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

Thrombocytopaenia Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00102726
• Other study ID #: 497115/003
• Status: Completed
• Phase: Phase 2
• First received: February 1, 2005
• Last updated: March 21, 2017
• Start date: February 2005
• Est. completion date: February 2007

Study information

• Verified date: March 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 183
• Est. completion date: February 2007
• Est. primary completion date: February 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Thrombocytopaenia
• Thrombocytopenia

Intervention

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.

Other:
• Placebo
Placebo administered orally daily on days 2 through 11 of each 21-day cycle.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Capital Federal	Buenos Aires
Argentina	GSK Investigational Site	La Plata	Buenos Aires
Argentina	GSK Investigational Site	Rosario	Santa Fe
Argentina	GSK Investigational Site	Rosario	Santa Fe
Austria	GSK Investigational Site	Vienna
Austria	GSK Investigational Site	Vienna
Austria	GSK Investigational Site	Vienna
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Czech Republic	GSK Investigational Site	Brno
Czech Republic	GSK Investigational Site	Praha 8
Germany	GSK Investigational Site	Bad Berka	Thueringen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hemer	Nordrhein-Westfalen
Germany	GSK Investigational Site	Marburg	Hessen
Germany	GSK Investigational Site	Regensburg	Bayern
Germany	GSK Investigational Site	Trier	Rheinland-Pfalz
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Székesfehérvár
India	GSK Investigational Site	Bangalore
India	GSK Investigational Site	Hyderabad, Andhra Pradesh
India	GSK Investigational Site	Kolkatta
India	GSK Investigational Site	Vellore
Italy	GSK Investigational Site	Benevento	Campania
Italy	GSK Investigational Site	Campobasso	Molise
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Roma	Lazio
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Mexico	GSK Investigational Site	Merida	Yucatán
Peru	GSK Investigational Site	Lima
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Szczecin
Poland	GSK Investigational Site	Wroclaw
Romania	GSK Investigational Site	Bucuresti
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow Region
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Cordoba
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Santa Cruz de Tenerife
Spain	GSK Investigational Site	Santander
Spain	GSK Investigational Site	Sevilla
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Tau-Yuan County
Ukraine	GSK Investigational Site	Dnepropetrovsk
Ukraine	GSK Investigational Site	Donetsk
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Lvov
United Kingdom	GSK Investigational Site	Chelmsford	Essex
United Kingdom	GSK Investigational Site	Colchester
United Kingdom	GSK Investigational Site	Dundee
United Kingdom	GSK Investigational Site	Leicester
United Kingdom	GSK Investigational Site	Truro	Cornwall
United States	GSK Investigational Site	Akron	Ohio
United States	GSK Investigational Site	Babylon	New York
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Boca Raton	Florida
United States	GSK Investigational Site	Bryan	Texas
United States	GSK Investigational Site	Colorado Springs	Colorado
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Greenbrae	California
United States	GSK Investigational Site	Hattiesburg	Mississippi
United States	GSK Investigational Site	Hollywood	Florida
United States	GSK Investigational Site	Jonesboro	Arkansas
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Mayfield Heights	Ohio
United States	GSK Investigational Site	Metairie	Louisiana
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newark	Delaware
United States	GSK Investigational Site	Ogden	Utah
United States	GSK Investigational Site	Salem	Virginia
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Tamarac	Florida
United States	GSK Investigational Site	Toledo	Ohio
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Tupelo	Mississippi

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Bulgaria,  Czech Republic,  Germany,  Hungary,  India,  Italy,  Korea, Republic of,  Mexico,  Peru,  Poland,  Romania,  Russian Federation,  Spain,  Taiwan,  Ukraine,  United Kingdom, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Safety and tolerability as indicated by physical exam, 12-lead ECGs, ophthalmologic examinations, clinical laboratory tests, clinical monitoring/observation, and AE reporting		throughout study
Secondary	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
Secondary	Change in platelet count from day 1 (baseline) to nadir during the first cycle and beyond the second cycle of carboplatin/paclitaxel		throughout study
Secondary	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
Secondary	The relationship between PK of SB-497115 andrelevant safety and efficacy endpoints will be explored		throughout study
Secondary	Dose intensity (percent of intended dose) of carboplatin/paclitaxel
Secondary	Carboplatin/paclitaxel-associated thrombocytopenia-related AEs, as defined by NCI
Secondary	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