Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-Blind, Randomized, Multicenter, Placebo-Controlled, Parallel Group, Dose Ranging Study to Assess the Efficacy, Safety, and Pharmacokinetics of an Oral Thrombopoietin Receptor Agonist(SB497115-GR) Administered at 50, 75, and 100 mg to Cancer Patients Receiving Multiple Cycles of Chemotherapy
Brief Summary: SB497115 is an oral agent which activates the thrombopoietin receptor and increases platelet counts in healthy volunteers. This study is examining several different doses of SB497115 versus placebo as treatment for patients with advanced solid tumors scheduled to receive chemotherapy with carboplatin and paclitaxel every 21 days. Patients will receive SB497115 on days 2-11 of each 21 day cycle for at least 2 cycles of chemotherapy and for a maximum of 8 cycles of chemotherapy.


Options:
A: 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
B: Inclusion Criteria:

* Has, or is expected to have, hypoproliferative thrombocytopenia, and is expected to have a platelet count of up to 10,000 ul for at least 5 days and be in the hospital for at least 5 days
* Weight is between 10 and 135 kilograms
* PT/INR, PTT, and fibrinogen assays that are measured within 72 hours before study entry are as follows:

  1. PT less than or equal to 1.3 times the upper limit of normal for the laboratory
  2. PTT less than or equal to 1.3 times the upper limit of normal for the laboratory
  3. Fibrinogen greater than or equal to 100 mg/dl
* Undergoing, or has completed, hematopoietic stem cell transplantation, for any diagnosis; OR has a diagnosis of acute or chronic leukemia, non-Hodgkins or Hodgkins lymphoma, myeloma, myelodysplasia, or non-hematologic malignancy and is undergoing, or has completed, chemotherapy
* During this hospitalization, the patient has not yet received any platelet transfusions related to the current or planned course of therapy (individual platelet transfusions given prior to the study and unrelated to thrombocytopenia will not exclude the patient)

Exclusion Criteria:

* Evidence of greater than or equal to Grade 2 bleeding (as determined by the Platelet Dose Trial Bleeding Scale)
* Receiving antithrombotic drugs
* Will receive bedside leuko-reduced platelet transfusions
* Present, or history of, platelet transfusion refractoriness within 30 days prior to study entry
* Pre-enrollment lymphocytotoxic antibody screen (PRA) known to be greater than or equal to 20% based on prior data
* Present, or history of, acute promyelocytic leukemia (APML), immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or hemolytic-uremic syndrome (HUS)
* Will be transfused at platelet trigger of greater than 10,000 platelets/ul
* Recent history of major surgery (within 2 weeks of study entry)
* Currently taking, or participating in a study involving, platelet substitutes, platelet growth factors, or pharmacologic agents intended to enhance or decrease platelet hemostatic function
* Pregnant
* Previously enrolled in this study
C: 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
D: Inclusion criteria:

* Subjects ≥18 years old, who are chemotherapy naïve, with histologically or cytologically confirmed advanced solid tumor (leukemia and lymphoma are excluded) who are scheduled to received carboplatin/paclitaxel as shown below. For the purpose of this study, advanced tumors are defined as tumors that are being treated with palliative intent (i.e., not being treated with curative intent).
* Subjects scheduled to receive first-line chemotherapy as carboplatin AUC 5-6 IV over 30 minutes plus paclitaxel 175-225 mg/m2 IV over 3 hours on day 1 every 21 days, with routine pre-medications, i.e., 20 mg dexamethasone \[or equivalent\] orally 6 and 12 hours pre-paclitaxel, 50 mg IV diphenhydramine \[or equivalent\] and 300 mg IV cimetidine \[or equivalent\] 30-60 minutes pre-paclitaxel.
* ECOG-Zubrod performance status is 0, or 1.
* Subject has no history of platelet disorders or dysfunction and no history of a bleeding disorder.
* Subjects have adequate:

hematologic function (ANC ≥ 1,500/mm3, hemoglobin ≥ 9 g/dL, and platelet count ≥100,000/mm3 and \< upper limit of normal range (eg, 400,000 to 450,000/mm3), hepatic function (bilirubin ≤ 2 mg/dL and alanine aminotransferase ≤ three times the upper limit of normal), renal function (creatinine ≤ 2.0 mg/dL).

* Subject has no physical limitation to ingest and retain oral medication.
* Subject has life expectancy of at least 6 months.
* Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of nonchildbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal \> 1 year), or of childbearing potential and use one of the following acceptable methods of contraception from two 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).

* Subject is able to understand and comply with protocol requirements and instructions and intend to complete the study as planned.
* Subject has signed and dated written informed consent.
* Chemotherapy naive patients with advanced solid tumors (without brain metastasis or rapid progression within 2 weeks) who are scheduled to receive standard first-line therapy with carboplatin and paclitaxel every 21 days.
* Adequate hematologic, hepatic and renal function.

Exclusion criteria:

* Any clinically relevant abnormality, other than cancer, identified on the screening examination, or any other medical condition or circumstance, which in the opinion of the Investigator, makes the subject unsuitable for participation in the study and/or would make the patient's data difficult to interpret.
* Subjects with a known history of rapidly progressive disease (marked increase in tumor size \[\>50%\], ascites, or serious symptoms related to underlying cancer in the preceding 4-week period), surgery within the previous 2 weeks, radiotherapy within the previous 4 weeks, or any prior chemotherapy.
* Subjects with known pre-existing cardiac disease, including congestive heart failure, arrhythmias requiring treatment, or myocardial infarction within the preceding 3 months.
* Subjects with abnormal resting 12-lead ECG at screening that would indicate preexisting cardiac disease, as noted in exclusion criterion 3.
* Subjects with known clotting disorder associated with hypercoaguability.
* Subject has consumed aspirin, aspirin-containing compounds, salicylates, quinine or non-steroidal anti-inflammatories (NSAIDs) for \> 3 consecutive days within 2 weeks of the study start and would require them at any time during the study.
* Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
* Subject has consumed liquid antacids (e.g. Maalox, Mylanta, Amphogel, milk of magnesia), chewable antacids (e.g. TUMS) or calcium supplements within 48 hours of the first dose of study medication, and/or will require these medications during the study.
* Subject has consumed rosuvastatin or pravastatin within 1 week of the first dose of study medication and/or will require these medications at any time during the study.
* Any history of drug-induced thrombocytopenia (e.g., quinine).
* Systemic anti-coagulant use within 4 weeks prior to study entry.
* Consumption of any herbal or dietary supplements, excluding vitamin or mineral supplements (See Exclusion 8 for calcium supplements), within 1 week of the study start.
* Female subjects who are lactating or have a positive beta-hCG at screening.
* 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.
* History of platelet or bleeding disorders.
* Patients using aspirin, aspirin-containing compounds, salicylates, antacids, rosuvastatin, pravastatin, non-steroidal anti-inflammatory drugs for greater than 3 days during and within 3 weeks prior to the study.
* Females who are pregnant or breastfeeding.

Answer: D