Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag
Condition: Thrombocytopaenia
MeSH terms: Thrombocytopenia
Intervention: Eltrombopag olamine; Placebo
Intervention description: thrombopoietin receptor agonist; Placebo tablets with no active pharmaceutical ingredient
Phase: Phase 2
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Enrollment: 130.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Solid Tumor; Eltrombopag; chemotherapy-induced thrombocytopenia; Thrombocytopenia

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.
    

Eligibility criteria:

        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.