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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT00303472
First received: March 16, 2006
Last updated: November 21, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Thrombocytopenia
MDS
Myelodysplastic Syndromes
Refractory Cytopenias
Drug: Romiplostim
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Part A: Number of Participants With Adverse Events [ Time Frame: Treatment period (4 weeks) plus treatment extension (1 year) ] [ Designated as safety issue: Yes ]
    The number of participants experiencing one or more adverse events during the treatment phase or extension phase of Part A.

  • Part B: Number of Participants With Adverse Events [ Time Frame: Treatment period (8 weeks) plus treatment extension (1 year) ] [ Designated as safety issue: Yes ]
    The number of participants experiencing one or more adverse events during the treatment phase or extension phase of Part B.


Secondary Outcome Measures:
  • Part A: Number of Participants With a Complete or Major Platelet Response [ Time Frame: Treatment Period (4 weeks) ] [ Designated as safety issue: No ]
    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.

  • Part B: Number of Participants With a Complete or Major Platelet Response [ Time Frame: Treatment Period (8 weeks) ] [ Designated as safety issue: No ]
    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.

  • Part A: Number of Participants With a Platelet Response Per IWG Criteria [ Time Frame: Treatment period (4 weeks) and extension period (52 weeks). ] [ Designated as safety issue: No ]
    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.

  • Part B: Number of Participants With a Platelet Response Per IWG [ Time Frame: Treatment period (8 weeks) and extension period (52 weeks). ] [ Designated as safety issue: No ]
    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.

  • Part B: Peak Platelet Count [ Time Frame: Treatment Period (8 weeks) ] [ Designated as safety issue: No ]
    Peak platelet count (10^9/L) during the treatment period.

  • Part B: Time to First Platelet Response [ Time Frame: Treatment Period (8 weeks) and extension period (52 weeks). ] [ Designated as safety issue: No ]
    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.

  • Part B: Duration of Platelet Response [ Time Frame: Treatment Period (8 weeks) and extension period (52 weeks) ] [ Designated as safety issue: No ]
    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).

  • Part B: Week 1 Cmax [ Time Frame: Week 1 ] [ Designated as safety issue: No ]
    Maximum observed serum concentration (Cmax) of romiplostim during Week 1

  • Part B: Week 1 Ctrough [ Time Frame: Week 1 ] [ Designated as safety issue: No ]
    Measured romiplostim concentration at the end of the week 1 dosing interval (Ctrough)

  • Part B: Week 1 AUC0-4 [ Time Frame: Week 1 ] [ Designated as safety issue: No ]
    Area under the romiplostim concentration-time curve from time zero to the last time point with quantifiable concentration (AUC0-4) during Week 1

  • Part B: Week 7 Cmax [ Time Frame: Week 7 ] [ Designated as safety issue: No ]
    Maximum observed serum concentration (Cmax) of romiplostim during Week 7.

  • Part B: Week 7 Ctrough [ Time Frame: Week 7 ] [ Designated as safety issue: No ]
    Measured romiplostim concentration at the end of the Week 7 dosing interval (Ctrough)

  • Part B: Week 7 AUC0-4 [ Time Frame: Week 7 ] [ Designated as safety issue: No ]
    Area under the romiplostim concentration-time curve from time zero to the last time point with quantifiable concentration (AUC0-4) during Week 7.

  • Part B: Week 1 Tmax [ Time Frame: Week 1 ] [ Designated as safety issue: No ]
    Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 1

  • Part B: Week 7 Tmax [ Time Frame: Week 7 ] [ Designated as safety issue: No ]
    Time at which the maximum concentration of romiplostum was observed after subcutaneous administration during Week 7


Enrollment: 72
Study Start Date: February 2006
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®
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.
Drug: Romiplostim
Other Names:
  • AMG 531
  • Nplate®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00303472

Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Additional Information:
Publications:
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT00303472     History of Changes
Obsolete Identifiers: NCT00548028
Other Study ID Numbers: 20050159
Study First Received: March 16, 2006
Results First Received: October 22, 2010
Last Updated: November 21, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Netherlands: CCMO (Centrale Commissie Mensgebonden Onderzoek): Central Committee Human Bound Research
Sweden: Medical Products Agency
United States: Food and Drug Administration

Keywords provided by Amgen:
MDS
Myelodysplastic Syndromes
Refractory Cytopenias
Thrombocytopenia

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Thrombocytopenia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Blood Platelet Disorders

ClinicalTrials.gov processed this record on April 17, 2014