• The toxicity profile at each dose level.
  

• The evaluation of early evidence of disease response (platelet count) and PK/PD evaluations.
  

Drug: AMG531
N/A

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis, progressive bone marrow failure, and the propensity to transform to acute myeloid leukemia (AML). Patients often present with complications related to anemia (fatigue), neutropenia (infections) and/or thrombocytopenia (bleeding). The therapeutic options for MDS remain limited. A small percentage of patients are candidates for curative therapies such as allogenic stem cell transplant. For the vast majority of patients the lack of acceptable donors, advanced age, and/or serious co-morbid medical conditions and organ dysfunction prevent access to this option. In fact, the standard of care in MDS has generally been accepted as supportive in nature. Transfusions for symptomatic anemia and symptomatic thrombocytopenia, antibiotics for infections, and growth factors designed to improve a cytopenia are all examples of the supportive care that is currently available.

Currently there are no thrombopoietic agents indicated for use in MDS leaving platelet transfusions as the only available treatment option. Platelet transfusions are associated with a number of side effects including febrile or allergic transfusion reactions, transmission of bacterial and viral infections, circulatory congestion, transfusion-related acute lung injury and alloimmunization. The increased demands on the blood supply in the future may further limit transfusion as chronic therapy. Therefore the management of MDS patients with thrombocytopenia remains unsatisfactory and novel therapies are needed which are easily tolerated by older patients. AMG 531 may be such a novel therapeutic option. AMG 531 is an Fc fusion protein (peptibody) that increases platelet production via the thrombopoietin (TPO) receptor, which signals and activates intracellular transcriptional pathways.

This study will assess the safety and efficacy of AMG 531 (Romiplostim) in thrombocytopenic subjects with low or intermediate-1 risk MDS. It is expected that AMG 531 will be well tolerated, and achieve at least a major platelet response in 30 percent.

Overall, the Amgen sponsored protocol has 3 parts. Part A (a phase 1/2, multi-center, open label, sequential cohort dose escalation study) that is no longer open for accrual. NIH subjects will be evaluated for participation in Part B only (a phase 2, multi-center, open label study) and then may choose to enter Part C, the treatment extension phase (up to 1 year continued therapy).

The primary objective of the study is to evaluate the safety and tolerability of AMG 531 in thrombocytopenic subjects with low or Intermediate-1 risk MDS. Secondary Objective(s) include: evaluating the platelet response (part A); assessing the pharmacodynamics (PD) and pharmacokinetics (PK) of three dosing schedules (part B) and assessing the long term safety (part C).

The primary endpoint is the incidence and severity of all adverse events and evaluation of antibody status and identification of the MTD (the dose where less than 34 percent of subjects experience a related grade 3-4 toxicity) in this study population.

• INCLUSION CRITERIA:

  1. Disease related

• Diagnosis of MDS using the World Health Organization classification.
• Low or Intermediate-1 risk MDS using the IPSS.

• The mean of two platelet counts taken during the screening period must be less than or equal to 50 times 10(9)/L, with no individual count greater than 55 times 10(9)/L (The mean platelet counts of 5 subjects enrolled at the MTD must be less than or equal to 20 times 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.

  2. Demographic

• Subjects must be greater than or equal to 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.

  3. Laboratory

• Adequate Liver Function, as evidenced by a serum bilirubin less than or equal to 1.5 times the laboratory normal range (except for patients with a confirmed diagnosis of Gilbert's Disease), ALT less than or equal to 3 times the laboratory normal range, and AST less than or equal to 3 times the laboratory normal range.

• A serum creatinine concentration less than or equal to 2 mg/dL (less than or equal to 176.6 micromol/L).

  4. Ethical

• Before any study-specific procedure, the appropriate written informed consent must be obtained.

EXCLUSION CRITERIA:

1. Disease Related

   • Currently receiving any treatment for MDS other than transfusions and erythropoeitic 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, 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 greater than or equal to 3 years before screening.
   • Prior history of bone marrow transplantation.
   • Persistent peripheral blood monocytosis (greater than or equal to 3 months with an absolute monocyte count greater than 1,000/microL).
   • Unstable angina, congestive heart failure [NYHA greater than class II], uncontrolled hypertension [diastolic greater than 100 mmHg], uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction.

2. Medications

   • 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 IL-11 (oprelvekin) within 4 weeks before screening.
   • Concurrent use of granulocyte growth factors (i.e. G-CSF (Neupogen[Registered Trademark], Granocyte[Registered Trademark]), pegfilgrastim (Neulasta[Registered Trademark]), GM-CSF (Leukine, Prokine, Sargramostim)).
   • Have ever previously received rTPO, PEG-rHuMGDF, eltrombopag, or AMG 531.
   • Less than 4 weeks since receipt of any therapeutic drug or device that is not FDA approved for any indication.

3. General

   • 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 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.