Myelodysplastic Syndromes
Conditions
Keywords
MDS either de novo or secondary, fitting any of the WHO classifications.
Brief summary
The primary endpoint of this study is to estimate morphologic complete remission rate. Estimation of response rate is also a secondary objection.
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.
Interventions
DRUGAzacitidine
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Complete Remission (CR) and Partial Remission (PR) | After 4 cycles of therapy (up to 112 days after start of treatment) | 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%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Hematologic Improvement | 4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)] | International Working Group (IWG) for Myelodysplasia (MDS). |
| 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 | 2 years after first dose of study drug or until participant is lost to follow-up or dies | Overall survival is defined as the date of first dose of study drug to the date of death from any cause. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
Enrollment to the study started on 08/17/2006 and enrollment to the study closed on 06/10/2008.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible (acute myeloid leukemia) | 3 |
Baseline characteristics
| Characteristic | Azacitidine |
|---|---|
| Age, Continuous | 69.5 years |
| Bone marrow cellularity at baseline | 68 percentage of bone marrow cellularity |
| Cytogenetics Complex | 11 participants |
| Cytogenetics Intermediate | 4 participants |
| Cytogenetics Normal | 7 participants |
| Duration of myelodysplastic syndrome (MDS) at study entry | 15.5 days |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 4 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 15 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 2 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Unknown | 1 participants |
| French, American, British (FAB) classification CMML | 2 participants |
| French, American, British (FAB) classification RA | 6 participants |
| French, American, British (FAB) classification RAEB | 12 participants |
| French, American, British (FAB) classification RAEB-t | 2 participants |
| Gender Female | 9 Participants |
| Gender Male | 13 Participants |
| International Prognostic Scoring System (IPSS) High | 6 participants |
| International Prognostic Scoring System (IPSS) Int-1 | 8 participants |
| International Prognostic Scoring System (IPSS) Int-2 | 7 participants |
| International Prognostic Scoring System (IPSS) Low | 1 participants |
| Region of Enrollment United States | 22 participants |
| Transfusion dependence Platelet | 3 participants |
| Transfusion dependence Red blood cell | 4 participants |
| Transfusion dependence Red blood cell and platelet | 3 participants |
| World Health Organization (WHO) classification AML | 2 participants |
| World Health Organization (WHO) classification CMML-1 | 2 participants |
| World Health Organization (WHO) classification RA | 3 participants |
| World Health Organization (WHO) classification RAEB-1 | 3 participants |
| World Health Organization (WHO) classification RAEB-2 | 9 participants |
| World Health Organization (WHO) classification RCMD | 3 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 12 / 24 |
Outcome results
Primary
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%.
Time frame: After 4 cycles of therapy (up to 112 days after start of treatment)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Rate of Complete Remission (CR) and Partial Remission (PR) | Complete remission (CR) | 5 participants |
| Azacitidine | Rate of Complete Remission (CR) and Partial Remission (PR) | Partial remission (PR) | 1 participants |
Secondary
Rate of Cytogenetic Response
Time frame: 2 years after first dose of study drug or until participant is lost to follow-up or dies
Population: This secondary outcome was not analyzed.
Secondary
Rate of Hematologic Improvement
International Working Group (IWG) for Myelodysplasia (MDS).
Time frame: 4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)]
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine | Rate of Hematologic Improvement | 0 participants |
Secondary
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.
Time frame: 2 years after first dose of study drug or until participant is lost to follow-up or dies
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine | Rate of Overall Survival | 444 days |
Secondary
Rate of Relapse After Hematopoietic Stem Cell Transplant in Individuals Treated With 5-azacitidine Prior to Transplant.
Time frame: 2 years after first dose of study drug or until participant is lost to follow-up or dies
Population: This secondary outcome was not analyzed.
Secondary
Rate of Transfusion Independence
Time frame: 4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)]
Population: Only participants with baseline transfusion dependence were assessed for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Rate of Transfusion Independence | Red blood cell | 2 participants |
| Azacitidine | Rate of Transfusion Independence | Platelet | 1 participants |
| Azacitidine | Rate of Transfusion Independence | Red blood cell and platelet | 0 participants |
Post Hoc
Duration of Response (DOR)
Time frame: 2 years after first dose of study drug or until participant is lost to follow-up or dies
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine | Duration of Response (DOR) | 450 days |
Post Hoc
Progression-free Survival (PFS)
PFS is defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, or death due to any cause. Disease progression * for patients w/ \<5% blasts; a ≥50% increase in blasts to \>5% blasts * for patients w/ 5% to 10% blasts; a ≥50 increase to \>10% blasts * for patients w/ 10% to 20% blasts; a ≥50% increase to \>20% blasts * for patients w/ 20% to 30% blasts; a ≥50% increase to \>30% blasts * One or more of the following ≥50% decrement from maximum remission/response levels in granulocytes or platelets, reduction in hemoglobin concentration by ≥2 g/dL or transfusion dependence
Time frame: 2 years after first dose of study drug or until participant is lost to follow-up or dies
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine | Progression-free Survival (PFS) | 339 days |
Post Hoc
Time to Best Response
Time frame: 4 weeks following last dose of azacitidine [median number of cycles 4.5 (1-20)]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine | Time to Best Response | 108 days |