Decitabine in Treating Patients With Myelofibrosis

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies the side effects and how well decitabine works in treating patients with myelofibrosis, a cancer of the blood system associated with fibrosis (scar tissue) in the bone marrow that is advanced and for which there is no standard therapy. Decitabine may block the actions of some proteins that are responsible for turning certain genes off in various cancers including myelofibrosis.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine response rate (complete and partial responses and hematological improvement) to decitabine in patients with myelofibrosis. II. To determine the safety of decitabine in patients with myelofibrosis. SECONDARY OBJECTIVES: I. To determine the effects of decitabine on specific epigenetic changes including methylation status of specific target genes and gene re-expression. II. To determine the effect of decitabine on hemoglobin F levels and on the absolute numbers of circulating cluster of differentiation (CD) 34+ progenitor cells and to investigate the potential utility of these markers as a surrogate for biologic activity of decitabine in myeloid metaplasia with myelofibrosis (MMM). OUTLINE: Patients receive decitabine subcutaneously (SC) on days 1-5 and 8-12. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity.

Official Title
-----------------
A Phase II Study of Decitabine in Myelofibrosis

Conditions
-----------------
Primary Myelofibrosis, Secondary Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Decitabine
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically or cytologically confirmed myeloid metaplasia with myelofibrosis (this includes all subtypes - chronic idiopathic myelofibrosis or angiogenic myeloid metaplasia, post thrombocythemic and post polycythemic myelofibrosis); patients must have anemia (hemoglobin < 11 g/dL) or palpable splenomegaly (measured in cm from costal margin - to be eligible); patients with palpable splenomegaly must have spleen size documented ultrasonographically as well; they must also meet standard diagnostic criteria for MMM Patients with morphologic evidence of advanced phases of the disease including accelerated (10-19% blasts) phase or with evidence of evolution to acute leukemia (>= 20% blasts) are also eligible for this study The Italian Diagnostic Criteria for MMM Necessary criteria Diffuse bone marrow fibrosis Absence of the Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells Optional criteria Splenomegaly of any grade Anisopoikilocytosis with tear drop erythrocytes Presence of circulating immature myeloid cells Presence of circulating erythroblasts Presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections Myeloid metaplasia Diagnosis of MMM is acceptable if the following combinations are present The two necessary criteria plus any other two optional criteria when splenomegaly is present OR The two necessary criteria plus any other four optional criteria when splenomegaly is absent Patients may have had prior chemotherapy or radiation therapy including splenic irradiation; prior therapy with erythropoietin, granulocyte-colony stimulating factor (GCSF), other growth factors or androgenic steroids is also permitted; there is no limit to the number of prior regimens received; at least 4 weeks must have elapsed since prior chemo or radiation therapy; at least 2 weeks must have elapsed since growth factor (erythropoietin, GCSF, granulocyte-macrophage colony-stimulating factor [GM-CSF]) or other therapy Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Total bilirubin =< 2mg/dL In patients with associated hemolytic anemia; total bilirubin > 2mg/dL is permissible as long as this is as a result of predominantly unconjugated hyperbilirubinemia; such patients may be enrolled only after discussion with the study chair Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal unless due to disease Serum creatinine =< 2mg/dL Patients must not be pregnant or nursing; women of child- bearing potential and men must agree to use an effective contraceptive method; 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: Prior therapy with decitabine Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational agents Patients with known central nervous system (CNS) disease should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine Uncontrolled intercurrent 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; breastfeeding should be discontinued if the mother is treated with decitabine Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (decitabine)<br>Patients receive decitabine SC on days 1-5 and 8-12. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. | Drug: Decitabine<br>* Given SC<br>* Other names: Dezocitidine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete Response, Partial Response, or Hematologic Improvement. | Complete response is normalization of counts and transfusion-independence. Partial response is hemoglobin increase to normal levels, multilineage improvement including absolute neutrophil count (ANC) and/or platelets. Hematologic improvement is red cell transfusion-independence or >50% increase in platelet levels. | Up to 36 weeks (6 cycles) | 
| Incidence of Toxicities, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 | Percentage of patients experiencing any toxicity, any grade level. Additional details on adverse events are reported in Adverse Events section. | Up to 30 days of last dose of decitabine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 1, Day 1 | 
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 1, Day 5 | 
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 1, Day 12 | 
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 2, Day 1 | 
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 2, Day 5 | 
| CD34+ Cells | CD34 positive(+) cells are determined by flow immunostaining and light scatter in peripheral blood. Samples are then analyzed by flow cytometry, and CD34+ cells quantitated after 75,000 CD45 events are studied. (At least 75,000 CD45 events must be studied to ensure accuracy of the assay). Absolute numbers are determined by multiplying the % CD34+ cells by the total white blood cell count obtained on a CBC that is processed simultaneously. | Cycle 2, Day 12 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 1, Day 1 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 1, Day 5 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 1, Day 12 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 2, Day 1 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 2, Day 5 | 
| CXCR4 | CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL) | Cycle 2, Day 12 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 1, Day 1 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 1, Day 5 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 1, Day 12 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 2, Day 1 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 2, Day 5 | 
| Hemoglobin F | Percentage of hemoglobin F as a proportion of total Hb (%HbF) measured by HPLC on peripheral blood samples. Midpoint of 0.5% imputed for values reported as below limit of detection (1.0%). Hemoglobin F has been previously shown to be upregulated by decitabine in other hematologic disorders- sickle cell disease specifically. The rationale for exploring it in this study was to evaluate its potential utility as a biomarker of drug effect/PD marker. | Cycle 2, Day 12 |