Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Blinded, Placebo-controlled, Two-Phase, Sequential Cohort, Dose Finding Study to Assess the Safety and Efficacy of an Oral Thrombopoietin Receptor Agonist, Eltrombopag (SB-497115-GR), Administered to Patients With Solid Tumors Receiving Gemcitabine Monotherapy or the Combination of Gemcitabine Plus Carboplatin or Cisplatin
Brief Summary: The present study is a randomized, blinded, placebo-controlled, two-Phase, sequential cohort, dose finding study to assess the safety and efficacy of eltrombopag in patients with solid tumors receiving gemcitabine monotherapy or the combination of gemcitabine plus carboplatin or cisplatin. Phase I of the study will examine safety and tolerability of various doses of eltrombopag to identify a dose and schedule of eltrombopag. Phase II will confirm that the chosen dose and schedule of eltrombopag from Phase I can deliver clinically meaningful benefit(s) to thrombocytopenic patients by improving platelet numbers.


Options:
A: Inclusion Criteria:

AML project

* inclusion in studies of the DSIL or OSHO group for AML
* AML M3/M3v can be included only when in complete remission
* age 16 - 80 years
* written informed consent

Autologous project

* AMl and ALL patients in first or second remission
* low grade or high grade non hodgkin lymphoma or morbus hodgkin or multiple myeloma
* conditioning regime: TBI 8-12 Gy/Cy 120 or BEAM or BU/CY or Melphalan 140-200mg/m2 or a similarly intensive chemotherapy regime
* age 16 - 65 years

Exclusion Criteria:

AML project

* known refractoriness to platelet transfusion
* known major bleeding with thrombocytopenia when the reason for bleeding is still ongoing
* known plasmatic coagulation disorder
* patient unable to give informed consent

Autologous project

* known refractoriness to platelet transfusion
* known major bleeding with thrombocytopenia when the reason for bleeding is still ongoing
* known plasmatic coagulation disorder
* patient unable to give informed consent
* patients with pulmonal or cerebral lesions due to infection or neoplasm
* patients with al-amyloidosis
B: Inclusion Criteria:Inclusion Criteria Subjects eligible for enrolment in Phase I and II of the study must meet all of the following criteria:

* Signed written informed consent.
* Age ≥ 18 years.
* Subjects with confirmed solid tumor and scheduled to receive at least two cycles of either gemcitabine monotherapy OR gemcitabine in combination with carboplatin or cisplatin at the same dosages and schedule in the study. Novel anticancer agents (e.g. bevacizumab, erlotinib) may be allowed if considered a standard treatment by the investigator. Subjects with only ONE current diagnosis of primary solid tumor will be allowed into the study.
* Note: For patients scheduled to receive any novel anticancer agents (e.g. bevacizumab, erlotinib), consultation and approval from the GSK medical monitor should occur before the subject is enrolled into the study.
* Life expectancy of at least 3 months, in the opinion of the investigator.
* ECOG-Zubrod performance status ≤ 2
* For Phase I: Pre-chemotherapy platelet count ≤ 300 Gi/L in the screening period before the subject start their first planned cycle of treatment with gemcitabine monotherapy OR gemcitabine in combination with carboplatin or cisplatin in the study.
* For Phase II (Part 1 and 2): Subjects must meet one of the following platelet count entry criteria:

  1. Subjects have not started the first cycle in this disease setting and have a platelet count \< 150 Gi/L in the screening period as measured within 3 days before Day -5, OR
  2. Subjects started chemotherapy for this disease setting and had platelet count \< 150 Gi/L on Day 1 in the preceding cycle before entry into the study, OR
  3. Platelet count \< 100 Gi/L at Day 8 in the preceding cycle before entry into the study, OR
  4. Platelet count \< 100 Gi/L at Day 15 in the preceding cycle before entry into the study (for subjects receiving Gemcitabine monotherapy) Note: For any of these platelet counts, a repeated platelet count may be allowed only once to ensure that the subject meets the above platelet count criteria and the latest count will be taken for the assessment of eligibility to the study..
* Subjects with previous chemotherapy treatment in a previous disease setting are allowed provided they have recovered from chemotherapy related toxicity except alopecia (and the lab parameters mentioned in Inclusion criteria in #9).
* Adequate organ function during screening period defined by the criteria below (adequate baseline organ function):
* SYSTEM LABORATORY VALUES
* Hematologic
* Platelets, see Inclusion criteria
* ANC (absolute neutrophil count) ≥1.5 × 109/L
* Hemoglobin ≥9 g/dL
* Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) Within 80 to 120% of the normal range
* Hepatic
* Albumin ≥2.5 g/dL
* Serum bilirubin ≤1.5 x ULN AST and ALT

  * 3 × ULN without liver metastases
  * 5 × ULN if documented liver metastases
* Renal
* Serum Creatinine ≤ 1.2 x ULN
* Subjects with AST, ALT or bilirubin values outside the range(s) in the table due to Gilbert's syndrome or asymptomatic gall stones are not excluded.
* Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to randomization and agree to use effective contraception, during the study and for 4 weeks following the last dose of investigational product.
* Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 2 weeks prior to randomization until 13 weeks after the last dose of study treatment.
* Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

* Lactating females.
* Pre-existing cardiovascular disease (congestive heart failure, New York Heart Association \[NYHA\] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), unstable angina, or subjects with a QTc \>450 msec (QTc \>480 msec for subjects with Bundle Branch Block) at study entry, or myocardial infarction within the preceding 6 months. Subjects with a34 pacemaker or defibrillator are not excluded provided that their cardiac function is within normal ranges.
* Note: For patients with pre-existing NYHA Grade II cardiovascular disease, the investigator should consult with GSK medical monitor before enrolling the subject into the study.
* Patients with known factor V leiden, antiphospholipid antibody syndrome, prothrombin gene mutations, ATIII deficiency, protein C deficiency, protein S deficiency OR recent history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism) within the preceding 6 months.
* Note: for patients with known risk factors for thromboembolism e.g., diabetes, hypercholesterolemia, recent major surgery etc., the investigator should consult with GSK medical monitor before enrolling the patient into the study and all risk factors should be documented in the CRF.
* Prior surgery within two weeks before study randomization or radiotherapy (RT) within four weeks before study randomization. Subjects with prior surgery or RT are not permitted into the study unless they have completely recovered from surgery and/or acute RT toxicity except for alopecia.
* Note: Note: patients with minor surgeries or outpatient procedures (e.g. insertion of central venous catheter) are immediately allowed in the study provided that there were no complications from the procedure or surgery.
* History of prior radiotherapy to more than 20% bone marrow bearing sites.
* History of platelet agglutination abnormality, platelet disorders or dysfunction or bleeding disorder that prevents reliable measurement of platelet counts.
* Subjects with a history of CNS metastases or clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan unless properly treated. Subjects with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to randomization will be excluded.
* Treated brain metastases are defined
* Having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed.
* Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician.

Note: if subject has performed a CT scan immediately prior to the screening period and CT could not be repeated, an MRI should be performed in the screening period to exclude the development of brain metastases and/or the progression of the pre-existing brain metastatic lesion(s).

* Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational product in the study. Concurrent participation in another interventional clinical trial or administration of any investigational drug during the study is also not permitted.
* A known immediate or delayed hypersensitivity reaction or idiosyncrasy that, in the opinion of the Investigator or GSK Medical Monitor is due to drugs chemically related to eltrombopag or excipients (e.g. mannitol).
* Subjects with known Hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV). Subjects with Gilbert's Syndrome are permitted into the study.
C: 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.
D: 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

Answer: B