Alternative Dosing Regimens of Subcutaneous Azacitidine for Myelodysplastic Syndromes

Study Overview
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Brief Summary
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The purpose of this study is to determine if azacitidine, combined with Best Supportive Care (BSC), is effective in treating myelodysplastic syndromes (MDS) when given according to a different doses and dosing schedules.

Detailed Description
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Comparison/Control Interventions: The comparison is azacitidine at different doses and schedules. Duration of Intervention: Treatment lasted for a maximum of 18 cycles, which is up to 24 months.

Official Title
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A Multicenter, Randomized, Open-Label Study Comparing Three Alternative Dosing Regimens of Subcutaneous Azacitidine Plus Best Supportive Care for the Treatment of Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of refractory anemia, refractory anemia with ringed sideroblasts and at least one of the following: a)Anemia with hemoglobin <110g/L and requires at least 1 unit packed red blood cell transfusions every 28 days; b)Thrombocytopenia with platelet counts <100 x 10^9/L; or c)Neutropenia with absolute neutrophil count <1.5 x 10^9/L. OR, Refractory anemia with excess blasts or refractory anemia with excess blast in transformation, according to the French-American-British classification system for MDS. At least 18 years of age. Have a life expectancy of >7 months. Unlikely to proceed to bone marrow or stem cell transplantation therapy following remission. Have serum bilirubin levels less than or equal to 1.5 times the upper limit of the normal (ULN) range for the laboratory. Have serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) or serum glutamic-pyruvic transaminase (alanine aminotransferase) levels less than or equal to 2 x ULN. Have serum creatinine levels less than or equal to 1.5 x ULN. Exclusion Criteria: Secondary MDS. Prior treatment with azacitidine. Any prior history of Acute Myeloid Leukemia (AML). Malignant or metastatic disease within the previous 12 months. Uncorrected red cell folate deficiency or vitamin B12 deficiency. Hepatic tumors. Radiation, chemotherapy, or cytotoxic therapy for non-MDS conditions in the previous 12 months. Known or suspected hypersensitivity to azacitidine or mannitol. Prior transplantation or cytotoxic therapy to treat MDS. Prior use of Revlimid and Thalomid allowed after 30 day washout. Serious medical illness likely to limit survival to less than or equal to 7 months. Treatment with androgenic hormones during the previous 14 days Active viral infection with known human immunodeficiency virus or vial hepatitis Type B or C. Treatment with other investigational drugs with the previous 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aza-5<br>Azacitidine administered subcutaneously at 75mg/m^2 for 5 days on a 28 day cycle. | Drug: azacitidine<br>* Azacitidine is administered subcutaneously Total of 18 cycles on treatment or early discontinuation.<br>|
| Experimental: Aza-5-2-2<br>Azacitidine administered subcutaneously at 75mg/m^2 for 5days with 2 days off, then for an additional 2 days, on a 28 day cycle. | Drug: azacitidine<br>* Azacitidine is administered subcutaneously Total of 18 cycles on treatment or early discontinuation.<br>|
| Experimental: Aza-5-2-5<br>Azacitidine administered subcutaneously at 50mg/m^2 for 5 days with 2 days off, then for an additional 5 days, on a 28 day cycle. | Drug: azacitidine<br>* Azacitidine is administered subcutaneously Total of 18 cycles on treatment or early discontinuation.<br>|
| Experimental: Maintenance Aza 5 days q 4 weeks<br>Azacitidine administered subcutaneously at 75mg/m^2 for 5 days every 4 weeks. | Drug: azacitidine<br>* Azacitidine is administered subcutaneously Total of 18 cycles on treatment or early discontinuation.<br>|
| Experimental: Maintenance Aza 5 days q 6 weeks<br>Azacitidine administered subcutaneously at 75mg/m^2 for 5 days every 6 weeks. | Drug: azacitidine<br>* Azacitidine is administered subcutaneously Total of 18 cycles on treatment or early discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants In Best Hematological Response Categories as Determined by the Investigator Using International Working Group 2000 (IWG 2000) Criteria For Myelodysplastic Syndromes (MDS) During the Initial Study Period. | Participant counts by best hematological response; complete remission(CR) is better than a partial remission(PR) which is better than stable disease(SD). Investigator determined responses followed IWG 2000 criteria for MDS CR: repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia PR is the same as CR for peripheral blood: bone marrow shows blasts decrease by >=50% or a less advanced FAB classification from pretreatment (see Population Descrip) | Day 1 (randomization) to 6 months | 
| Number of Participants With Best Hematological Improvement Derived Using International Working Group 2000 (IWG 2000) Criteria for MDS During the Initial Study Period. | IWG 2000 Criteria: Pretreatment=hemoglobin <110g/L or RBC transfusion-dependence, platelet count <100x10^9/L or platelet transfusion dependence, absolute neutrophil count <1.5x10^9/L. Erythroid response: Major->20g/L increase in hemoglobin or transfusion independence. Minor- 10-20g/L increase in hemoglobin or >=50% decrease in transfusion requirements. Platelet response: Major-absolute increase of platelet count by >=30x10^9/L or platelet transfusion independence. Minor->=50% increase in platelet count with net increase >10x10^9/L but <30x10^9/L. (continued in Population Description) | Day 1 (randomization) to 6 months | 
| Number of Participants With Overall Best Hematologic Response and Hematologic Improvement Based on IWG 2000 Criteria For MDS During the Initial Study Period | Number of participants whose best hematological outcome was either complete remission (CR), partial remission (PR) (as determined by the investigator), or any hematologic improvement (based on the IWG 2000 criteria for MDS). See previous outcomes for detailed definitions. | Day 1 (randomization) to 6 months | 
| Number of Participants Who Improved or Maintained The Hematologic Response From the Initial Study Period (Based on IWG 2000 Criteria For MDS) During the Maintenance Period | Hematologic response during the maintenance period are compared to the response in the initial study period. Initial response could have been a complete remission, a partial remission, stable disease or a hematologic improvement. Maintenance period best response is after randomization to a maintenance arm for those randomized, and is after the start of cycle 7 for those remaining on initial period treatment throughout the study. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Hemoglobin Values | The median values for hemoglobin based on blood tests performed on study day 1 (prior to study treatment) constitute a baseline measure for hemoglobin. Baseline values are used to compare to values following treatment. | Day 1 (randomization) | 
| Change From Baseline in Hemoglobin at End of Initial Study Period (6 Months) | The difference between hemoglobin values at the end of the initial study period minus the hemoglobin values at baseline. | 6 months | 
| Change From Baseline in Hemoglobin at the End of the Maintenance Study Period | The difference between hemoglobin values at the end of the maintenance study period minus the hemoglobin values at baseline. | 24 months | 
| Baseline Platelet Values | The median values for platelets based on blood tests performed on study day 1 (prior to study treatment) constitute a baseline measure for platelets. Baseline values are used to compare to values following treatment. | Day 1 (randomization) | 
| Change From Baseline in Platelets at the End of Initial Study Period (6 Months) | The difference between platelet values at the end of the initial study period minus the platelet values at baseline. | 6 months | 
| Change From Baseline in Platelets at the End of the Maintenance Study Period (Month 24) | The difference between platelet values at the end of the maintenance study period minus the platelet values at baseline. | 24 months | 
| Baseline Absolute Neutrophil Count (ANC) Values | The median values for ANC based on blood tests performed on study day 1 (prior to study treatment) constitute a baseline measure for ANC. Baseline values are used to compare to values following treatment. | Day 1 (randomization) | 
| Change From Baseline in Absolute Neutrophil Count (ANC) at the End of Initial Study Period (6 Months) | The difference between ANC values at the end of the initial study period minus the ANC values at baseline. | 6 months | 
| Change From Baseline in Absolute Neutrophil Count (ANC) at the End of the Maintenance Study Period (Month 24) | The difference between ANC values at the end of the maintenance study period minus the ANC values at baseline. | 24 months | 
| Red Blood Cell (RBC) Transfusion Status at Baseline and End of Initial Study Period (6 Months) | Shift table comparing the RBC transfusion status of patients at the end of the initial study period to the transfusion status at baseline. | 6 months | 
| Platelet Transfusion Status at Baseline and End of Initial Study Period (6 Months) | Shift table comparing the platelet transfusion status of patients at the end of the initial study period to the transfusion status at baseline. | 6 months | 
| Red Blood Cell (RBC) Transfusion Status at Baseline and End of Maintenance Study Period (24 Months) | Shift table comparing the RBC transfusion status of patients at the end of the maintenance study period to the transfusion status at baseline. | 24 months | 
| Platelet Transfusion Status at Baseline and End of Maintenance Study Period (24 Months) | Shift table comparing the platelet transfusion status of patients at the end of the maintenance study period to the transfusion status at baseline. | 24 months | 
| Change From Baseline in the Number of Infections Requiring Treatment With IV Antibiotics Per Treatment Cycle (28 Days) for the Initial Study Period | Baseline uses the average number of infections requiring IV antibiotic treatment from the 28 days prior to and including the day of first dose to an initial treatment arm. Initial study period values total the number of infections requiring IV antibiotic treatment divided by the number of treatment cycles (each cycle is approximately one month). | 6 months | 
| Change From Baseline in the Number of Infections Requiring Treatment With IV Antibiotics Per Treatment Cycle (28 Days) for the Maintenance Study Period | Baseline uses the average number of infections requiring IV antibiotic treatment from the 28 days prior to and including the day of first dose to an initial treatment arm. Maintenance study period values total the number of infections requiring IV antibiotic treatment divided by the number of treatment cycles (each cycle is approximately one month). | 24 months |