Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag

NCT01147809 | Completed Phase 2 Results

• 1 other identifier: 112765
• Study Type: interventional
• Target: 130
• Locations: 13 countries
• Sites: 86

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.

Conditions

Thrombocytopaenia

Keywords

Solid Tumor; Eltrombopag; chemotherapy-induced thrombocytopenia; Thrombocytopenia

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE): Pre-therapy, On-therapy + 30 Days and Post-therapy in Phase I

  AEs are coded using the standard Medical Dictionary for Regulatory Activities (MedDRA) and were graded by the investigator according to National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE), version 4.0. AE is any untoward medical occurrence temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a MP. For marketed MPs, this also includes failure to produce expected benefits, abuse, or misuse. SAE event is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or, is a congenital anomaly/birth defect.

  From Cycle 1, Day 1 (C1D1) until at least 30 days post-investigational product discontinuation (longer for AEs considered related to study participation)

• Number of Participants With Indicated Maximum Toxicity Grades for the Indicated Hematology Parameters, at Anytime Post-Baseline in Phase I

  Hematology parameters with a related NCI CTCAE (version 4.0) toxicity grading were summarized by toxicity grade at each scheduled assessment, the maximum toxicity grade reached by a participant post-Baseline was summarized. Hematology parameters included hemoglobin (increased), hemoglobin (anemia), lymphocytes (increased), lymphocytes (decreased), total absolute neutrophil count (ANC), platelets (PLT) and white blood cells (WBC). The Baseline value is defined as the value reported immediately prior to the administration of the first dose of chemotherapy in Cycle 1. Post-Baseline is defined as any time after the first dose of chemotherapy in Cycle 1 up to and including all follow-up visits. Only those participant available at the indicated time points were analyzed (represented by n=X,X,X,X in the category titles).

  After Baseline (C1D1), on-treatment and 30 day follow-up

• Number of Participants With Indicated Maximum Toxicity Grades for the Indicated Clinical Chemistry Laboratory Parameters, at Anytime Post-Baseline in Phase I

  Clinical chemistry laboratory parameters with a related NCI CTCAE (version 4.0) toxicity grading were summarized by toxicity grade at each scheduled assessment. Clinical chemistry laboratory parameters included albumin (Alb), urea/blood urea nitrogen (BUN), creatinine, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), direct bilirubin (DB) and international normalized ratio/Prothrombin time (PT). The Baseline value is defined as the value reported immediately prior to the administration of the first dose of chemotherapy in Cycle 1. Post-Baseline is defined as any time after the first dose of chemotherapy in Cycle 1 up to and including all follow-up visits. Only those participants available at the indicated time points were analyzed (represented by n=X,X,X,X in the category titles).

  After Baseline (C1D1), on-treatment and 30 day follow-up

• Number of Participants With a Change From Baseline in Creatinine of >=26.5 Micromoles/Liter (UMOL/L) in Phase I

  The number of participants with at least 1 change from Baseline in creatinine, with an increase \>=26.5 UMOL/L are reported. Creatinine clearance is estimated using the Cockcroft-Gault formula which is a method to approximate kidney function. The Baseline value is defined as the value reported immediately prior to the administration of the first dose of chemotherapy in Cycle 1.

  After Baseline (C1D1), on-treatment and 30 day follow-up

• Number of the Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Scores at the Indicated Time Points in Phase I

  ECOG-Zubrod scores for the performance status are defined as follows: Score 0: Fully active, 1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2: ambulatory and capable of all self-care but unable to carry out any work activities, 3: capable of only limited self-care, 4: completely disabled, 5: dead. The data is presented for the participants with the ECOG performance score at the indicated time points during the study.

  Screening, C1D1, C2D1, C2D8, C2D15, C3D1, C4D1, C4D22, C5D1, C5D8, C6D1, C6D15

• Number of Participants With Electrocardiogram (ECG) Findings at Anytime Post-Baseline in Phase I

  A single safety 12-lead ECG was performed using a standard 12-lead ECG machine at screening and post-dose on C2D4. Three further ECGs were carried out at C2D8, C5D8 and C6D15. Change in ECG findings were categorized as 'Clinically significant change: favorable', 'No change or insignificant change' or 'Clinically significant change (CSC): unfavorable' as determined by the investigator. The Baseline value is defined as the value reported immediately prior to the administration of the first dose of chemotherapy in Cycle 1. Any time post-Baseline is defined by counting the participants under the worst result experienced post-Baseline. The best to worst order is 'Clinically significant change: favorable', 'No change or insignificant change', and then 'Clinically significant change (CSC): unfavorable. Only those participants available at the indicated time points were analyzed (represented by n=X,X,X,X in the category titles).

  C2D4, C2D8, C5D8, C6D15

• Mean Day 1 Scheduled Pre-chemotherapy Platelet Count Evaluated Across Cycles 1 to 6 in Phase II

  Scheduled pre-chemotherapy platelet count is defined within each cycle as the platelet count assessment on which the decision to give or delay chemotherapy was made. This was averaged for each participant across Cycles 1 to 6 and a natural log transformation was applied to the average. The log-transformed values were compared between eltrombopag and placebo groups using an analysis of covariance (ANCOVA) model adjusting for cycle duration (21-day vs. 28-day), Baseline loge(platelet count) and part of study (part 1 or 2 of phase II). Only those participants available at indicated time points were analyzed (represented by n=X,X).

  Day 1 (averaged across cycles 1 to 6)

Secondary Outcomes (30)

• Average Pre-chemotherapy Platelet Count at the Indicated Time Points in Phase I

  C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, C3D8, C3D15, C4D1,C4D8, C4D15, C5D1,C5D8, C5D15, C6D1,C6D8 and C6D15

• Average Within-subject Central Laboratory Platelet Count Prior to Scheduled Chemotherapy Across Cycles 2 to 6 in Phase I

  Day 1 (averaged across Cycles 2 to 6), Day 8 (averaged across Cycles 2 to 6)

• Platelet Count Nadir for Each Chemotherapy Cycle in Phase I

  Cycle 1 to Cycle 6

• Central Laboratory Average Daily Area Under the Curve Platelet-time Course Across Cycles 2 to 6 in Phase I

  All assessments from Cycle 2 Day 1 to last assessment in Cycle 6

• Number of Participants With Thrombocytopenia of Grade 1, 2, 3 or 4 Across All the Chemotherapy Cycles in Phase I, Using Central Laboratory Platelet Count

  Cycle 1 to Cycle 6

Study Arms (2)

Eltrombopag

ACTIVE COMPARATOR

Drug: eltrombopag olamine thrombopoietin receptor agonist

Drug: Eltrombopag olamine

Placebo

PLACEBO COMPARATOR

Other: Placebo Placebo tablets with no active pharmaceutical ingredient

Other: Placebo

Interventions

Eltrombopag olamine DRUG

thrombopoietin receptor agonist

Eltrombopag

Placebo OTHER

Placebo tablets with no active pharmaceutical ingredient

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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
• Platelet count \< 100 Gi/L at Day 8 in the preceding cycle before entry into the study, OR
• 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..
• Adequate organ function during screening period defined by the criteria below (adequate baseline organ function):
• SYSTEM LABORATORY VALUES
• Hematologic

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (86)

GSK Investigational Site

Sedona, Arizona, 86336, United States

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GSK Investigational Site

Hot Springs, Arkansas, 71913, United States

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GSK Investigational Site

Rancho Cucamonga, California, 91730, United States

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GSK Investigational Site

Norwich, Connecticut, 06360, United States

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GSK Investigational Site

Jacksonville, Florida, 32256, United States

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GSK Investigational Site

New Port Richey, Florida, 34655, United States

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GSK Investigational Site

Rome, Georgia, 30165, United States

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GSK Investigational Site

Savannah, Georgia, 31405, United States

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GSK Investigational Site

Wichita, Kansas, 67214, United States

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GSK Investigational Site

Bethesda, Maryland, 20817, United States

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GSK Investigational Site

Rockville, Maryland, 20850, United States

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GSK Investigational Site

Columbia, Missouri, 65201, United States

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GSK Investigational Site

Las Vegas, Nevada, 89169, United States

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GSK Investigational Site

Cherry Hill, New Jersey, 08003, United States

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GSK Investigational Site

Albany, New York, 12206, United States

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GSK Investigational Site

Greensboro, North Carolina, 27403, United States

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GSK Investigational Site

Bend, Oregon, 97701, United States

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GSK Investigational Site

Philadelphia, Pennsylvania, 19106, United States

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GSK Investigational Site

Wynnewood, Pennsylvania, 19096, United States

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GSK Investigational Site

Providence, Rhode Island, 02903, United States

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GSK Investigational Site

Providence, Rhode Island, 02906, United States

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GSK Investigational Site

Greenville, South Carolina, 29605, United States

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GSK Investigational Site

Arlington, Texas, 76014, United States

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GSK Investigational Site

Austin, Texas, 78731, United States

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GSK Investigational Site

Bedford, Texas, 76022, United States

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GSK Investigational Site

Dallas, Texas, 75246, United States

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GSK Investigational Site

San Antonio, Texas, 78217, United States

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GSK Investigational Site

Tyler, Texas, 75702, United States

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GSK Investigational Site

Norfolk, Virginia, 23502, United States

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GSK Investigational Site

Edmonds, Washington, 98026, United States

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GSK Investigational Site

Tacoma, Washington, 98405, United States

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GSK Investigational Site

Vancouver, Washington, 98684, United States

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GSK Investigational Site

Yakima, Washington, 98902, United States

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GSK Investigational Site

Charleroi, 6000, Belgium

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GSK Investigational Site

Leuven, 3000, Belgium

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GSK Investigational Site

Libramont, 6800, Belgium

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GSK Investigational Site

Namur, 5000, Belgium

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GSK Investigational Site

Edmonton, Alberta, T6G 1Z2, Canada

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GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

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GSK Investigational Site

Olomouc, 775 20, Czechia

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GSK Investigational Site

Prague, 100 00, Czechia

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GSK Investigational Site

Prague, 150 06, Czechia

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GSK Investigational Site

Helsinki, 00290, Finland

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GSK Investigational Site

Tampere, 33520, Finland

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GSK Investigational Site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

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GSK Investigational Site

Augsburg, Bavaria, 86150, Germany

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GSK Investigational Site

Munich, Bavaria, 80335, Germany

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GSK Investigational Site

Munich, Bavaria, 81241, Germany

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GSK Investigational Site

Goslar, Lower Saxony, 38642, Germany

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GSK Investigational Site

Hanover, Lower Saxony, 30171, Germany

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GSK Investigational Site

Essen, North Rhine-Westphalia, 45122, Germany

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GSK Investigational Site

Dresden, Saxony, 01127, Germany

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GSK Investigational Site

Dresden, Saxony, 01307, Germany

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GSK Investigational Site

Berlin, State of Berlin, 10367, Germany

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GSK Investigational Site

Berlin, State of Berlin, 14169, Germany

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GSK Investigational Site

Athens, 115 27, Greece

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GSK Investigational Site

Athens, 115 28, Greece

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GSK Investigational Site

Heraklion, Crete, 71100, Greece

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GSK Investigational Site

Thessaloniki, 564 29, Greece

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GSK Investigational Site

Budapest, 1529, Hungary

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GSK Investigational Site

Győr, 9022, Hungary

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GSK Investigational Site

Kaposvár, 7400, Hungary

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GSK Investigational Site

Törökbálint, Hungary

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GSK Investigational Site

Zalaegerszeg, 8900, Hungary

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GSK Investigational Site

Madurai, 625107, India

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GSK Investigational Site

Pune, 411001, India

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GSK Investigational Site

Pune, 411004, India

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GSK Investigational Site

Dublin, 4, Ireland

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GSK Investigational Site

Dublin, 7, Ireland

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GSK Investigational Site

Tallaght, Dublin, 24, Ireland

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GSK Investigational Site

Ashkelon, 78306, Israel

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GSK Investigational Site

Haifa, 34362, Israel

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GSK Investigational Site

Jerusalem, 91031, Israel

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GSK Investigational Site

Kfar Saba, 44281, Israel

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GSK Investigational Site

Tel Aviv, 64239, Israel

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GSK Investigational Site

Zrifin, 70300, Israel

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GSK Investigational Site

Modena, Emilia-Romagna, 41100, Italy

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GSK Investigational Site

Aviano (PN), Friuli Venezia Giulia, 33081, Italy

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GSK Investigational Site

Milan, Lombardy, 20133, Italy

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GSK Investigational Site

Sassari, Sardinia, 07100, Italy

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GSK Investigational Site

Pisa, Tuscany, 56126, Italy

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GSK Investigational Site

Bialystok, 15-540, Poland

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GSK Investigational Site

Konin, 62-500, Poland

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GSK Investigational Site

Olsztyn, 10-357, Poland

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GSK Investigational Site

Poznan, 60-569, Poland

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GSK Investigational Site

Poznan, 61-866, Poland

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Related Publications (1)

• Winer ES, Safran H, Karaszewska B, Richards DA, Hartner L, Forget F, Ramlau R, Kumar K, Mayer B, Johnson BM, Messam CA, Mostafa Kamel Y. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015 Jan;4(1):16-26. doi: 10.1002/cam4.326. Epub 2014 Aug 28.

  PMID: 25165041 DERIVED

MeSH Terms

Conditions

Thrombocytopenia

Condition Hierarchy (Ancestors)

Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2010
• First Posted: June 22, 2010
• Study Start: June 1, 2010
• Primary Completion: January 1, 2015
• Study Completion: March 1, 2015
• Last Updated: April 18, 2016
• Results First Posted: April 18, 2016

Record last verified: 2016-03

Locations

IT (5); PL (5); IN (3); IE (3); DE (11); CZ (3); HU (5); FI (2); IL (6); US (33); BE (4); CA (2); GR (4)