Determination of Safe and Effective Dose of Romiplostim (AMG 531) in Subjects With Myelodysplastic Syndrome (MDS)Receiving Hypomethylating Agents

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of Romiplostim (AMG 531) on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 and/or receipt of platelet transfusions) in subjects with low or intermediate risk Myelodysplastic Syndrome (MDS) receiving hypomethylating agents. It is hypothesized that Romiplostim administration, at the appropriate dose and schedule, will result in reduction in the incidence of clinically significant thrombocytopenic events in low or intermediate risk MDS subjects receiving hypomethylating agents.

Official Title
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A Randomized, Double Blind, Placebo Controlled Study Evaluating the Efficacy and Safety of Romiplostim (AMG 531) Treatment of Subjects With Low or Intermediate Risk Myelodysplastic Syndrome (MDS) Receiving Hypomethylating Agents

Conditions
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MDS, Myelodysplastic Syndromes, Thrombocytopenia

Intervention / Treatment
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* Drug: Placebo
* Biological: AMG 531 (Romiplostim)
* Drug: Azacitidine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Diagnosis of MDS by bone marrow biopsy based on the World Health Organization (WHO) classification - Low, Intermediate-1 or Intermediate-2 risk category MDS using the IPSS (International Prognostic Scoring System) - Planned to receive either azacytidine 75 mg/m2 by subcutaneous administration each day for 7 days or decitabine 20 mg/m2 by intravenous administration each day for 5 days for at least 4 cycles Exclusion Criteria: Prior exposure to >3 cycles hypomethylating agents Prior history of leukemia or aplastic anemia Prior history of bone marrow transplantation Prior malignancy (other than in situ cervical cancer or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ³ 3 years before randomization Active or uncontrolled infections Unstable angina, congestive heart failure [NYHA (New York Heart Association) > class II], uncontrolled hypertension [diastolic > 100 mmHg], uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction History of arterial thrombosis ( eg, stroke or transient ischemic attack) in the past year History of venous thrombosis that currently requires anti-coagulation therapy Received IL-11 within 4 weeks of screening Less than 4 weeks since receipt of any therapeutic drug or device that is not FDA approved for any indication Have previously received any other thrombopoietic growth factor

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose level 1 500 AMG 531 (Part A - azacitidine)<br>500 mcg AMG 531 weekly via subcutaneous injection + 75 mg/m2 azacitidine for 4 cycles | Biological: AMG 531 (Romiplostim)<br>* AMG 531 (Romiplostim) will be administered weekly by subcutaneous injection at a dose of 500 or 750 μg during Part A and 750 μg during Part B for the 4 cycle treatment period, depending on randomization.<br>Drug: Azacitidine<br>* hypomethylating agent<br>|
| Active Comparator: Dose level 1 750 AMG 531 (Part B - decitabine)<br>750 mcg AMG 531 weekly via subcutaneous injection + 20 mg/m2 decitabine for 4 cycles | Biological: AMG 531 (Romiplostim)<br>* AMG 531 (Romiplostim) will be administered weekly by subcutaneous injection at a dose of 500 or 750 μg during Part A and 750 μg during Part B for the 4 cycle treatment period, depending on randomization.<br>Drug: Decitabine<br>* hypomethylating agent<br>|
| Active Comparator: Dose level 2 750 AMG 531 (Part A - azacitidine)<br>750 mcg AMG 531 weekly via subcutaneous injection + 75 mg/m2 azacitidine for 4 cycles | Biological: AMG 531 (Romiplostim)<br>* AMG 531 (Romiplostim) will be administered weekly by subcutaneous injection at a dose of 500 or 750 μg during Part A and 750 μg during Part B for the 4 cycle treatment period, depending on randomization.<br>Drug: Azacitidine<br>* hypomethylating agent<br>|
| Placebo Comparator: Placebo (Part A - azacitidine)<br>Placebo weekly via subcutaneous injection + 75 mg/m2 azacitidine for 4 cycles | Drug: Placebo<br>* Subjects in the control group will receive a placebo subcutaneous injection on a weekly basis during the 4 cycle treatment period.<br>Drug: Azacitidine<br>* hypomethylating agent<br>|
| Placebo Comparator: Placebo (Part B - decitabine)<br>Placebo weekly via subcutaneous injection + 20 mg/m2 decitabine for 4 cycles | Drug: Placebo<br>* Subjects in the control group will receive a placebo subcutaneous injection on a weekly basis during the 4 cycle treatment period.<br>Drug: Decitabine<br>* hypomethylating agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a Clinically Significant Thrombocytopenic Event | Occurrence of a clinically significant thrombocytopenic event within the participant, defined as any platelet count obtained from day 15 of cycle 1 through the end of the interim follow-up visit that was less than 50 x 10^9/L or receipt of platelet transfusions at any time through the interim follow-up visit. | Treatment period (up to 20 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | Occurrence of hypomethylating agent dose reduction and delay due to thrombocytopenia | Treatment period (up to 20 weeks) | 
| Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | CR = decrease in bone marrow blast (≤5%) and improvement in peripheral blood counts (Hgb ≥ 11 g/dL, platelets ≥ 100x10^9/L, neutrophils ≥ 1x10^9/L, peripheral blasts=0%). PR = improvement in peripheral blood counts plus a decrease in bone marrow blasts ≥50% but not ≤5, or decrease in International Prognostic Scoring System score. | Treatment period (up to 20 weeks) | 
| Platelet Transfusion | Occurrence of one or more platelet transfusions from study day 1 through the interim follow-up visit (16 weeks) | Study day 1 through the interim follow-up visit (up to 20 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, Myelodysplastic Syndromes, Refractory Cytopenias, Thrombocytopenia