A Study of 5-Azacitidine (Vidaza®) in Patients With Chronic Myelomonocytic Leukemia

A Phase II Study of the Efficacy, Safety and Determinants of Response to 5-Azacitidine (Vidaza®) in Patients With Chronic Myelomonocytic Leukemia (CMML)

The primary objective of this study is:

Response to treatment will be evaluated according to the revised International Working Group (IWG) categories natural history, hematologic improvement and cytogenetic response1;2. The primary objective is:

To determine the rate of complete hematologic response and hematologic improvement (according to IWG 2006 criteria) in CMML patients treated with 5-azacitidine.

Study Overview

• Status: Completed
• Conditions: Chronic Myelomonocytic Leukemia
• Intervention / Treatment: Drug: 5-Azacitidine

Detailed Description

In this study, eligible patients with a confirmed diagnosis of CMML will be treated with 5-azacitidine to determine the rates of complete hematologic response, hematologic improvement, complete and partial cytogenetic response, and overall and progression free survival.

To develop biomarkers associated with response and gain insights into the mechanisms that determine response, gene expression profiling, genome-wide SNP array analysis, microRNA analysis, and DNA methylation analysis will be performed prior to therapy and at defined time points during the study. Phosphoproteomics profiling may be included in the analysis.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Diagnosis of CMML as defined by the WHO criteria

   1. Persistent peripheral blood monocytosis of more than 1 x 109/L for at least 3 months and
   2. No Philadelphia chromosome or BCR-ABL fusion gene and
   3. Less than 20% blasts in the blood or bone marrow and
   4. Dysplasia in one or more of the myeloid lineages* * In the absence of dysplasia in one or more of the myeloid lineages, the diagnosis of CMML can still be made if a) - c) are met AND an acquired clonal chromosomal abnormality is present in the bone marrow cells, the monocytosis has been present for more than 3months AND all other causes of monocytosis have been ruled out.
2. Age of 18 years or older. Both men and women and members of all races and ethnic groups will be included.
3. ECOG performance status <3

4. Adequate organ function defined as:

   1. Total bilirubin <2.5 x upper limit of normal (ULN)
   2. Direct bilirubin <2 x ULN
   3. Creatinine <2 mg/dL
   4. ALT and AST <2.5 x ULN
5. Ability to understand and the willingness to sign a written informed consent document
6. Willingness to use adequate contraception for the duration of the study

Exclusion Criteria:

1. Progression to acute myeloid leukemia (defined by at least 20% blasts in the blood or bone marrow). In the unlikely event that progression to acute leukemia is demonstrated in the "screening" bone marrow biopsy, it is at the discretion of the investigator to enroll the patient after adequate discussion of the findings and alternative therapies. Enrollment of such a patient must be reported to the HCI PI.
2. Presence of activating mutations of the platelet derived growth factor receptors alpha or beta, which would suggest likely benefit from imatinib treatment (these mutations will usually be obvious from karyotyping and fluorescence in situ hybridization studies)
3. Known or suspected hypersensitivity to 5-azacitidine or mannitol
4. Clinically significant heart disease (New York Heart Association Class III or IV) or other serious intercurrent illnesses or psychiatric illness/social situations that would limit compliance with study requirements
5. Major surgery within 28 days before registration (exception: central venous line placement), or lack of full recovery from prior major surgery
6. Prior therapy with a hypomethylating agent
7. Cytotoxic chemotherapy less than 2 weeks prior to starting study medication (exception: hydroxyurea and/or anagrelide)
8. Erythropoietin or darbepoietin, G-CSF, GM-CSF, thalidomide or lenalidomide less than 2 weeks from day 1 of cycle 1
9. Concomitant cytotoxic chemotherapy (exception: hydroxyurea for up to 1 week per cycle)
10. Concomitant therapy with other investigational agents
11. Other active malignancies except basal cell carcinoma of the skin and carcinoma in situ of the cervix.
12. Pregnancy or breastfeeding (possible risk to the fetus or infant)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All patients; All participants enrolled.

Drug: 5-Azacitidine; Administered on Days 1-7 of each Cycle. Subcutaneous administration: To provide a homogeneous suspension, the contents of the syringe must be re-suspended by inverting the syringe 2-3 times and vigorously rolling the syringe between the palms for 30 seconds immediately prior to administration. The 5-azacitidine suspension is administered subcutaneously. Intravenous Administration: 5-Azacitidine solution is administered intravenously. Administer the total dose over a period of 10-40 minutes.; Other Names: Vidaza®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Complete Hematologic Response (According to IWG 2006 Criteria) in CMML Patients Treated With 5-azacitidine.	Complete Hematologic Response is defined as: bone marrow evaluation shows <= 5% myeloblasts with normal maturation of all cells lines; peripheral blood evaluation shows hemoglobin >= 11 g/dL, neutrophils >= 1000/mL, platelets >= 100,000/mL, 0% blasts	24 months

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Celgene
• Investigators: Principal Investigator: Michael Deininger, MD, University of Utah

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 29, 2011
• First Submitted That Met QC Criteria: May 9, 2011
• First Posted (Estimate): May 10, 2011

Study Record Updates

• Last Update Posted (Estimate): June 13, 2016
• Last Update Submitted That Met QC Criteria: May 10, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: CMML; Chronic Myelomonocytic Leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Leukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: HCI47081