Decitabine in Treating Patients With Myelofibrosis

• ClinicalTrials.gov Identifier: NCT00095784
• Recruitment Status: Active, not recruiting
• First Posted: November 9, 2004
• Results First Posted: January 5, 2015
• Last Update Posted: December 1, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Primary Myelofibrosis; Secondary Myelofibrosis	Drug: Decitabine; Other: Laboratory Biomarker Analysis	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Decitabine in Myelofibrosis
• Actual Study Start Date: September 29, 2004
• Actual Primary Completion Date: July 1, 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (decitabine); 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; Given SC; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Response Rate (Complete Response, Partial Response, or Hematologic Improvement. [ Time Frame: Up to 36 weeks (6 cycles) ]

   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.

2. Incidence of Toxicities, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 [ Time Frame: Up to 30 days of last dose of decitabine ]
   Percentage of patients experiencing any toxicity, any grade level. Additional details on adverse events are reported in Adverse Events section.

Secondary Outcome Measures :

1. CD34+ Cells [ Time Frame: Cycle 1, Day 1 ]
   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.
2. CD34+ Cells [ Time Frame: Cycle 1, Day 5 ]
   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.
3. CD34+ Cells [ Time Frame: Cycle 1, Day 12 ]
   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.
4. CD34+ Cells [ Time Frame: Cycle 2, Day 1 ]
   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.
5. CD34+ Cells [ Time Frame: Cycle 2, Day 5 ]
   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.
6. CD34+ Cells [ Time Frame: Cycle 2, Day 12 ]
   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.
7. CXCR4 [ Time Frame: Cycle 1, Day 1 ]
   CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
8. CXCR4 [ Time Frame: Cycle 1, Day 5 ]
   CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
9. CXCR4 [ Time Frame: Cycle 1, Day 12 ]
   CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
10. CXCR4 [ Time Frame: Cycle 2, Day 1 ]
    CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
11. CXCR4 [ Time Frame: Cycle 2, Day 5 ]
    CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
12. CXCR4 [ Time Frame: Cycle 2, Day 12 ]
    CXCR4 gene expression level measured by real-time RT_PCR. Ratio of CXCR4 vs a housekeeping gene (i.e., ABL)
13. Hemoglobin F [ Time Frame: Cycle 1, Day 1 ]

    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.

14. Hemoglobin F [ Time Frame: Cycle 1, Day 5 ]

    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.

15. Hemoglobin F [ Time Frame: Cycle 1, Day 12 ]

    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.

16. Hemoglobin F [ Time Frame: Cycle 2, Day 1 ]

    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.

17. Hemoglobin F [ Time Frame: Cycle 2, Day 5 ]

    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.

18. Hemoglobin F [ Time Frame: Cycle 2, Day 12 ]

    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.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Illinois

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States, 60637

Decatur Memorial Hospital

Decatur, Illinois, United States, 62526

NorthShore University HealthSystem-Evanston Hospital

Evanston, Illinois, United States, 60201

Ingalls Memorial Hospital

Harvey, Illinois, United States, 60426

Loyola University Medical Center

Maywood, Illinois, United States, 60153

Illinois CancerCare-Peoria

Peoria, Illinois, United States, 61615

Central Illinois Hematology Oncology Center

Springfield, Illinois, United States, 62702

Southern Illinois University School of Medicine

Springfield, Illinois, United States, 62702

United States, Indiana

Fort Wayne Medical Oncology and Hematology Inc-Parkview

Fort Wayne, Indiana, United States, 46845

Northern Indiana Cancer Research Consortium

South Bend, Indiana, United States, 46628

United States, Maryland

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States, 21201

United States, Michigan

Oncology Care Associates PLLC

Saint Joseph, Michigan, United States, 49085

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Olatoyosi M Odenike; University of Chicago Comprehensive Cancer Center

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00095784
• Other Study ID Numbers: NCI-2011-01444; NCI-2011-01444 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000393839; NCI-6814; UCCRC-13327A; 13327A ( Other Identifier: University of Chicago Comprehensive Cancer Center ); 6814 ( Other Identifier: CTEP ); N01CM62201 ( U.S. NIH Grant/Contract ); N01CM62207 ( U.S. NIH Grant/Contract ); P30CA014599 ( U.S. NIH Grant/Contract )
• First Posted: November 9, 2004
• Results First Posted: January 5, 2015
• Last Update Posted: December 1, 2021
• Last Verified: November 2021

Additional relevant MeSH terms:

Primary Myelofibrosis; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Decitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors