Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag

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

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.

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.