Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Pilot Study of a Thrombopoietin-Receptor Agonist (TPO-R Agonist), Eltrombopag, in Aplastic Anemia Patients With Immunosuppressive-Therapy Refractory Thrombocytopenia
Brief Summary: Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe cytopenias, requiring regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications.

Thrombopoietin (TPO) is the principal endogenous regulator of platelet production and also stimulates hematopoietic stem and progenitor cells. A small molecule oral TPO-agonist, eltrombopag has been shown to increase platelets in healthy subjects and in patients with immune thrombocytopenic purpura (ITP), and received FDA approval in 2008 for the treatment of thrombocytopenia in ITP. This Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia will test the safety and potential efficacy of eltrombopag treatment patients with refractory thrombocytopenia following immunosuppression for aplastic anemia.

Subjects will initiate study medication at an oral dose of 50 mg/day, which will be increased up to 150 mg/day as clinically indicated to the lowest dose that maintains a stable platelet count 20,000/(micro)L above baseline while maximizing tolerability. Response will be assessed at 3-4 months. Platelet response is defined as platelet count increases to 20,000/L above baseline at three months. or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive weeks compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater than 0.5 times 10(9)/L. Subjects with response at 3-4 months may continue study medication (extended access) until they meet an off study criteria. The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia. Secondary objectives include the analysis of the incidence and severity of bleeding episodes, and the impact on quality of life.


Options:
A: Inclusion Criteria:

1. Age ≥ 18
2. Able to give written informed consent for a clinical trial
3. Scheduled to undergo an autologous or an allogeneic stem cell transplantation from a sibling, related donor, or unrelated donor using a conditioning regimen containing at least 400 cGy TBI
4. Transplantation is being performed for one of the following medical conditions:

   * Acute myelogenous leukemia
   * Acute lymphoblastic leukemia
   * Chronic myelogenous leukemia in chronic, accelerated, or blastic phase
   * Myelodysplastic syndrome
   * Myeloproliferative diseases such as chronic myelomonocytic leukemia, agnogeneic myeloid metaplasia with myelofibrosis, polycythemia vera, or essential thrombocythemia
   * Hodgkin's lymphoma
   * Non-Hodgkin's lymphoma
   * Multiple myeloma
   * Chronic lymphocytic leukemia
   * Other malignancies or marrow disease such as aplastic anemia where transplant would be appropriate with approval of principal investigator
5. Patients with therapy-related AML or MDS may be included if their prior malignancy has been in remission for at least 12 months. If the remission is less than 12 months, approval of the principal investigator is required. Entry could be allowed if the malignancy is controlled and not expected to relapse e.g. localized prostate cancer treated with XRT.
6. Patients must meet all other pre-transplantation criteria of the transplant center including acceptable tests of heart, liver, kidney, and lung function (Standard screening for HSCT per PI, and co-investigators).
7. Karnofsky performance status must be ≥70%.

Exclusion Criteria:

1. TBI dose less than 400 cGY
2. Cord blood transplantation
3. HIV infection
4. Pregnancy or breastfeeding
5. Creatinine or bilirubin or ALT or AST greater than two times the upper limit of normal, unless the abnormal bilirubin is due to Gilbert's syndrome
6. Active infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents
7. Concomitant enrollment in another therapeutic clinical study except with PI approval
8. Must not have previously received eltrombopag
9. Patients with moderate or severe liver disease (ALT, AST, or bilirubin ≥ 2X the upper limit of normal, unless the abnormal bilirubin is due to Gilbert's syndrome) will be excluded
10. Patients with high risk of thromboembolism based on genetic syndromes , or past thromboembolic disease in the past 6 months will be excluded from the study, with the exception of those with catheter related clots
B: Inclusion Criteria:

1. Healthy subjects with no clinically significant abnormality identified by physician by evaluation of medical history, physical examination, clinical laboratory tests or electrocardiogram (ECG).
2. Male and female subjects between the ages of 18 to 64 years of age inclusive, at the time of signing the informed consent.
3. Subject is able to understand and comply with the protocol requirements, instructions and restrictions.
4. Capable of giving written informed consent which includes compliance with the requirements and restrictions listed in the consent form.
5. Body weight ≥ 50kg (110 lbs) for men and ≥ 45 kg (99 lbs) for women and body mass index (BMI) of 18.5 to 29.9 kg/m2 inclusive.
6. A platelet count within normal range and not \> 400,000 plt/uL.
7. Male subjects, who are not surgically sterile, must agree on abstinence or to use a double barrier method, such as, a condom plus spermicidal agent (foam/gel/film/cream/suppository). This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of medication.
8. A female subject is eligible to participate if she is neither pregnant nor lactating, and falls into one of the following categories:

   * non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or bilateral oophorectomy, or post-menopausal females defined as being amenorrheic for greater than one year and having serum estradiol and follicle stimulating hormone levels consistent with menopause.
   * child-bearing potential with negative beta human chorionic gonadotropin (beta/hCG) test and agrees to comply with recognized non-hormonal contraceptive methods from screening or at least two weeks prior to first dose (whichever is earlier) until the follow-up visit. Recognized non-hormonal contraceptive methods include: complete abstinence from intercourse, male partner sterilization, two forms of barrier contraception (e.g. condom and occlusive cap (diaphragm or cervical/vault caps with spermicide), or intrauterine device (IUD), or intrauterine system (IUS) with a \< 1% failure rate stated in the product label.

Exclusion Criteria:

1. History of Gilbert's syndrome.
2. Any previous history of deep vein thrombosis or any other thromboembolic event.
3. History of thrombocytopenia or bleeding due to abnormal platelet number or function.
4. Clotting factor abnormalities associated with hypercoagulability, specifically Factor V Leiden, Protein C or Protein S deficiency or antithrombin III deficiency.
5. Elevated blood pressure (BP) at screening (systolic \> 140 mm Hg, diastolic \> 85 mm Hg). If the subject's BP is elevated on the first measurement, complete two additional BP measurements two minutes apart and average the three assessments to evaluate this criteria. If averaged BP exceeds the safety criteria, the subject should be excluded.
6. History of atrial fibrillation, mitral valve prolapse, significant heart murmur or vascular bruit.
7. Prolonged QTc interval (Bazett's) at screening (for females \> 450 msec and for males \> 430 msec). If the QTc interval is prolonged on the initial ECG, then complete two additional ECGs 5 minutes apart and take the average QTc measurements of all three ECGs to evaluate this criteria. If averaged QTc exceeds the safety criteria, the subject should be excluded.
8. Female subjects currently receiving hormone replacement therapy (HRT).
9. Positive for HIV, hepatitis B virus or hepatitis C virus assays at screening.
10. Positive urine drug screen including alcohol at screening or pre-dose (Day -1).
11. History of alcohol/drug abuse or dependence within 12 months of the study.
12. History of alcohol consumption in the past six months exceeding 7 units/week for women and 14 units/week for men (where 1 unit = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor).
13. Urinary cotinine levels indicative of smoking at screening or pre-dose (Day -1). History of regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
14. Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication.
15. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
16. Use of prescription or non-prescription drugs (including aspirin and non-steroidal anti-inflammatory drugs \[NSAIDs\]), vitamins, herbal and dietary supplements within seven days (or 14 days if the drug is a potential enzyme inducer, such as St. John's Wort) or five half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.
17. Subjects who have donated plasma within seven days prior to the screening visit or where participation in this study would result in donation of blood in excess of 500 mL within a 56-day period.
18. History of sensitivity to any of the study medications, or components thereof.
C: Inclusion Criteria:

In order to be eligible for study entry, subjects must comply with the following:

* Males from 3 months old to 80 years old
* Signed written informed consent obtained prior to study entry
* Clinical diagnosis of WAS or XLT
* Platelet levels less than 100 x 109/L
* Adequate renal and hepatic function (creatinine and bilirubin less than or equal to 1.5 x IULN, AST and ALT less than or equal to 2.5 x IULN)

Exclusion Criteria:

Any patient is ineligible for study entry if he/she:

* Over the age of 80
* Women (only males are eligible)
* fertile men who are not practicing or who are unwilling to practice birth control while enrolled in the study or until at least 6 months after treatment
* Aspirin, aspirin-containing compounds, salicylates, non-steroidal anti-inflammatory medications (NSAIDS), clopidogrel or ticlopidine, warfarin or other vitamin K antagonists, unfractionated or low molecular heparin within 7 days of first infusion
* Red blood cell transfusion in the past four weeks
* Elevated (\> 1.5 x ULN) prothrombin time (PT) or partial thromboplastin time (PTT)
* New York Heart Classification III or IV heart disease. Other severe cardiovascular or cardiopulmonary disease, including COPD.
* Known HIV infection, hepatitis B or C infection
* Any infection requiring antibiotic treatment within 3 days
* Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
* Prior malignancy with less than a 5-year disease-free interval, excluding nonmelanoma skin cancers and carcinoma in situ of the cervix
D: * 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.

Answer: D