A Phase II Study of Intravenous Azacitidine Alone in Patients With Myelodysplastic Syndromes

The primary endpoint of this study is to estimate morphologic complete remission rate. Estimation of response rate is also a secondary objection.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Azacitidine

Detailed Description

Myelodysplastic syndrome (MDS) is a hematological disorder characterized by ineffective hematopoiesis. The only known curative treatment for patients with MDS is allogeneic stem cell transplantation. However, only a minority of patients are candidates for this aggressive therapy. DNA hypomethylation agents have been shown to have activity in this disorder and are postulated to work by reversing this epigenetic mechanism of gene-silencing. Recently, 5-azacitidine, administered subcutaneously for seven days, received approval by the FDA for the therapy of MDS based on a randomized trial which demonstrated a diminished risk of leukemic transformation and improved survival when compared to best supportive care.

The subcutaneous route of administration can present challenges to implementing this therapy. In the CALGB studies 8921 and 9221, approximately 23% of patients had significant injection site pain. Moreover, 35 % of patients had injection site bruising which can be extensive in thrombocytopenic patients. Due to limitations on drug concentration and administration volumes for subcutaneous dosing, patients often need to have two or three injections at separate sites each day to meet target dosing. In addition, the schedule of administration is inconvenient in an outpatient setting secondary to the need to schedule administrations over weekends. Therefore, there is great interest in pursuing an abbreviated intravenous route for administration of the drug.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine

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. Pathological MDS either de novo or secondary, fitting any of the FAB classifications, confirmed by institutional pathologist within 2 weeks prior to start of treatment. Patients with 5% bone marrow blasts must also meet one of the following criteria:

   • Symptomatic anemia with either hemoglobin less than 10.0 g/dL or requiring RBC transfusion
   • Thrombocytopenia with a history of two or more platelet counts < 50,000 / µL or a significant hemorrhage requiring platelet transfusions, or
   • Neutropenia with two or more absolute neutrophil counts less than 1,000 /µL.
2. ECOG performance status of 0-2.
3. Must give written informed consent indicating their awareness of the investigational nature of this study and its potential hazards.
4. Adequate renal and hepatic function (creatinine ≤ 150% of institutional upper limit of normal, total bilirubin ≤ 150% institutional upper limit of normal, AST ≤ 200% institutional upper limit of normal).
5. Life expectancy of at least 12 weeks.
6. Have not received any chemotherapy within 4 weeks of study enrollment and must have recovered from any treatment-related toxicities.
7. Women of childbearing age must have a negative serum pregnancy test prior to initiating therapy.
8. Sexually active women of childbearing potential must use effective birth control during the trial and for an appropriate period after the trial.
9. Men must be willing to avoid fathering a new child while receiving therapy with azacitidine.
10. ≥18 years, no upper age limit
11. Individuals who are candidates for hematopoietic stem cell transplantation and who meet all other study criteria may participate in the study and receive intravenous azacitidine alone as a treatment prior to transplantation.

Exclusion Criteria:

1. Known CNS leukemia.
2. Previously received Azacitidine (Vidaza®, Pharmion Corp., Boulder CO) or decitabine (Dacogen®, MGI Pharma Inc. Bloomington, MN).
3. Known or suspected hypersensitivity to azacitidine or mannitol.
4. Receiving any other investigational agents within 30 days of first dose of study drug.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure of NYHA class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
6. Known positive serology for HIV.
7. Had radiotherapy within 14 days prior to study enrollment.
8. Known presence of hepatic tumors.
9. <18 years of age
10. Exclude women who are pregnant or breast feeding.

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: Azacitidine; Azacitidine 75 mg/m2 IV on days 1-5 of each 28 day cycle. Patients that do not respond after two cycles will have the dose increased to 100 mg/m2. Patients who achieve a CR will receive 3 additional 28 day cycles and then begin treatment on days 1-5 of a 56 day cycle. Individuals who demonstrate a loss of response will resume 28 day cycles.	Drug: Azacitidine; Other Names: Vidaza; 5-azacitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Complete Remission (CR) and Partial Remission (PR)	Defined according to the modified International Working Group (IWG) (2006) response criteria for myelodysplasia: CR=bone marrow with <5% myeloblasts and 0% peripheral blasts, hemoglobin ≥11g/dL, platelets ≥ 100 x 10^9/L, and neutrophils ≥1.0 x 10^9/L. Residual dysplasia was allowed. PR= All of the CR criteria if abnormal before treatment except: bone marrow blasts decreased by ≥50% over pretreatment but still >5%.	After 4 cycles of therapy (up to 112 days after start of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Hematologic Improvement	International Working Group (IWG) for Myelodysplasia (MDS).	4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)]
Rate of Transfusion Independence		4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)]
Rate of Cytogenetic Response		2 years after first dose of study drug or until participant is lost to follow-up or dies
Rate of Overall Survival	Overall survival is defined as the date of first dose of study drug to the date of death from any cause.	2 years after first dose of study drug or until participant is lost to follow-up or dies
Rate of Relapse After Hematopoietic Stem Cell Transplant in Individuals Treated With 5-azacitidine Prior to Transplant.		2 years after first dose of study drug or until participant is lost to follow-up or dies

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: October 4, 2006
• First Submitted That Met QC Criteria: October 5, 2006
• First Posted (Estimate): October 6, 2006

Study Record Updates

• Last Update Posted (Estimate): December 12, 2016
• Last Update Submitted That Met QC Criteria: October 27, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: MDS either de novo or secondary, fitting any of the WHO classifications.
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: 06-0585