Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag

Thrombocytopaenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01147809
• Other study ID #: 112765
• Status: Completed
• Phase: Phase 2
• First received: May 20, 2010
• Last updated: August 17, 2015
• Start date: June 2010
• Est. completion date: March 2015

Study information

• Verified date: August 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Helsinki Committee, Tel Aviv Sourasky Medical CenterItaly: Comitato Etico, Dell' Azienda Ospedaliera UniversitariaIsrael: Helsinki Committee, Carmel Medical CenterItaly: Comitato Etico IndipendenteHungary: National Institute of PharmacyBelgium: Federal Agency for Medicines and Health Products, FAMHPIreland: Irish Medicines BoardItaly: Dott. Antonio Contu Ospedale Civile "SS Annunziata" A.S.L. Sassari Viale ItaliaIsrael: Helsinki Committee, Assaf Harofeh Medical CenterIndia: Drugs Controller General of IndiaIsrael: Helsinki Committee, Meir Medical CenterIsrael: Helsinki Committee, Barzilai Medical CenterFinland: FIMEA (Finnish Medicines Agency)Italy: Comitato Etico Provinciale di Modena, Policlinico di Modena Azienda OspedalieraPoland: URZ.D REJESTRACJI PRODUKTÓW LECZNICZYCH, WYROBÓW MEDYCZNYCH I PRODUKTÓW BIOBÓJCZYCH,CEBKGermany: Bundesinstitut für Arzneimittel und MedizinprodukteItaly: Comitato di Bioetica Azienda Sanitaria Locale n.1 di SassariIsrael: Helsinki Committee, Shaare Zedek Medical CenterCanada: Health CanadaUnited States: Food and Drug AdministrationCzech Republic: Statni ustav pro kontrolu lecivIreland: Ministry of HealthGreece: National Drug OrganisationItaly: Comitato Per La Sperimentazione Clinica dei Medicinali Dell'azienda Ospedaliero
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: March 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Thrombocytopaenia
• Thrombocytopenia
• Thrombocytosis

Intervention

Drug:
• Eltrombopag olamine
thrombopoietin receptor agonist

Other:
• Placebo
Placebo tablets with no active pharmaceutical ingredient

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Charleroi
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Libramont
Belgium	GSK Investigational Site	Namur
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Toronto	Ontario
Czech Republic	GSK Investigational Site	Olomouc
Czech Republic	GSK Investigational Site	Praha 10
Czech Republic	GSK Investigational Site	Praha 5
Finland	GSK Investigational Site	Helsinki
Finland	GSK Investigational Site	Tampere
Germany	GSK Investigational Site	Augsburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Goslar	Niedersachsen
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenchen	Bayern
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Heraklion, Crete
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Gyor
Hungary	GSK Investigational Site	Kaposvár
Hungary	GSK Investigational Site	Törökbálint
Hungary	GSK Investigational Site	Zalaegerszeg
India	GSK Investigational Site	Madurai
India	GSK Investigational Site	Pune
India	GSK Investigational Site	Pune
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Tallaght, Dublin
Israel	GSK Investigational Site	Ashkelon
Israel	GSK Investigational Site	Haifa
Israel	GSK Investigational Site	Jerusalem
Israel	GSK Investigational Site	Kfar Saba
Israel	GSK Investigational Site	Tel Aviv
Israel	GSK Investigational Site	Zrifin
Italy	GSK Investigational Site	Aviano (PN)	Friuli-Venezia-Giulia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Modena	Emilia-Romagna
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Sassari	Sardegna
Poland	GSK Investigational Site	Bialystok
Poland	GSK Investigational Site	Konin
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Poznan
United States	GSK Investigational Site	Albany	New York
United States	GSK Investigational Site	Arlington	Texas
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bedford	Texas
United States	GSK Investigational Site	Bend	Oregon
United States	GSK Investigational Site	Bethesda	Maryland
United States	GSK Investigational Site	Cherry Hill	New Jersey
United States	GSK Investigational Site	Columbia	Missouri
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Edmunds	Washington
United States	GSK Investigational Site	Greensboro	North Carolina
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Hot Springs	Arkansas
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	New Port Richey	Florida
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Norwich	Connecticut
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Providence	Rhode Island
United States	GSK Investigational Site	Providence	Rhode Island
United States	GSK Investigational Site	Rancho Cucamonga	California
United States	GSK Investigational Site	Rockville	Maryland
United States	GSK Investigational Site	Rome	Georgia
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Sedona	Arizona
United States	GSK Investigational Site	Tacoma	Washington
United States	GSK Investigational Site	Tyler	Texas
United States	GSK Investigational Site	Vancouver	Washington
United States	GSK Investigational Site	Wichita	Kansas
United States	GSK Investigational Site	Wynnewood	Pennsylvania
United States	GSK Investigational Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czech Republic,  Finland,  Germany,  Greece,  Hungary,  India,  Ireland,  Israel,  Italy,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 (C) 1, Day (D) 1 (C1D1) until Follow-up (FU) (assessed up to 9 months)	No
Primary	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).	Baseline (C1D1) and up to 9 months	No
Primary	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).	Baseline (C1D1) and up to 9 months	No
Primary	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.	Baseline (Day 1 of Cycle 1) and up to 9 months	No
Primary	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. Not available (NA) is presented as "99999".	Screening, C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, C3D8, C3D15, C4D1,C4D8, C4D15, C5D1,C5D8, C5D15, C6D1,C6D8 and C6D15	No
Primary	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, pre-dose on Day 1 and 2 hours post-dose; pre-dose on Day 8 and 2 hours post-dose; and pre-dose on Day 15. ECG findings were categorized as normal, abnormal-not clinically significant (NCS), and abnormal-clinically significant (CS) as determined by the investigator. 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'. The Baseline value is defined as the value reported immediately prior to the administration of the first dose of chemotherapy in Cycle 1. Only those participants available at the indicated time points were analyzed (represented by n=X,X,X,X in the category titles).	Baseline (C1D1) and up to 9 months	No
Primary	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).	Cycle 1 to Cycle 6	No
Secondary	Average pre-chemotherapy platelet count at the indicated time points in Phase I	Pre-chemotherapy platelet count is defined for Cycle 1 as the platelet count (from central laboratory data) immediately preceding the first dose of chemotherapy within Cycle 1. For all subsequent cycles it is defined as the platelet count (from central laboratory data) immediately preceding, but limited to within 2 days prior to the first dose of chemotherapy at Day 1. For Group A, the chemotherapy cycle consisted of 21 days and for Group B, the chemotherapy cycle consisted of 28 days. Blood samples were collected to estimate platelet count at the following time points: Group A; Days 1 and 8 of Cycles 1 to 6. Group B; Days 1, 8 and 15 of Cycles 1 to 6. Only those participants available at indicated time points were analyzed (represented by n=X, X, X, X).	C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, C3D8, C3D15, C4D1,C4D8, C4D15, C5D1,C5D8, C5D15, C6D1,C6D8 and C6D15	No
Secondary	Average within-subject central laboratory platelet count prior to scheduled chemotherapy across Cycles 2 to 6 in Phase I	Within-subject platelet count for each participant was calculated by summing up the visit platelet counts from each of Cycles 1 to 6 and dividing it by the number of cycles in which the participant had data. The average within a treatment group was calculated by summing up the values from each participant within the treatment group and dividing it by the number of participants. These platelet counts are different from the pre-chemotherapy platelet counts for cycles where the chemotherapy dose was delayed. Average within-subject central laboratory platelet count prior to scheduled chemotherapy across Cycles 2 to 6 are summarized. Blood samples were collected on Days 1 and 8 of Cycles 2 to 6 for Group A and on Days 1, 8 and 15 from Cycles 2 to 6 for Group B to estimate the average within subject platelet count prior to scheduled chemotherapy. Only those participants available at the indicated time points were analyzed (represented by n=X,X,X,X in the category titles).	From Cycle 2 to Cycle 6	No
Secondary	Platelet count nadir for each chemotherapy cycle in Phase I	Platelet nadir is defined as the lowest platelet count (from central laboratory data) reported after the first dose of chemotherapy within each cycle. Platelet count nadir is defined for each cycle. For Group A, the chemotherapy cycle consisted of 21 days and for Group B, the chemotherapy cycle consisted of 28 days. Blood samples were collected to estimate platelet nadir count at the following time points: Group A; Days 1, 4, 8, 15 and 17 of Cycles 1 and 2, at Days 1, 4, 8, 15 and 17 of Cycle 3 to 6. Group B; Days 1, 4, 8, 15, 22 and 24 of Cycles 1 to 6. Only those participants available at indicated time points were analyzed (represented by n=X, X, X, X).	Cycle 1 to Cycle 6	No
Secondary	Central Laboratory average daily area under the curve platelet-time course across Cycles 2 to 6 in Phase I	Average daily area under the curve platelet-time course is defined as the area-under-the-curve (calculated using the trapezoidal rule) divided by total duration. It was calculated across all cycles. For Group A, the chemotherapy cycle consisted of 21 days and for Group B, the chemotherapy cycle consisted of 28 days. Blood samples were collected to estimate thrombocytes at the following time points: Group A; Days 1, 4, 8, 15 and 17 of Cycles 1 to 6. Group B; Days 1, 4, 8, 15, 22 and 24 of Cycles 1 to 6.	Cycle 2 to Cycle 6	No
Secondary	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	As per the CTCAE version 4.0, par. with a platelet count	Cycle 1 to Cycle 6	No
Secondary	Maximum duration of thrombocytopenia across Cycles 2 to 6 in Phase I, estimated using central laboratory platelet counts	Duration of thrombocytopenia is defined as a period of time in days from the first report of a platelet count with NCI CTCAE Grade 1-4 until the first subsequent report of a platelet count no longer meeting those criteria, regardless of rescue medication usage. It was assessed between Day 1 of Cycle 2 and up to and including any Conclusion/Early Withdrawal visit assigned to the same cycle for participants completing up to 6 cycles, and between Day 1 of Cycle 2 and up to and including the end of Cycle 6 for participants continuing beyond 6 cycles. The chemotherapy cycle for Group A was 21 days and for Group B was 28 days. Blood samples were collected to estimate thrombocytes at the following time points: Group A; Days 1, 4, 8, 15 and 17 of Cycles 2 to 6. Group B; Days 1, 4, 8, 15, 22 and 24 of Cycles 2 to 6.	Cycle 2 to Cycle 6	No
Secondary	Central Laboratory platelet count for time taken to reach platelet nadir for each chemotherapy cycle in Phase I	Platelet nadir is defined within each cycle as the lowest platelet count reported after the Day 1 chemotherapy dose. The time taken to reach platelet nadir is defined within each cycle. For Group A, the chemotherapy cycle consisted of 21 days and for Group B, the chemotherapy cycle consisted of 28 days. Blood samples were collected to estimate platelet nadir count at the following time points: Group A; Days 1, 4, 8, 15 and 17 of Cycles 1 to 6. Group B; Days 1, 4, 8, 15, 22 and 24 of Cycles 1 to 6. Only those participants available at indicated time points were analyzed (represented by n=X, X, X, X).	Cycle 1 to Cycle 6	No
Secondary	Time to recovery from platelet nadir for each chemotherapy cycle in Phase I, estimated using central laboratory platelet counts	Platelet nadir is defined within each cycle as the lowest platelet count reported after the Day 1 chemotherapy dose. Time to recovery (TR) (>100Gi/L or >150Gi/L) from platelet nadir is defined within each cycle as the time in days from the platelet nadir to the time at which platelet count returns to >=100Gi/L or >=150Gi/L within the same cycle or up to and including Day 1 of the next cycle. For the last cycle in the study, time to recovery was calculated in the same manner but up to and including any Conclusion/Early Withdrawal visit which has been assigned to the same cycle. For Group A, the chemotherapy cycle consisted of 21 days and for Group B, the chemotherapy cycle consisted of 28 days. Blood samples were collected to estimate platelet count at: Group A; Days 1, 4, 8, 15 and 17 of Cycles 1 to 6. Group B; Days 1, 4, 8, 15, 22, and 24 of Cycles 1 to 6. Only those participants available at indicated time points were analyzed (represented by n=X, X, X, X).	Cycle 1 to Cycle 6	No
Secondary	Dose intensity of gemcitabine plus cisplatin (G+Cis)/gemcitabine plus carboplatin (G+Cb) and gemcitabine across chemotherapy Cycles 1 to 6 in Phase I	Dose intensity of chemotherapy is defined as the actual dose of chemotherapy given as a percentage of the scheduled C1D1/C1D8 dose, as applicable, within this study: Cycle Dose Intensity (%) = Total Actual dose (mg/m^2) within Cycle *100/ Total Scheduled dose (mg/m^2) in Cycle 1; wherein Actual Dose (mg/m^2) = Actual dose (mg)/Body Surface Area reported on electronic case report form (eCRF).	Cycle 1 to Cycle 6	No