Determination of Safe Dose of Romiplostim (AMG 531) in Patients With Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of romiplostim in thrombocytopenic patients with low or Intermediate-1 risk MDS. In addition, the study will evaluate the platelet response to romiplostim.

Official Title
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An Open Label, Sequential Cohort, Dose Escalation Study to Evaluate the Safety and Efficacy of AMG 531 in Thrombocytopenic Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Conditions
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MDS, Thrombocytopenia, Myelodysplastic Syndromes, Refractory Cytopenias

Intervention / Treatment
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* Drug: Romiplostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of MDS using the World Health Organization classification Low or Intermediate-1 risk MDS using the International Prognostic Scoring System (IPSS) The mean of two platelet counts taken during the screening period must be ≤ 50 x 10^9/L, with no individual count > 55 x 10^9/L (The mean platelet counts of 5 subjects enrolled at the maximum tolerated dose (MTD) must be ≤ 20 x 10^9/L). Standard of care platelet assessments taken prior to Informed Consent may be used as 1 of the 2 counts taken within 3 weeks prior to study day 1. Must be ≥ 18 years of age at the time of obtaining informed consent Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of screening Adequate Liver Function, as evidenced by a serum bilirubin ≤ 1.5 times the laboratory normal range (except for patients with a confirmed diagnosis of Gilbert's Disease), alanine aminotransferase (ALT) ≤ 3 times the laboratory normal range, and aspartate aminotransferase (AST) ≤ 3 times the laboratory normal range A serum creatinine concentration ≤ 2 mg/dL (≤ 176.6 µmol/L) Before any study-specific procedure, the appropriate written informed consent must be obtained (see Section 12.1) Exclusion Criteria: Currently receiving any treatment for MDS other than transfusions and erythropoietic growth factors. If granulocyte growth factors are currently being received, they cannot be used on or after study day 1 Clinically significant bleeding within 2 weeks prior to screening (eg, gastrointestinal (GI) bleeds, intracranial hemorrhage) Prior malignancy (other than controlled prostate cancer, in situ cervical cancer or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ≥ 3 years before screening Prior history of bone marrow transplantation Persistent peripheral blood monocytosis (≥ 3 months with an absolute monocyte count > 1,000/µL) Unstable angina, congestive heart failure (New York Heart Association [NYHA] > class II), uncontrolled hypertension (diastolic > 100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction Received Anti-Thymocyte Globuline (ATG) within 6 months of screening Received hypomethylating agents, immunomodulating agents, histone deacetylase inhibitors, cyclosporine or mycophenolate within 6 weeks of screening Received interleukin (IL)-11 (oprelvekin) within 4 weeks before screening Concurrent use of granulocyte growth factors (i.e. granulocyte-colony stimulating factor [G-CSF; Neupogen, Granocyte], pegfilgrastim [Neulasta], granulocyte macrophage-colony stimulating factor [GM-CSF; Leukine, Prokine, Sargramostim]) Have ever previously received recombinant thrombopoietin (rTPO), pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), eltrombopag, or romiplostim Less than 4 weeks since receipt of any therapeutic drug or device that is not Food and Drug Administration (FDA) approved for any indication Other investigational procedures are excluded History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past year History of venous thrombosis that currently requires anti-coagulation therapy Untreated B12 or folate deficiency Subject is evidently pregnant (eg, positive human chorionic gonadotropin [HCG] test) or is breast feeding Subject is not using adequate contraceptive precautions Subject has known hypersensitivity to any recombinant E coli-derived product Subject previously has enrolled in this study Subject will not be available for follow-up assessment Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: 300 µg romiplostim<br>Cohort 1 in Part A, participants received romiplostim 300 µg subcutaneously once weekly for 3 weeks. Participants who completed Part A could continue to receive weekly injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part A: 700 µg romiplostim<br>Cohort 2 in Part A, participants received romiplostim 700 µg subcutaneously once weekly for up to 3 weeks. Participants who completed Part A could continue to receive weekly injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part A: 1000 µg romiplostim<br>Cohort 3 in Part A, participants received romiplostim 1000 µg subcutaneously once weekly for up to 3 weeks. Participants who completed Part A could continue to receive weekly injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part A: 1500 µg romiplostim<br>Cohort 4 in Part A, participants received romiplostim 1500 µg subcutaneously once weekly for up to 3 weeks. Participants who completed Part A could continue to receive weekly injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part B: 750 µg romiplostim SC QW<br>Part B participants received romiplostim 750 µg subcutaneously (SC) once weekly (QW) for 8 weeks. Participants who complete Part B could continue to receive weekly injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part B: 750 µg romiplostim SC Q2W<br>Part B participants received romiplostim 750 µg subcutaneously every two weeks (Q2W) for 8 weeks. Participants who complete Part B could continue to receive injections of romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|
| Experimental: Part B: 750 µg romiplostim IV Q2W<br>Part B participants received romiplostim 750 µg intravenously (IV) once every two weeks for 8 weeks. Participants who complete Part B could continue to receive romiplostim for up to 1 year in the extension treatment phase. | Drug: Romiplostim<br> <br> * Other names: Nplate®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Adverse Events | The number of participants experiencing one or more adverse events during the treatment phase or extension phase of Part A. | Treatment period (4 weeks) plus treatment extension (1 year) | 
| Part B: Number of Participants With Adverse Events | The number of participants experiencing one or more adverse events during the treatment phase or extension phase of Part B. | Treatment period (8 weeks) plus treatment extension (1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With a Complete or Major Platelet Response | Participants with a complete or major response during the treatment phase. A complete platelet response was defined as a platelet count ≥ 100 x 10^9/L during the treatment phase. A major platelet response was defined as an increase in absolute platelet count of ≥ 30 x 10^9/L for patients starting with > 20 x 10^9/L platelets, or an increase from ≤ 20 x 10^9/L to > 20 x 10^9/L and by at least 100%. Any participant receiving rescue medication was considered a non-responder. Platelet transfusions were considered rescue medication. | Treatment Period (4 weeks) | 
| Part B: Number of Participants With a Complete or Major Platelet Response | Participants with a complete or major response during the treatment phase. A complete platelet response was defined as a platelet count ≥ 100 x 10^9/L during the treatment phase. A major platelet response was defined as an increase in absolute platelet count of ≥ 30 x 10^9/L for patients starting with > 20 x 10^9/L platelets, or an increase from ≤ 20 x 10^9/L to > 20 x 10^9/L and by at least 100%. Any participant receiving rescue medication was considered a non-responder. Platelet transfusions were considered rescue medication. | Treatment Period (8 weeks) | 
| Part A: Number of Participants With a Platelet Response Per IWG Criteria | The number of participants with a platelet response according to the modified International Working Group (IWG) criteria. Response was defined as an absolute increase of ≥ 30 x 10^9/L with Baseline platelet count > 20 x 10^9/L, or with a Baseline count ≤ 20 x 10^9/L, increasing to above 20 x 10^9/L and by at least 100% during the treatment or extension period and maintained for at least 8 consecutive weeks. Platelet transfusion was not considered a rescue medication but platelet counts ≤72 hours after platelet transfusion were excluded from the analysis. | Treatment period (4 weeks) and extension period (52 weeks). | 
| Part B: Number of Participants With a Platelet Response Per IWG | The number of participants with a platelet response according to the modified International Working Group (IWG) criteria. Response was defined as an absolute increase of ≥ 30 x 10^9/L with Baseline platelet count > 20 x 10^9/L, or with a Baseline count ≤ 20 x 10^9/L, increasing to above 20 x 10^9/L and by at least 100% during the treatment or extension period and maintained for at least 8 consecutive weeks. Platelet transfusion was not considered a rescue medication but platelet counts ≤72 hours after platelet transfusion were excluded from the analysis. | Treatment period (8 weeks) and extension period (52 weeks). | 
| Part B: Peak Platelet Count | Peak platelet count (10^9/L) during the treatment period. | Treatment Period (8 weeks) | 
| Part B: Time to First Platelet Response | Participants achieving first platelet response according to IWG criteria, by study week. Platelet response was defined as an absolute increase of ≥ 30 x 10^9/L with Baseline platelet count > 20 x 10^9/L, or with a Baseline ≤ 20 x 10^9/L increasing the platelet count to above 20 x 10^9/L and by at least 100% for 8 consecutive weeks. Platelet counts obtained within 72 hours of platelet transfusion were not evaluable for platelet response. | Treatment Period (8 weeks) and extension period (52 weeks). | 
| Part B: Duration of Platelet Response | Duration of platelet response per IWG criteria (absolute increase of ≥ 30 x 10^9/L with Baseline platelet count > 20 x 10^9/L, or with a Baseline ≤ 20 x 10^9/L increasing the platelet count to above 20 x 10^9/L and by at least 100% for 8 consecutive weeks). | Treatment Period (8 weeks) and extension period (52 weeks) | 
| Part B: Week 1 Cmax | Maximum observed serum concentration (Cmax) of romiplostim during Week 1 | Week 1 | 
| Part B: Week 1 Ctrough | Measured romiplostim concentration at the end of the week 1 dosing interval (Ctrough) | Week 1 | 
| Part B: Week 1 AUC0-4 | Area under the romiplostim concentration-time curve from time zero to the last time point with quantifiable concentration (AUC0-4) during Week 1 | Week 1 | 
| Part B: Week 7 Cmax | Maximum observed serum concentration (Cmax) of romiplostim during Week 7. | Week 7 | 
| Part B: Week 7 Ctrough | Measured romiplostim concentration at the end of the Week 7 dosing interval (Ctrough) | Week 7 | 
| Part B: Week 7 AUC0-4 | Area under the romiplostim concentration-time curve from time zero to the last time point with quantifiable concentration (AUC0-4) during Week 7. | Week 7 | 
| Part B: Week 1 Tmax | Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 1 | Week 1 | 
| Part B: Week 7 Tmax | Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 7 | Week 7 | 

 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