SB-497115 (Oral Thrombopoietin Receptor Agonist) Versus Placebo In Adult Cancer Patients Receiving Chemotherapy

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

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.

Study Overview

• Status: Completed
• Conditions: Thrombocytopaenia
• Intervention / Treatment: Drug: SB497115; Other: Placebo

Detailed Description

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 (SB-497115-GR) Administered at 50, 75, and 100 mg to Cancer Patients Receiving Multiple Cycles of Chemotherapy

• Study Type: Interventional
• Enrollment (Actual): 183
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • GSK Investigational Site
  • Buenos Aires, Argentina, C1416DRW
    • GSK Investigational Site
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, C1405BCK
      • GSK Investigational Site
    • La Plata, Buenos Aires, Argentina, 1900
      • GSK Investigational Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • GSK Investigational Site
    • Rosario, Santa Fe, Argentina, S2000KZE
      • GSK Investigational Site
• Austria
  • Vienna, Austria, A-1090
    • GSK Investigational Site
  • Vienna, Austria, A-1100
    • GSK Investigational Site
  • Vienna, Austria, A-1140
    • GSK Investigational Site
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • GSK Investigational Site
  • Sofia, Bulgaria, 1527
    • GSK Investigational Site
  • Sofia, Bulgaria, 1756
    • GSK Investigational Site
  • Sofia, Bulgaria, 1784
    • GSK Investigational Site
• Czech Republic
  • Brno, Czech Republic, 656 53
    • GSK Investigational Site
  • Praha 8, Czech Republic, 180 81
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 13353
    • GSK Investigational Site
  • Hamburg, Germany, 21075
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • GSK Investigational Site
  • Bayern
    • Regensburg, Bayern, Germany, 93049
      • GSK Investigational Site
  • Hessen
    • Marburg, Hessen, Germany, 35033
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Hemer, Nordrhein-Westfalen, Germany, 58675
      • GSK Investigational Site
  • Rheinland-Pfalz
    • Trier, Rheinland-Pfalz, Germany, 54290
      • GSK Investigational Site
  • Schleswig-Holstein
    • Grosshansdorf, Schleswig-Holstein, Germany, 22927
      • GSK Investigational Site
  • Thueringen
    • Bad Berka, Thueringen, Germany, 99437
      • GSK Investigational Site
• Hungary
  • Budapest, Hungary, 1529
    • GSK Investigational Site
  • Székesfehérvár, Hungary, 8000
    • GSK Investigational Site
• India
  • Bangalore, India, 560 034
    • GSK Investigational Site
  • Hyderabad, Andhra Pradesh, India, 500482
    • GSK Investigational Site
  • Kolkatta, India, 700 054
    • GSK Investigational Site
  • Vellore, India, 632 004
    • GSK Investigational Site
• Italy
  • Campania
    • Benevento, Campania, Italy, 82100
      • GSK Investigational Site
  • Lazio
    • Roma, Lazio, Italy, 00168
      • GSK Investigational Site
  • Lombardia
    • Milano, Lombardia, Italy, 20141
      • GSK Investigational Site
  • Molise
    • Campobasso, Molise, Italy, 86100
      • GSK Investigational Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 135-710
    • GSK Investigational Site
• Mexico
  • Yucatán
    • Merida, Yucatán, Mexico, 97500
      • GSK Investigational Site
• Peru
  • Lima, Peru, Lima 34
    • GSK Investigational Site
• Poland
  • Olsztyn, Poland, 10-228
    • GSK Investigational Site
  • Poznan, Poland, 60-569
    • GSK Investigational Site
  • Poznan, Poland, 61-866
    • GSK Investigational Site
  • Szczecin, Poland, 70-891
    • GSK Investigational Site
  • Wroclaw, Poland, 53-413
    • GSK Investigational Site
• Romania
  • Bucuresti, Romania, 022328
    • GSK Investigational Site
• Russian Federation
  • Moscow, Russian Federation, 117997
    • GSK Investigational Site
  • Moscow, Russian Federation, 115 478
    • GSK Investigational Site
  • Moscow, Russian Federation, 129301
    • GSK Investigational Site
  • Moscow Region, Russian Federation, 143 423
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 198255
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 197758
    • GSK Investigational Site
• Spain
  • Badalona, Spain, 08916
    • GSK Investigational Site
  • Barcelona, Spain, 08036
    • GSK Investigational Site
  • Cordoba, Spain, 14004
    • GSK Investigational Site
  • Madrid, Spain, 28006
    • GSK Investigational Site
  • Santa Cruz de Tenerife, Spain, 38320
    • GSK Investigational Site
  • Santander, Spain, 38008
    • GSK Investigational Site
  • Sevilla, Spain, 41014
    • GSK Investigational Site
• Taiwan
  • Taipei, Taiwan, 100
    • GSK Investigational Site
  • Tau-Yuan County, Taiwan, 333
    • GSK Investigational Site
• Ukraine
  • Dnepropetrovsk, Ukraine, 49102
    • GSK Investigational Site
  • Donetsk, Ukraine, 83092
    • GSK Investigational Site
  • Kyiv, Ukraine, 03115
    • GSK Investigational Site
  • Lvov, Ukraine, 79031
    • GSK Investigational Site
• United Kingdom
  • Colchester, United Kingdom, CO3 3NB
    • GSK Investigational Site
  • Dundee, United Kingdom, DD1 9SY
    • GSK Investigational Site
  • Leicester, United Kingdom, LE1 5WW
    • GSK Investigational Site
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR1 3LJ
      • GSK Investigational Site
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 7ET
      • GSK Investigational Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85715
      • GSK Investigational Site
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • GSK Investigational Site
  • California
    • Greenbrae, California, United States, 94904-2007
      • GSK Investigational Site
    • Long Beach, California, United States, 90813
      • GSK Investigational Site
    • Los Angeles, California, United States, 90095
      • GSK Investigational Site
    • Los Angeles, California, United States, 90033
      • GSK Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • GSK Investigational Site
  • Delaware
    • Newark, Delaware, United States, 19718
      • GSK Investigational Site
  • Florida
    • Boca Raton, Florida, United States, 33428
      • GSK Investigational Site
    • Hollywood, Florida, United States, 33021
      • GSK Investigational Site
    • Tamarac, Florida, United States, 33321
      • GSK Investigational Site
  • Georgia
    • Savannah, Georgia, United States, 31405
      • GSK Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21237-3998
      • GSK Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • GSK Investigational Site
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • GSK Investigational Site
    • Tupelo, Mississippi, United States, 38801
      • GSK Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • GSK Investigational Site
  • New York
    • Babylon, New York, United States, 11702
      • GSK Investigational Site
    • New York, New York, United States, 10032
      • GSK Investigational Site
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • GSK Investigational Site
  • Ohio
    • Akron, Ohio, United States, 44304
      • GSK Investigational Site
    • Mayfield Heights, Ohio, United States, 44124
      • GSK Investigational Site
    • Toledo, Ohio, United States, 43614-5809
      • GSK Investigational Site
  • Texas
    • Bryan, Texas, United States, 77802
      • GSK Investigational Site
  • Utah
    • Ogden, Utah, United States, 84403
      • GSK Investigational Site
  • Virginia
    • Salem, Virginia, United States, 24153
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; SB-497115-GR 50mg. administered orally daily on days 2 through 11 for each 21-day cycle.	Drug: SB497115; SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Active Comparator: Arm 2; SB-497115-GR 75 mg administered orally dailey on days 2-11 of each 21-day cycle.	Drug: SB497115; SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Active Comparator: Arm 3; SB-497115 100mg administered orally daily on days 2 through 11 of each 21-day cycle.	Drug: SB497115; SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Placebo Comparator: Placebo Arm; Placebo administered orally daily on days 2 through 11 of each 21-day cycle.	Other: Placebo; Placebo administered orally daily on days 2 through 11 of each 21-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in baseline platelet count from the first day of the second cycle of chemotherapy to the lowest count observed (nadir) during the cycle(21 days)	throughout entire study

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability, pharmacodynamics, changes in platelet count during cycle 1(21 days) and beyond cycle 2(21 days), population PK, and deliver intended doses of chemotherapy without thrombocytopenia related AEs	Throughout entire study
Safety and tolerability as indicated by physical exam, 12-lead ECGs, ophthalmologic examinations, clinical laboratory tests, clinical monitoring/observation, and AE reporting	throughout study
Pharmacodynamic parameters including platelet count, grade of thrombocytopenia,serum thrombopoietin, and platelet aggregation/activation during the first and second cycles of carboplatin/paclitaxel	During first and second cycles of carboplatin/paclitaxel
Change in platelet count from day 1 (baseline) to nadir during the first cycle and beyond the second cycle of carboplatin/paclitaxel	throughout study
Population PK of SB-497115, including clearance (CL/F), absorption rate constant(ka), and volume of distribution (V/F) with assessment of demographic covariates influencing SB-497115 PK	throughout study
The relationship between PK of SB-497115 andrelevant safety and efficacy endpoints will be explored	throughout study
Dose intensity (percent of intended dose) of carboplatin/paclitaxel
Carboplatin/paclitaxel-associated thrombocytopenia-related AEs, as defined by NCI
Common Terminology Criteria for Adverse Events, CTCAE v3.0, to include the number of platelet transfusions, bleeding events (hematoma), hemorrhage/bleeding,petechiae/purpura), clinical laboratory tests, and clinical observations	throughout study

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Hayes S, Mudd PN Jr, Ouellet D, Johnson BM, Williams D, Gibiansky E. Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia. Cancer Chemother Pharmacol. 2013 Jun;71(6):1507-20. doi: 10.1007/s00280-013-2150-9. Epub 2013 Apr 6.
• Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010 Oct;26(10):2339-46. doi: 10.1185/03007995.2010.510051.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): February 1, 2007

Study Registration Dates

• First Submitted: February 1, 2005
• First Submitted That Met QC Criteria: February 1, 2005
• First Posted (Estimate): February 2, 2005

Study Record Updates

• Last Update Posted (Actual): March 23, 2017
• Last Update Submitted That Met QC Criteria: March 21, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: chemotherapy; platelets; thrombopoietin; chemotherapy induced
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Thrombocytopenia
• Other Study ID Numbers: 497115/003