Determination of Safe Dose of Romiplostim (AMG 531) in Patients With Myelodysplastic Syndromes (MDS)
November 21, 2013 updated by: Amgen
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)
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.
Study Overview
Status
Completed
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
72
Phase
- Phase 2
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
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:
- 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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Part A: 300 µg romiplostim
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.
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Other Names:
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Experimental: Part A: 700 µg romiplostim
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.
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Other Names:
|
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Experimental: Part A: 1000 µg romiplostim
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.
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Other Names:
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Experimental: Part A: 1500 µg romiplostim
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.
|
Other Names:
|
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Experimental: Part B: 750 µg romiplostim SC QW
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.
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Other Names:
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Experimental: Part B: 750 µg romiplostim SC Q2W
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.
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Other Names:
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Experimental: Part B: 750 µg romiplostim IV Q2W
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.
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Part A: Number of Participants With Adverse Events
Time Frame: Treatment period (4 weeks) plus treatment extension (1 year)
|
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
Time Frame: Treatment period (8 weeks) plus treatment extension (1 year)
|
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
Time Frame: Treatment Period (4 weeks)
|
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)
|
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Part B: Number of Participants With a Complete or Major Platelet Response
Time Frame: Treatment Period (8 weeks)
|
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
Time Frame: Treatment period (4 weeks) and extension period (52 weeks).
|
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
Time Frame: Treatment period (8 weeks) and extension period (52 weeks).
|
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).
|
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Part B: Peak Platelet Count
Time Frame: Treatment Period (8 weeks)
|
Peak platelet count (10^9/L) during the treatment period.
|
Treatment Period (8 weeks)
|
|
Part B: Time to First Platelet Response
Time Frame: Treatment Period (8 weeks) and extension period (52 weeks).
|
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
Time Frame: Treatment Period (8 weeks) and extension period (52 weeks)
|
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)
|
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Part B: Week 1 Cmax
Time Frame: Week 1
|
Maximum observed serum concentration (Cmax) of romiplostim during Week 1
|
Week 1
|
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Part B: Week 1 Ctrough
Time Frame: Week 1
|
Measured romiplostim concentration at the end of the week 1 dosing interval (Ctrough)
|
Week 1
|
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Part B: Week 1 AUC0-4
Time Frame: Week 1
|
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
|
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Part B: Week 7 Cmax
Time Frame: Week 7
|
Maximum observed serum concentration (Cmax) of romiplostim during Week 7.
|
Week 7
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Part B: Week 7 Ctrough
Time Frame: Week 7
|
Measured romiplostim concentration at the end of the Week 7 dosing interval (Ctrough)
|
Week 7
|
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Part B: Week 7 AUC0-4
Time Frame: Week 7
|
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
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Part B: Week 1 Tmax
Time Frame: Week 1
|
Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 1
|
Week 1
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Part B: Week 7 Tmax
Time Frame: Week 7
|
Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 7
|
Week 7
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
February 1, 2006
Primary Completion (Actual)
May 1, 2008
Study Completion (Actual)
May 1, 2008
Study Registration Dates
First Submitted
March 16, 2006
First Submitted That Met QC Criteria
March 16, 2006
First Posted (Estimate)
March 17, 2006
Study Record Updates
Last Update Posted (Estimate)
December 16, 2013
Last Update Submitted That Met QC Criteria
November 21, 2013
Last Verified
November 1, 2013
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 20050159
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.