (MRD) on a bone marrow aspirate or peripheral blood sample, at any routine measurement post-HSCT
    • Any patient entering into HSCT with MRD by flow cytometry
    • Any patient entering into HSCT with cytogenetic abnormalities as measured by metaphase cytogenetics or fluorescent in situ hybridization (FISH) probes
    • Any patient entering into HSCT without a morphological remission (> 5% blasts by differential of the aspirate)
  • High risk of relapse after non-myeloablative allogeneic HSCT for acute leukemia, defined as:

    • Relapse risk score > 0
    • Any patient entering into HSCT with MRD by flow cytometry
    • Any patient entering into HSCT with cytogenetic abnormalities as measured by metaphase cytogenetics or FISH probes
    • Any patient entering into HSCT without a morphological remission (> 5% blasts by differential of the aspirate)
  • High risk of relapse after myeloablative or non-myeloablative allogeneic HSCT for MDS, defined as:

    -Intermediate, poor, or very poor cytogenetics by revised International Prognostic Scoring System (IPSS)

  • 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 or tyrosine kinase inhibitors of breakpoint cluster region (BCR)-v-abl Abelson murine leukemia viral oncogene homolog 1 (Abl)
  • 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, unless a screening echocardiogram or multiple gate acquisition scan performed either within 1 month prior to or during study screening results in a left ventricular ejection fraction that is >= 45% (or institutional lower limit of normal value)
  • Corrected QT (QTc) interval > 470 msec
  • Active cardiac arrhythmias with rapid ventricular response (defined as heart rate greater than 100 beats/minute)
  • Known human immunodeficiency virus (HIV) infection
  • Grade III/IV acute graft-versus-host disease (GVHD)
  • Current use or anticipated need for food or drugs that are known strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers, including their administration within 7-days prior to study entry; azole antifungals are excepted
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01841333

Contacts
Contact: Nicole Ayodeji 720-848-0701 Nikki.Ayodeji@ucdenver.edu

Locations
United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Nicole Ayodeji    720-848-0701    Nikki.Ayodeji@ucdenver.edu   
Principal Investigator: Dan A Pollyea, MD, MS         
United States, Washington
Seattle Cancer Care Alliance Not yet recruiting
Seattle, Washington, United States, 98109
Contact: Vivian Oehler, MD    206-667-1340      
Principal Investigator: Vivian Oehler, MD         
Sponsors and Collaborators
University of Colorado, Denver
The Leukemia and Lymphoma Society
Investigators
Principal Investigator: Daniel A Pollyea, MD, MS University of Colorado, Denver
  More Information

No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01841333     History of Changes
Other Study ID Numbers: 12-1558.cc, NCI-2013-00824
Study First Received: April 23, 2013
Last Updated: July 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Colorado, Denver:
Lymphoblastic leukemia in remission
Myeloid leukemia in remission
Recurrent lymphoblastic leukemia
Recurrent myeloid leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on September 29, 2014