Blood and Lymph Conditions

All Conditions

Thrombocytopenia

Blood Platelet Disorders

Hematologic Diseases

Cytopenia

SB-497115-GR 50mg. administered orally daily on days 2 through 11 for each 21-day cycle.

SB-497115-GR 75 mg administered orally dailey on days 2-11 of each 21-day cycle.

SB-497115 100mg administered orally daily on days 2 through 11 of each 21-day cycle.

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

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.

SB497115

Placebo

GSK Clinical Trials

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.

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

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

GlaxoSmithKline

Symptoms and General Pathology

Neoplasms

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Central Nervous System Depressants

Other Dietary Supplements

Azacitidine

Benzocaine

Antimetabolites

Enzyme Inhibitors

Tannic Acid

Eligible subject will receive a starting dose of eltrombopag of 200 milligrams (mg) (100 mg for subjects of East Asian heritage). Dose modifications of eltrombopag will be permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at a safe and effective level (i.e. a level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine

Eligible subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine

Eltrombopag will be round film-coated tablets containing eltrombopag equivalent to 50 mg (white to off-white), 200 mg and 300 mg (green) of eltrombopag free acid

Eltrombopag

Subcutaneous Injection (IV if local standard)

Eltrombopag matching placebo tablets will be supplied

Novartis Pharmaceuticals

Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin receptor agonist that may be beneficial in medical disorders associated with thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura \[ITP\], liver disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350 subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of \<75 Giga (10\^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind, parallel group, placebo-controlled study designed to explore the platelet supportive care effects of eltrombopag versus placebo in combination with the standard of care hypomethylating agent, azacitidine. The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints include overall survival, disease response, and disease progression.

A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)

A Randomized, Double-blind, Placebo-controlled, Phase III, Multi-centre Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With IPSS Intermediate-1, Intermediate 2 and High-risk Myelodysplastic Syndromes (MDS) SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine

A subject is defined as being platelet transfusion independent if they received no platelet transfusions within the first 4 cycles of treatment with azacitidine. Subjects who died or withdrew from investigational product within the first four cycles were treated as failures (i.e. not transfusion independent) in the analysis

Overall survival is defined as the time from randomization until death due to any cause and deaths have been presented. Subjects still alive at the time of the analysis and subjects who have withdrawn from the study will be censored at the time of last contact

Progression-free survival, defined as the time from randomization until either disease progression or death. The modified 2006 IWG criteria for MDS used for progression assessment For patients with: Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Progression-free survival, defined as the time from randomization until either disease progression or death. The modified 2006 IWG criteria for MDS used for progression assessment For patients with:

Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Progression to AML in MDS patients with baseline bone marrow blast \< 20% was defined as meeting definition of disease progression according to the modified 2006 IWG response criteria for MDS with the additional requirement that bone marrow blast or peripheral blast increases from \< 20% at baseline to ≥ 20% postbaseline. Progression assessment For patients with:

Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Best disease response is categorized as complete remission (CR), partial remission (PR), or marrow CR, stable disease, disease progression, or as non-evaluable; according to modified 2006 International Working Group (IWG) criteria for MDS

HI based on the modified IWG criteria for MDS. HI - Platelets (BL \<100Gi/L), response criteria= BL \<20: increase to\>20 and 100% at least for 56 days or BL \>=20: absolute increase of \>=30. HI - Neutrophils (BL \<1.0 Gi/L), response criteria=100% increase and an absolute increase \>0.5 Gi/L over BL for at least 56 days. HI-Hemoglobin (BL \<g/dL), response criteria=Hgb increase by \>=1.5 g/dL over BL, RBC transfusions(given for Hgb\<=9.0) reduced by \>=4 per 8w from BL

Platelet transfusion independence is defined for each cycle as the number of participants who continue to the end of a cycle without requiring a platelet transfusion

Bleeding will be assessed by recording AEs or serious adverse events (SAEs) as graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

The proportion of subjects with any delay, reduction or interruption in dosage of Azacitidine excluding those for non-medical reasons will be analyzed

The EQ-5D is a general health status and health utility measure which captures 5 dimensions of health state: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. (EQ-5D is a trademark of the Stichting EuroQol Group) . C=cycle, D=Day

The FACIT-Fatigue subscale measures severity and impact of fatigue on functioning and Health Related QoL experienced in the past 7 days. Scale is a 13 item measure of fatigure. Items are scored on a 0-4 response scale ranging from "not at all" to "very much so". All items are summed to create a single fatigure score with a range from 0 to 52. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatiigue (The FACIT Fatigue Scale is owned by David Cella, Ph.D.)

MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations

MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations, office visits including consultations, laboratory and diagnostic tests (lab results, imaging etc.), and procedures prior to therapy initiation and during therapy will be collected

Eltrombopag concentrations were analyzed using a population PK model along with data from other studies in healthy volunteers and in patients with MDS and/or AML. Post-hoc PK parameters were derived. Only patients from this study were included (163)

An analysis of variance (ANOVA) on AUC0-infinity. The PK parameters were log transformed prior to analysis. The model included treatment as a fixed effect. Point estimates and their associated 90% CI were constructed for the differences in PK parameter values. The point estimates and their associated 90% CI were then back transformed to provide point estimates and 90% CI for the azacitidine + eltrombopag:azacitidine + placebo PK parameter ratios.

An analysis of variance (ANOVA) on Cmax . The PK parameters were log transformed prior to analysis. The model included treatment as a fixed effect. Point estimates and their associated 90% CI were constructed for the differences in PK parameter values. The point estimates and their associated 90% CI were then back transformed to provide point estimates and 90% CI for the azacitidine + ltrombopag:azacitidine + placebo PK parameter ratios.

Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine

Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine

Total

Age, Continuous

Sex: Female, Male

White

East Asian/Japanese/S.E. Asian

Central/South Asian

Other

Missing

Race/Ethnicity, Customized

Int - 1 (0.5-1.0)

Int - 2 (1.5 - 2.0)

High Risk (≥ 2.5)

A bone marrow examination for the determination of IPSS was performed during the screening period, or within 3 months prior to randomization. Assessment of bone marrow blasts was to be completed by bone marrow slide review. The patient's IPSS risk category is determined by adding together all of the IPSS scores within the three disease factors (blast cells, chromosomal changes, presence of cytopenias). That number is matched to one of the following four IPSS risk categories: Low, Intermediate-1, Intermediate-2, or High. The higher the score the higher the risk.

IPSS risk score

< 10

≥ 10 - <20

≥ 20 - <50

≥ 50 - <100

≥ 100

missing

Platelet Count

Platelet transfusion dependence

The IDMC recommended terminating the study for futility (primary) and safety (secondary). Due to early termination of the trial, the final analysis of OS took place at the same time as the final analysis of the primary end point.

Study Director

Yes - platelet transfusion independent

No - platelet transfusion independent

Intent-to-Treat population, comprised of all randomized patients

Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy

Confidence Intervals estimated using the Brookmeyer-Crowley method. Hazard ratios are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower risk with eltrombopag compared with Placebo. Log-rank test stratified by IVRS stratification factors

Overall Survival (OS)

Death

Disease progression

The intent-to-treat (ITT) population included all the patients randomized in the study

Summary of Progression Free Survival From Investigator Assessment (ITT)

Summary of Progression Free Survival From Central Review (ITT)

Participants progressed-AML - investigator assess

Participants progressed to AML - Central Review

Summary of AML Progression From Investigator Assessment and Central Review (ITT)

Complete response - CR

Marrow complete response

Partial response - PR

Stable disease

Progressive disease

Not evaluable

Overall Response (CR+Marrow+PR

Best Disease Response From Investigator Assessment (ITT)

Overall Response (CR+Marrow+PR)

Best Disease Response From Central Review (ITT)

Platelets

Neutrophils

Hemoglobin

Platelets and neutrophils

Platelets and hemoglobin

Neutrophils and hemoglobin

Platelets, neutrophils and hemoglobin

Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT)

Screening (179,177)

Cycle 1 (175,173)

Cycle 2 (135,158)

Cycle 3 (105,131)

Cycle 4 (93,116)

Cycle 5 (76,108)

Cycle 6 (65,90)

Cycle 7 (47,74)

Cycle 8 (37,61)

Cycle 9 (28,46)

Cycle 10 (23,38)

Cycle 11 (19,29)

Cycle 12 (15,21)

Cycle 13 (12,16)

Cycle 14 (6,11)

Cycle 15 (3,5)

Cycle 16 (0,3)

Cycle 17 (0,3)

Number of Participants Who Were Platelet Transfusion Independent (ITT Set)

Any event - Grade 3

Any event - Grade 4

Any event - Grade 5

Bleeding Adverse Events (AEs) >= Grade 3

Overall dose delay

Overall dose reduction

Overall dose interruption

Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions

Mobility C1, D1 (176, 173) L1- no problem walking

Mobility C1,D1 (176, 173) L2- some problem walking

Mobility C1, D1 (176,173) L3- confined to bed

Mobility Wk 4 FU (71,72) L1- no problem walking

Mobility Wk 4 FU (71,72) L2- some problem walking

Mobility Wk 4 FU (71,72) L3- confined to bed

Self-Care C1, D1 (176,173) L1-no problems

Self-Care C1, D1 (176,173) L2-some problems

Self-Care C1, D1 (176,173) L3-unable to

Self-Care Wk4 FU (71,72) L1-no problems

Self-Care Wk4 FU(71,72) L2-some problems

Self-Care Wk4 FU (71,72) L2-unable to wash/dress

Usual activities C1,D1(175,173) L1-no problem

Usual activities C1,D1(175,173) L2-some problem

Usual activities C1,D1(175,173) L3-unable to

Usual activities Wk4 FU (71,72) L1-no problem

Usual activities Wk4 FU (71,72) L1-some problem

Usual activities Wk4 FU (71,72) L3-unable to

Pain/discomfort C1,D1(176,173) L1-none

Pain/discomfort C1,D1(176,173) L2-moderate

Pain/discomfort C1,D1(176,173) L3-extreme

Pain/discomfort Wk4 FU (71,72) L1-none

Pain/discomfort Wk4 FU (71,72) L2-moderate

Pain/discomfort Wk4 FU (71,72) L3-extreme

Anxiety/depression C1 D1(176,173) L1-none

Anxiety/depression C1 D1(176,173) L2-moderately

Anxiety/depression C1 D1(176,173) L3-extremely

Anxiety/depression Wk4 FU(71,72) L1-none

Anxiety/depression Wk4 FU(71,72) L2-moderately

Anxiety/depression Wk4 FU(71,72) L3-extremely

Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™)

Cycle 1 Day 1 (175,172)

Week 4 Follow-up (68,70)

Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT)

In-patient hospitalizations - entire study (91,66)

Out-patient hospitalizations - entire study (4,2)

Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient

Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests

Medical or surgical specialist visits

Home healthcare visits by medical professional

Primary physician care visits

Nurse practitioner, physic assistant, nurse visits

Telephone consultations

Emergency visits not resulting in hospital stay

Medical Resource Utilization (MRU): Use of Site Specific Medical Resources

Cmax

Cmin

All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis.

Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose

Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose

all patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis

AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine

All patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis

Cmax -Pharmacokinetic Parameter of Azacitidine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SB-497115 (Oral Thrombopoietin Receptor Agonist) Versus Placebo In Adult Cancer Patients Receiving Chemotherapy	NCT00102726	Thrombocytopaen...	SB497115 Placebo	18 Years -	GlaxoSmithKline
A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)	NCT02158936	Thrombocytopaen...	Eltrombopag Azacitidine Placebo Placebo	18 Years -	Novartis
A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia	NCT01440374	Thrombocytopaen...	eltrombopag placebo	18 Years - 110 Years	Novartis
Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag	NCT01147809	Thrombocytopaen...	Eltrombopag ola... Placebo	18 Years -	GlaxoSmithKline
A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)	NCT02158936	Thrombocytopaen...	Eltrombopag Azacitidine Placebo Placebo	18 Years -	Novartis

Spots Global Cancer Trial Database for thrombocytopaenia