Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

PF-04449913 in Treating Patients with Acute Leukemia or Myelodysplastic Syndromes at High Risk of Relapse after Donor Stem Cell Transplant

Protocol: OSU-14053

Full Title

A Phase II Study of PF-04449913 For the Treatment of Acute Leukemia and Myelodysplastic Syndrome Patients with High Risk of Post-Allogeneic Stem Cell Transplantation Relapse

Purpose

This phase II trial studies how well Hedgehog inhibitor PF-04449913 works in treating patients with acute leukemia or myelodysplastic syndromes at high risk of relapse after donor stem cell transplant. Drugs used in chemotherapy, such as Hedgehog inhibitor PF-04449913, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Study Objective

PRIMARY OBJECTIVES:

I. Determine whether PF-04449913 (Hedgehog inhibitor PF-04449913) can prevent relapse in high risk acute leukemia or myelodysplastic syndromes (MDS) patients who receive an allogeneic stem cell transplantation.

SECONDARY OBJECTIVES:

I. Determine the toxicity profile of PF-04449913 in this population.

II. Determine the impact of this intervention on overall survival (OS).

OUTLINE:

Beginning 28-50 days after allogeneic stem cell transplant, patients receive Hedgehog inhibitor PF-04449913 orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 90 days and then annually for 5 years.

Are you eligible?

Inclusion Criteria:

World Health Organization (WHO)-confirmed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or 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)

Persistent evidence of morphological dysplasia in at least one lineage at the time of transplantation

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 (using Fridericia’s correction formula) > 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, family 3, subfamily A, polypeptide 4 (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