Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Pilot Phase I Dose Finding Safety Study of a Thrombopoietin-receptor Agonist, Eltrombopag, in Patients With Myelodysplastic Syndrome Treated With Azacitidine
Brief Summary: Patients with Myelodysplastic Syndromes (MDS) often suffer from low platelet levels which may lead to bleeding complications. Treatment with cytotoxic agents can decrease the platelet levels further. Eltrombopag is a relatively new drug that increases the platelet level in the blood by working directly on the bone marrow. It is available for treatment of the disease Immunological Thrombocytopenic Purpura (ITP). In this study patients with MDS and low platelet levels that are treated with the cytotoxic agent Azacitidine will also receive Eltrombopag. The administration of Eltrombopag to MDS patients treated with Azacitidine may result in less dose reductions and less treatment delays for Azacitidine and may reduce the need for thrombocyte transfusions and lower the risk of bleeding complications.

This is a phase I study, meaning that our major goal is to investigate the safety and tolerability for Eltrombopag in this patient group. It will also generate a basis for a phase II-III-study.


Options:
A: * INCLUSION CRITERIA:

  1. Diagnosis of aplastic anemia, with refractory thrombocytopenia following at least one treatment course of horse or rabbit ATG/cyclosporine.
  2. Platelet count less than or equal to 30,000/microL
  3. Age greater than or equal to 12 years old

EXCLUSION CRITERIA:

1. Diagnosis of Fanconi anemia
2. Infection not adequately responding to appropriate therapy
3. Patients with a PNH clone size in neutrophils of greater than or equal to 50%
4. HIV positivity
5. Creatinine \> 2.5
6. Bilirubin \> 2.0
7. SGOT or SGPT \> 5 times the upper limit of normal
8. Hypersensitivity to eltrombopag or its components
9. Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential
10. History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1 breast cancer, cervical carcinoma in situ, etc)
11. Unable to understand the investigational nature of the study or give informed consent
12. History of congestive heart failure arrhythmia requiring chronic treatment, arterial or venous thrombosis (not excluding line thrombosis) within the last 1 year, or myocardial infarction within 3 months before enrollment
13. ECOG Performance Status of 3 or greater
14. Treatment with horse or rabbit ATG or Campath within 6 months of study entry. Concurrent stable treatment with cyclosporine or G-CSF is permitted.
B: 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
C: Inclusion Criteria:

1. Adult subjects (18 years of age or older) with advanced MDS or sAML/MDS requiring treatment with Azacitidine as approved by EMEA:

   * MDS classified as Intermediate 2-risk or high risk according to the international prognostic scoring system (IPSS) or
   * Chronic myelomonocytic leukaemia (CMML) with 10-29% bone marrow blasts without myeloproliferative disease or
   * Acute myeloblastic leukaemia (AML) with 20-30% bone marrow blasts with multilineage dysplasia according to the WHO classification.
2. Platelet counts \< 75 x 109 /L at start of Azacitidine treatment.
3. Subjects must have platelet count and platelet transfusion data available over a period of 4 weeks prior to inclusion.
4. During the 8 weeks prior to inclusion in study, subjects must have a baseline bone marrow examination including all of the following:

   * cytomorphology to confirm bone marrow blasts
   * cytogenetics
5. ECOG Status 0-2.
6. Subject is able to understand and comply with protocol requirements and instructions.
7. Subject has signed and dated informed consent.
8. Adequate baseline organ function defined by the criteria below:

   * total bilirubin (except for Gilbert's Syndrome) \</= 1.5xULN
   * ALT and AST \</= 3xULN
   * creatinine \</= 2.5 xULN
9. Subject is practicing an acceptable method of contraception (documented in CRF).Female subjects (or female partners of male subjects) must either be of non childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal \> 1 year), or of childbearing potential and use 1 of the following highly effective methods of contraception (i.e., Pearl Index \< 1.0%) from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:

   * Complete abstinence from intercourse;
   * Intrauterine device (IUD);
   * Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);
   * Male partner is sterile prior to entry into the study and is the only partner of the female;
   * Systemic contraceptives (combined or progesterone only).

Exclusion criteria:

1. Subjects with a diagnosis of acute promyelocytic leukemia.
2. Patients with short life expectancy (less than 3 months)
3. Patients with bone marrow fibrosis that does not allow bone marrow aspiration (so-called "dry tap") or fibrosis grade II or III (grading according to European consensus on grading bone marrow fibrosis.
4. History of treatment for cancer other than MDS or sAML/MDS with systemic chemotherapy and/or radiotherapy within the last 2 years.
5. Patients with clinically significant splenomegaly, or \> 16 cm spleen in length measured by ultrasound
6. Patients with known liver cirrhosis
7. Patients with East Asian ancestry such as Chinese, Japanese, Taiwanese or Korean.
8. History of treatment with romiplostim or other TPO-R agonists.
9. subjects with a QTc \> 450 msec (QTc \> 480 msec for subjects with Bundle Branch Block).
10. Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
11. Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin \[B-hCG\] pregnancy test) at screening or pre-dose on Day 1.
12. Current alcohol or drug abuse.
13. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
14. Active and uncontrolled infections.
15. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
D: Inclusion Criteria:

* Age 16 years or more
* Confirmed diagnosis of MYH9-related disease
* Average platelet count for the previous year less than 50x10e9/L
* Written informed consent

Exclusion Criteria:

* Diseases known to involve the risk of thromboembolic events (e.g. atrial fibrillation)
* History of thrombosis within 1 year
* Use of drugs that affect platelet function (including but not limited to, aspirin, clopidogrel or NSAIDS) or anti-coagulants
* Females who are pregnant or nursing (a negative pregnancy test in required before enrollment of fertile women)
* Formal refusal of any recommendation of a safe contraception
* Alcohol or drug addiction
* Altered renal function as defined by creatinine of 20 mg/L or more
* Any other disease or condition that by the advise of the responsible physician would make the treatment dangerous for the patient or would make the patient ineligible for the study, including physical, psychiatric, social and behavioral problems. HCV positivity and liver diseases will not be considered an exclusion criterion since a phase II study showed that eltrombopag was effective and safe in this patient population.

Answer: C